The Function of Allergy: Immunological Defense Against Toxins

VOLUME 66, No. 1 THE QUARTERLY REVIEW OF BIOLOGY MARCH 1991

THE FUNCTION OF ALLERGY: IMMUNOLOGICAL DEFENSE AGAINST TOXINS

MARGIE PROFET Division ofBiochemistry & MolecularBiology, BarkerHall, Universityof California, Berkeley,California 94720 USA

ABSTRACT Thispaper proposes that the mammalian immune response known as 'allergy"evolved as a last lineof defense against the extensive array of toxic substances that exist in theenvironment in the formof secondary plant compounds and venoms. Whereas nonimmunological defenses typically can targetonly classes of toxins, the immune system is uniquelycapable of the fine-tuning required to targetselectively the specific molecular configurations ofindividual toxins. Toxic substances are commonlyallergenic. The pharmacological chemicals released by the body's mast cells during an IgE antibody-mediatedallergicresponse typically cause vomiting diarrhea, coughing tearing sneezing orscratching which help to expelfrom the body the toxic substance that triggered the response; individualsfrequently develop aversions tosubstances that have triggered such responses. A strong allergicresponse often includes a decrease in bloodpressure, which slows the rate at whichtoxins circulatetotarget organs. The immune system identifies as toxic the following kinds of substances: (1) thoselow-molecular-weight substances that bind covalently toserum proteins (e.g., many plant toxins);(2) nontoxicproteins that act as carriersoftoxins with low molecular weights (e.g., plant proteinsassociated with plant toxins); (3) specificsubstances ofhigh molecular weight that harmed individualsin ancestralmammalian populations for a spanof time that was significant from the standpointofnatural selection (e.g., the toxic proteins of bee venom). Substancesthat bind covalently toserum proteins generally are acutely toxic, and because many ofthese substances also bind covalently tothe DNA oftarget cells, they are potentially mutagenic andcarcinogenic as well. Thus, by protecting against acute toxicity, allergy may also defend against mutagensand carcinogens. The toxin hypothesis explains the main phenomena ofallergy: why IgE- mediatedallergies usually occur within minutes of exposure toan allergenand why they are often sosevere; why the manifestations ofallergy include vomiting diarrhea, coughing sneezing scratching tearingand a dropin blood pressure; why covalent binding of low-molecular-weight substances toserum proteinsfrequently causesallergy; why allergies occur to manyfoods, pollens, venorns, metals,and drugs; why allergic cross-reactivity occurstofoods andpollenfrom unrelated botanicalfumi- lies;why allergy appears to be so capricious and variable; and why allergy ismore prevalent inindus- trialsocieties than it is inforagingsocieties. This hypothesis also has implicationsfor thediagnosis, prevention,and treatment ofallergy.

INTRODUCTION nonallergicimmune response, the activation and proliferationof immune defenses against ALLERGY IS COMMONLY perceived a foreignantigen usually ensure swift contain- ?1to be an immunologicalanomaly. In the mentof that antigen upon subsequentexpo-

TheQuarterly Review of Biology, March 1991,Vol. 66, No. 1. ? 1991by the Universityof Chicago Press. All rightsreserved. 0033-5770/91/6601-0002$01.00

23 This content downloaded from 141.218.001.105 on August 06, 2016 07:56:10 AM All use subject to University of Chicago Press Terms and Conditions (http://www.journals.uchicago.edu/t-and-c). 24 THE QUARTERLY REVIEW OF BIOLOGY VOLUME 66 sures, with decreasingly severe pathological evolvedto protect mammals against helminths consequences. In the allergicresponse, by con- (e.g., Godfrey,1975; Dessaint and Capron, trast, the activation and proliferationof im- 1989).Other researchers, however, have noted mune defenses against an antigen can cause thatthe IgE antibodiesproduced during hel- increasinglysevere pathological consequences minthinfections appear to be ineffectivein upon subsequent exposures to that antigen. combattingsuch infections and, in fact,may Most antigensthat cause significantnonaller- causemore harm than good to the host through gic immune responses are pathogens, such as injurioustissue inflammation(Ogilvie and bacteria and viruses, whereas most allergenic Jones,1973; Mitchell, 1979;Jassim et al., 1987). antigens (allergens) are seeminglyinnocuous Furthermore,the overwhelming majority of al- substances, such as foods and pollens, which lergensare not helminths, helminth products, are oftentolerated by the immune systemsof or substancescontaining helminths; rather, many individuals. theyare pollens,foods, drugs, venoms, and metals.The hypothesisthat allergy functions AllergiesAre Usually Viewedas to combathelminths cannot account for the ImmunologicalMistakes IgE-mediatedresponses (IgE responses)to the Althoughmany ofthe physiologicalmecha- thousandsof naturallyoccurring substances nisms of the allergic response have been re- thathave turned out to be allergenic,and itim- vealed since the discovery by Ishizaka and pliesthat the vast majority of allergic responses Ishizaka (1967) ofthe allergy-inducing IgE class areimmunological mistakes (i.e., it implies that of antibody,a functionalexplanation of allergy allergicresponses are to substancesthat IgE has remained elusive. Currentlythere are two antibodieswere not designed by selection to tar- main views of allergy.One view is that allergy get). Dessaint and Capron (1989:118),for is an aberrant or malfunctioningform of im- example,suggest that "a numberof clinically munological response: "Allergyappears to be significantallergic responses to environmen- a geneticallydetermined disorder character- tal antigensmay reflect the inappropriate ac- ized by a tendencyto formIgE antibodies in tivationof immunologiccircuits or effector response to challenge with protein antigens. pathwaysordinarily initiated by helminths." The basic defectmay be a dysregulationof im- Werethe function of allergy to protectagainst mune responsiveness,affecting also the anti- helminths,however, the mechanisms of allergy body pattern normally induced" (Hammar- wouldbe so ill-designedfor their intended pur- stromand Smith, 1987:529); such statements posethat they almost always malfunction. (The are not uncommon in the allergyliterature. It helminthhypothesis is discussedin detailbe- is this view that is generallypresented to the low.)Platts-Mills (1987) refinesthe helminth allergicpublic, in statementssuch as 'Research- hypothesis,suggesting that immunological ers have found that, ironically,allergy results hypersensitivity(as allergy is oftendescribed) frommalfunctioning of the immune system" maybe theunfortunate but necessary cost of and "It is not yetknown where in this system maintainingsufficient immune surveillance the 'mistake'that leads to allergyoccurs" (Na- againsthelminths. It is notclear, however, why tionalJewishCenter forImmunology and Re- IgE-mediatedresponses should be the only spiratoryMedicine, 1986:1,2).This view,how- kindof immune response to pathogens that fre- ever, cannot account for the evolution of a quentlyentails severe hypersensitivity toseem- specific class of mammalian antibody (IgE) inglyinnocuous substances. In summary,each whose sole known purpose is to triggerthe ofthe aforementioned explanations for allergy symptomsof allergy. regardsmost incidences of allergy as immuno- The othermain view ofallergy is thatit func- logical errorsin whichthe immunesystem tions to defend against helminths (parasitic respondsto primarily innocuous substances as worms)-a view thatplaces allergyin thetradi- ifthey were dangerous. tional immunologicalrole ofdefending against pathogens and their harmfulproducts. High TheMechanisms ofAllergy Manifest levels of IgE antibodies often accompany Evidenceof Adaptive Design chronichelminth infections, leading some re- The evolutionarypersistence of the allergic searchersto conclude thatthe allergicresponse capability,despite its physiologicalcosts, im-

pliesthe existence of an adaptivebenefit for this faces of the immune system'sB lymphocytes capabilitythat outweighs the costs; thisunder- (B cells) and T lymphocytes(T cells) exhibit mines the view thatallergy is an immunologi- specificmolecular configurationsthat enable cal error. The specialized mechanisms that themto bind to antigensthat complement those collectively constitute the allergic response configurations.The set ofall B cells and T cells appear to manifestadaptive design in the pre- displays a vast array of molecular configura- cision, economy, efficiency,and complexity tions, enabling the immune systemto defend withwhich theyachieve the goal ofproducing againsta vastarray of antigens. In orderto elicit allergy[see Williams's(1966) criteriafor detect- a primaryimmune response, an antigengener- ing adaptive design]. IgE antibody molecules allymust have a minimummolecular weight of are functionally distinguished from other about 2,000; antigensof lower molecular weight classes of antibodies by theirallergy-inducing usually can triggeran immune response only properties, and they are structurallydistin- ifthey are bound as haptens to a high-molecu- guishedfrom other classes by a particularchain lar-weightcarrier, such as a serum protein. B (type epsilon) in one of their molecular sub- cells in the bloodstreamand lymphaticsystem units. The IgE class ofantibodies is thoughtto bind to antigensthat complement their molec- have evolved in vertebrateswithin the last 300 ular binding sites (surface immunoglobulin million years,before the evolutionof modern molecules) and, when activatedby T cells, se- mammals (Hadge and Ambrosius, 1984). Al- crete numerous antibodies (immunoglobulin thoughmost mammalian specieshave notbeen molecules) that neutralize the antigens and testedfor IgE antibodies or allergiccapability, mark themfor elimination. Mammalian anti- IgE-mediated allergicresponses are knownto bodies are produced as fiveclasses -IgM, IgA, occur in many placental species, including IgD, IgG, IgE -which differin theirconcen- monkeys,dogs, rats, mice, cows, rabbits, and trationsin the bloodstream,their distribution guinea pigs (Neoh et al., 1973; Klein, 1982: sites throughoutthe body, theirtendencies to 549; Stokes et al., 1987; Kepron et al., 1987). bind to certaintypes of antigen,and thephysi- Allergy-likesymptoms occur in nonplacental ological responses they elicit. mammals and in many nonmammals as well. The onlyknown immune response mediated The marsupial quokka (Setonixbrachyurus), for by IgE antibodies is immediate-typeallergy, example,has an IgE-like antibodythat induces in which symptoms are usually manifested immediate hypersensitivity(Manning and withina fewminutes to an hour afterexposure Turner, 1976:157); this antibody may be ho- to theallergen. (The IgE responseto helminths mologous to the IgE. Various species of rep- can be regarded as a type of allergy,and will tilesand birdssuffer immediate symptoms that be discussed below.) The serum levels of IgE resemble mammalian allergies when re- antibodies are normally orders of magnitude exposed to a particularantigen in immuniza- lowerthan thelevels of IgM, IgG, and IgA an- tion experiments(Gershwin, 1978). Fletcher tibodies, but they oftenincrease manyfoldat and Baldo (1974) have shownthat flatfish have the onset of allergy. There is substantial in- immediate hypersensitivityresponses to fun- dividual variation in IgE and other antibody gal extracts(but theseresponses apparently oc- levels(Geller-Bernstein et al., 1988). In general, curredupon initialrather than subsequent ex- IgE levels are higher in allergic than in posure to the extract, and so may neither nonallergicindividuals (Berciano et al., 1987; functionallyresemble mammalian allergiesnor Abdullah et al., 1987; Bennettet al., 1987; Husz representhomologous genes). These findings et al., 1988; Burrows et al., 1989), but the indicate that the evolutionary age of IgE- respectiveranges overlap. What may be impor- mediated allergyis likelyto match or surpass tant in the relationshipof IgE levels to allergy thatof placental mammals, which Prager and is not the absolute serum level of IgE, but Wilson (1988) report to be 60 to 80 million rather,for any givenindividual, the ratio of the years. IgE antibodylevels before and afterthe devel- The immunological mechanisms of allergy opment of allergy and the ratio of IgE levels constitutea networkof specialized cells and to those of other classes of antibodies. molecules that recognize a specificantigen as Certain typesof allergy have delayed symp- foreignand initiateits containment.The sur- toms (typicallybeginning about 24 hours af-

This content downloaded from 141.218.001.105 on August 06, 2016 07:56:10 AM All use subject to University of Chicago Press Terms and Conditions (http://www.journals.uchicago.edu/t-and-c). 26 THE QUARTERLY REVIEW OF BIOLOGY VOLUME 66 terexposure to theallergen) which are medi- duringsome allergicresponses, may serve to ated primarilyby T cellsrather than by IgE expelthe allergen from the eyes, as pointedout antibodies.Although most of the following dis- to me byPaul Ewald.)The chemicalsreleased cussionrefers to classical,IgE-mediated al- bymast cells also cause dilationof the periph- lergy,T-cell-mediated allergyin particular, eralblood vessels,leading to peripheralpool- contactallergy, which can occurafter contact ingof the blood that results in a dropin blood withsubstances such as poison ivy- is dis- pressureand, in severecases, anaphylactic cussedbelow in relationto the typeof aller- shock(Hood et al., 1984:461). gens thattypically elicit it. AlthoughT-cell- If allergyis an adaptation,then the above- mediatedresponses in generalare regarded as mentionedeffects must serve some function. adaptive,T-cell-mediated allergies are usually As Platts-Mills(1984) emphasizes,a biologi- regardedas maladaptive.A similarfunctional cal rolefor IgE antibodiesmust be associated hypothesisfor IgE-mediated allergy and T-cell- withthe release of chemicals from mast cells, mediatedcontact allergy is presentedhere. because the quantityof IgE antibodiespro- Allergyoccurs upon reexposure to an antigen ducedin an allergicresponse is insufficientto thathas previouslytriggered the formation of neutralizeor agglutinatethe antigen. The al- IgE antibodies.IgE antibodiesare produced lergic responsethus differsmarkedly from whenhelper T cellsinduce antigen-bound B otherimmune responses in thatIgE antibod- cellsto proliferateand differentiateinto IgE- ies performtheir main functionalrole by co- secretingplasma cells. Many ofthese IgE an- optingnonimmunological mechanisms (e.g., tibodiesthen bind to specialized IgE receptors vomiting,diarrhea). The allergicresponse on thesurfaces of mast cells, which contain var- appearsto be welldesigned to hinder the aller- ious potentallergy-inducing chemicals, such gen fromentering the bloodstreamand cir- as histamine(Wasserman, 1980; Morley et al., culatingto thevarious organs. Vomiting, di- 1984),and whichare present in the connective arrhea,sneezing, coughing, shedding tears, tissuesand on manyepithelial surfaces, includ- and scratchingmediate the expulsion of the al- ingthose of the respiratory tract, gastrointes- lergenfrom the stomach, intestines, nasal pas- tinaltract, urinary tract, nasal passages,and sages,lungs, eyes, and skin,respectively. The skin(Meggs and Metcalfe,1984; Schickand drop in blood pressureis likelyto retardthe Austen,1987). [IgE antibodiesalso bind to rateat whichthe allergencirculates through receptorson basophils,which in essence are cir- thebloodstream. The inflammationof tissues culatingmast cells, and on eosinophils;these helpsto walloff the allergen in localizedareas cellsare presentin thebloodstream and con- and therebyprevent its rapid dissemination nectivetissue (Gleich and Adolphson,1986).] throughoutthe body. IgE antibodiesthat are synthesizedlocally in Thesedesign features of allergy indicate that responseto allergens can circulate in the blood- theallergic response evolved to defend against streamand becomedistributed on mastcells some sortof immediate danger. Allergy does throughoutthe body (Platts-Mills, 1984). The notgenerally occur to viruses, bacteria, or pro- allergicresponse begins when an allergenbinds tozoa(Platts-Mills, 1984), nor would many of to IgE antibodiesthat are bound to mastcells, thesymptoms of allergy- particularly the drop immediatelyactivating the mast cells to in blood pressure- be veryeffective against degranulateand releasetheir chemicals. The thesepathogens. (Vomiting and diarrhea, how- degranulationof mast cells in theupper gas- ever,are rapidlyacting defenses against the trointestinalregion causes immediatevomit- toxinsof ingested bacteria.) A subsequenten- ing;in the lower intestinal region, diarrhea; in counterwith a pathogenusually does not pose therespiratory tract, constriction of the bron- an immediatedanger, because pathogensare chialtubes and coughing;in the nasal passages, quicklykilled (and thusnot allowedto repli- sneezing;and in theskin, itching that leads to cate)by the immunological defenses that have scratching(Meggs and Metcalfe,1984; Hood beengenerated against them during the previ- et al., 1984:461;Sheffer, 1988). Thus, as soon ous exposure.The symptomsof allergy would, as theimmune system detects an allergenit in- on theother hand, be highlyeffective against itiatesa sequenceof physiological events to rap- toxins.Toxins can be presentin significant idlyexpel the allergen. (Tearing, which occurs amountswith each exposure- forexample,

witheach wasp sting or each bite of mushroom. ing cells. Because toxinsare so prevalentin the Penetrationof the body by toxinsthat have environment,mammals have developeda mul- provedto be harmfulin the individual'spast titude of ways to combat them (discussed be- necessitatesurgent, critical action because low). Most of these defenses, however, are manytoxins can harm an organismwithin generaldefenses that are effectiveagainst toxins minutesof entering the bloodstream. By bind- ofdiverse molecular configurations, rather than ing to targetcells, some toxins can cause specialized defensesthat targetspecific toxins irreparableharm to theneurological, cardio- (Ames et al., 1990b). For example, the con- vascular,endocrine, reproductive, metabolic, tinual sheddingof the epithelialsurfaces of or- renalor other physiological systems (Freeland gans thatare regularlyexposed to toxins,such andJanzen,1974). Furthermore, unlike patho- as the gut, lungs, and skin, helps to protect gens,specific plant and venomtoxins are gener- against all typesof toxin. Other defenses,such allyavoidable, in that the plants and venomous as DNA repairenzymes and antioxidants,pro- animalsthemselves are generally avoidable; the tectagainst damage caused by many different severityand rapidityof an allergicattack may types of toxin. Even the most specialized facilitatethe identification ofthe offending al- nonimmunological defenses against toxins- lergenso thatit can be avoidedin thefuture. detoxificationenzymes produced by the liver Protectionagainst toxins thus seems to be a and other organs - generallytarget classes of likelycandidate for the functionof allergy. toxicityrather than only the specificmolecu- Toxinshave played a significantbut under- lar configuration of a particular toxin (see recognizedrole in allergy research. They were Jacoby, 1980). crucialto the 1902 discoveryof allergicana- It is highlyadaptive fora partof the immune phylaxis-when toxinsfrom the tentacles of a systemto be specialized fortargeting specific poisonousjellyfish, injected into dogs already toxinsbecause, ofall thetypes of defense mech- sensitizedto thetoxins, caused vomiting,di- anisms against microscopic entities,only the arrheaand fatalshock (Portier and Richet, immune systemis capable offine-tuning itself 1902).Nevertheless, the possibility that allergy so as to selectivelytarget the specificmolecu- evolvedto defend against toxins has beenover- lar configurationsof the foreignantigens it en- looked,and thetoxicity of most allergens has counters. (By analogy, even though animals not been appreciated.For example,Platts- have various general defense mechanisms Mills (1984:1-2) states that "the substance againstpathogens, it is highlyadaptive for them thatelicits the [allergic] reaction does notap- also to have immune systemscapable of tar- pear to be harmfulin the absenceof theim- getingspecific pathogens.) The part ofthe im- muneor allergicresponses [to it]. For exam- mune system that is specialized to defend ple,pollen grains, hay dust and nickelare not against toxins would be expected to differin toxicmaterials in themselves." These materials, some of its design featuresfrom the parts that however,are toxic: pollen grains contain an ar- are specialized to defendagainst pathogens be- rayof toxins - e.g.,phenolic acids, sesquiter- cause eliminating toxins and eliminating penelactones, and alkaloids(Stanley and Lin- pathogens require differenttactics. IgE anti- skens,1974; Ohmoto et al., 1978;Mabry and bodies defendagainst plant and venom toxins Gill, 1979;Herminghaus et al., 1988;Meurer indirectly- by initiatinga sequence of chemi- et al., 1988); hay dust is ofteninfested by cal events to expel the toxins or to slow their toxicfungal spores (Davies et al., 1984); and circulationthroughout the body; by contrast, nickelis one of the mostcarcinogenic of the the immune systemfor the most part defends manytoxic metals in the natural environment against pathogens directly- by killingeither (Kasprzak, 1987). the pathogensthemselves or the cells thatthey This paper arguesthat allergy is designed have infected.The immunesystem provides the to be a lastline of defense against toxins; that major mode ofdefense against pathogens,but is, theallergic response is triggeredwhen the only the "back-up" mode of defense (allergy) individual'sprimary antitoxin defense mech- against toxins. anismshave proven on a previousoccasion to Evidence forthe hypothesis that the allergic be insufficientin preventinga specifictoxin capability evolved as a defense against toxins frompersisting in the bloodstream and damag- (hereafter,the "toxin hypothesis") includes the

This content downloaded from 141.218.001.105 on August 06, 2016 07:56:10 AM All use subject to University of Chicago Press Terms and Conditions (http://www.journals.uchicago.edu/t-and-c). 28 THE QUARTERLY REVIEW OF BIOLOGY VOLUME 66 following:(1) Toxins are ubiquitous. In addi- significantlyelevate their levels of toxin (Beier, tion to causing acute damage, manytoxins are 1990; Harvell, 1990). Toxins exist even in the mutagenic or carcinogenic and cause irrepar- mostseemingly innocuous partsof plants, such able, cumulativedamage. (2) Chemical corre- as theedible parts of bananas, potatoes,oranges, lates of toxicity,such as the covalent binding cherries,cabbage, spinach, celery,cocoa, and ofexogenous substancesto serumproteins, fre- nutmeg (Ames et al., 1990a). [For reviews of quentlytrigger allergy. Covalent binding is cor- natural plant toxins see Rosenthal and Jan- related with allergenicity, acute toxicity, zen (1979), Keeler and Tu (1983), Concon mutagenicity and carcinogenicity.(3) Most (1988a), and Beier (1990).] knownallergens appear to be eitherthemselves Many non-plant organisms also use toxic toxic substances or carrierproteins that bind defenses. Diverse species of insects, reptiles, well to low-molecular-weighttoxins. (4) The and marine animals produce venom to deter symptomsof allergyhave the attributesof an predators or to capture prey. Various patho- evolvedmechanism: the chemicals released by gens are also toxic: many gram-positivebacte- mast cells cause vomiting,diarrhea, coughing, ria secretepotent exotoxins, and gram-negative sneezing,scratching, and tearing-which may bacteria shed endotoxins when they die (Al- rapidlyexpel toxins-and a decrease in blood cock, 1983). Toxic substances are also present pressure-which may slow the rate of circula- in the inorganic environment.Certain metals tionof toxins to targetorgans. (Althougha life- in the natural environment,such as nickeland threateningallergy-induced drop in blood pres- lead, are highlytoxic in doses exceeding trace sure,like a life-threateningfear-induced increase amounts (Kasprzak, 1987). Herbivorous in adrenalin, would rarely be advantageous, animals absorb metals primarily by eating a mild to moderate decrease in blood pressure plants thathave taken up metals fromthe soil would be advantageous if it retarded the flow (see Veien and Andersen, 1986). Some nuts, of blood that contained dangerous levels of forexample, contain metals at concentrations toxin,just as a moderate increase in adrena- that would be toxic to humans ifhumans re- lin is advantageous to an animal threatened lied on themas a main food source (Furr et al., by a predator.) 1979).

TOXINS ARE UBIQUITOUS IN Many ToxinsAre Also Mutagenicor Carcinogenic THE NATURAL ENVIRONMENT Although the functionof plant toxins is to A toxin,broadly defined, is a nonnutritional cause acute toxicity,a secondaryeffect of many substance that exerts a biodynamic effecton ofthese chemicals is to cause mutationor can- the body (Schultes and Hofmann, 1987:10). cer. For example, exogenous substances that All plantsproduce toxins- commonlyreferred exertacute toxic effectsby binding covalently to as "secondaryplant compounds" -to deter and nonselectivelyto cellular macromolecules predation by animals and infectionby patho- often can also bind covalentlyto DNA and gens. Since the productionof secondary com- cause mutations. Exogenous substances that pounds entailslarge energeticcosts to a plant, cause cancer appear to do so eitherby mutat- natural selection would rapidly eliminate the ing DNA directlyor by being sufficientlytoxic productionof any such compound thatwas not to cause substantialcell death and subsequent toxicto some ofthe plant'sherbivorous preda- cell proliferation(Ames, 1989). Natural muta- tors or pathogens. Plant toxinsharm animals gens and carcinogens are widespread among in a varietyof ways, such as by blockingrecep-- plants (Ames et al., 1990a). For example, the torsites for neurotransmitters, interfering with naturally occurring carcinogen allyl isothio- specific cellular functions,or inhibiting en- cyanate is in cabbage, cauliflower(Buttery et zymesthat degrade othertypes of toxin. Differ- al., 1976), brussels sprouts (MacLeod and ent toxinsare designed to harm differentphys- Pikk, 1978), and radish (Cole, 1975); the car- iologicalsystems. Most plant speciessynthesize cinogen and mutagen 8-methoxypsoralenis in at least a few dozen toxins in order to defend celery (Beier et al., 1983) and parsnip (Ivie et against a wide array of herbivoresthat differ al., 1981); and the carcinogen safroleis in cin- in theirsusceptibilities to differenttoxins. Un- namon (Lemberkovics and Petri, 1988), black der the stressof herbivore attack, many plants pepper (Richard andJennings, 1971),nutmeg

(Archer,1988), and cocoa (van derWal et al., of the nasal passages,lungs, gastrointestinal 1971).In summary,many toxins also aremuta- tract,and genitourinarytract. (6) Mechanisms gens and carcinogens;hence, by defending fordetoxifying toxins - forexample, the ex- againstenvironmental toxins, particularly those tensivearray of enzymes in the liver, the major thatbind covalently,allergy simultaneously organof detoxification, and inthe gastrointes- conferssome protection against mutation and tinaltract, skin, lungs, and variousother or- cancer. gans(Freeland andJanzen, 1974; Gram, 1980; Bickersand Kap5as, 1980). (7) Mechanisms MammalsHave Numerous Defenses forpreventing mutation and cancer,such as againstToxins themachinery for DNA repair.In humans,for Because toxinsare so dangerousand ubiq- example,specialized enzymes must repair the uitous,and are so oftencoupled to nutritious damage fromapproximately 10,000 endoge- sourcesof food,many animals have evolved nous oxidativehits per cell per day (Ames, elaborate physiologicaland psychological 1989).The reasonthat most cancers occur in mechanismsto detect, avoid, destroy, and elim- old age maybe, at least in part,the resultof inatetoxins. Allergy seems to be designedto thesenescence of these protective mechanisms be a last line of defenseagainst toxins when (see Fraga et al., 1990).The existenceand ef- theseother mechanisms prove insufficient, ei- fectivenessof such mechanisms testifies to the therbecause of a defectin one ofthe mecha- potencyof mutationand canceras selective nismsor becauseof the ability of a particular forcesthroughout mammalian evolutionary toxinto evade thesedefensive mechanisms. history.(8) Mechanismsfor preventing mu- Plant toxinsare not equallyeffective against tatedcells from proliferating, such as thecon- allpotential herbivores, and herbivore defenses tinualshedding of the surface layers of the gas- are not equallyeffective against all potential trointestinaltract, lungs, skin, genitourinary toxins(which is themajor reason why humans tract,and eyes(Wright and Alison, 1984). findonly a small subsetof plantspecies edi- The lipid-solubilityof manytoxins that are ble). Mammaliandefenses against toxins are ingested,inhaled, or touchedenables them to diverseand multi-level;they include the fol- permeateblood vesselsand lymphaticvessels lowingadaptations: (1) Mechanismsfor detect- readilyand thusenter the circulatory system. ingand avoiding dangerous levels of toxin, such To preventthe body from being harmed by cir- as theolfactory and gustatoryperception of bit- culatingtoxins, the detoxification enzymes in terand pungentcompounds, which are com- theliver must degrade them rapidly to non- monlycorrelated with toxicity (Garcia and toxicexcretable compounds that can be elimi- Hankins,1975; Chapman and Blaney,1979). natedby the kidneys. For example, an average (2) Mechanismsfor remembering which foods medicinaldose of the drug pentobarbitalis havecaused deleterious effects and fordevelop- degradedby human detoxificationenzymes ingaversions to suchfoods (Rozin and Kalat, withina fewhours, whereas without these en- 1971;Freeland andJanzen, 1974). (3) Mecha- zymesthe drug would not be completelyinac- nismsfor avoiding overloading the body with tivatedfor over 100 years (Freeland and Jan- any one toxin,such as seekinga diversityof zen, 1974).Detoxification generally comprises plantfoods; even specialized herbivores seek twophases: in thefirst phase, enzymes cata- dietarydiversity- koalas, for example, eat six- lyzethe conjugation of the molecule to a reac- teen differentspecies of eucalyptusand, in tive group, creatingan intermediatecom- captivity,will refuse to eat ifoffered only one pound;in thesecond phase, enzymes catalyze species(Freeland andJanzen, 1974). (4) Mech- theconjugation of this intermediate compound anismsfor circumventing the most toxic parts to an endogenoussubstrate (Monks and Lau, offoods, such as thepeeling of fruits [humans, 1988).The resultantmolecule is water-soluble in addition,cook manyof their foods, which and is thereforeeasily excreted by the kidneys, deactivatessome of the toxins (Kingsbury, 1983; unlikemost toxic parent compounds, which are Stahl,1984)]. (5) Mechanismsfor trapping or lipophilicand thereforedifficult to excrete be- neutralizingtoxins before they are absorbed cause of the permeabilityof blood vesselsto intothe circulatory system, such as thesecre- lipophilicsubstances and theconsequent reab- tionof IgA antibodiesat theepithelial surfaces sorptioninto the bloodstreamof such sub-

This content downloaded from 141.218.001.105 on August 06, 2016 07:56:10 AM All use subject to University of Chicago Press Terms and Conditions (http://www.journals.uchicago.edu/t-and-c). 30 THE QUARTERLY REVIEW OF BIOLOGY VOLUME 66 stancesfrom the kidneys (Welling, 1986). With- can sometimesreach carcinogenic levels when out detoxificationenzymes, herbivoreswould theyare created faster than they can be deacti- succumb to the toxic effectsof almost all ofthe vatedby means of conjugation to second-phase secondary plant compounds they ingest substrates;studies in bothmice and humans, (Kingsbury, 1983). The coevolutionarystrug- forexample, have found that high levels of the gle betweenplants and theirherbivorous pred- enzymearyl-hydrocarbon-hydroxylase arecor- ators, between toxins and detoxificationsys- relatedwith increased risk for certain types of tems, has resulted in wide interspecies and cancer(Amsbaugh et al., 1986).Furthermore, intraspeciesvariation in the compositionof en- compoundsthat induce the synthesisof cer- zymes, so that a toxin that is lethal for one taindetoxification enzymes, particularly of the mammal may be detoxifiedreadily by another cytochromeP-450 familyof enzymes,can (Freeland andJanzen, 1974; Rhoades, 1979). potentiatecarcinogenesis by increasing the rate The relationshipof variability in enzyme com- ofproduction of the reactive intermediates that position to variabilityin allergysusceptibility are formedduring the detoxification of other is discussed below in the section on the seem- compounds(Parke, 1975). ing capriciousness of allergy. Anythingthat undermines a general defense Although a mammal may maintain only againsttoxins - resulting,for example, in in- small storesof most typesof detoxification en- creasedmucosal permeability, deficient num- zymes, because of the energeticcosts of syn- bersof IgA antibodiesguarding the epithelial thesizingand maintainingenzymes, the pres- surfaces,or insufficentproduction of detox- ence ofa toxinfrequently induces the liverand ificationenzymes - can increasethe rate of certainother organs to increasethe production penetrationof toxins into the bloodstream or ofenzymes capable of degrading that particu- theduration of toxin circulation. Toxins that lar toxin(Breckenridge, 1975). Enzyme induc- reachthe bloodstream can interactwith serum tion is thereforean importantmammalian de- proteinsto form immunogenic structures that fenseagainst the continuallyevolving array of triggerthe production of IgE antibodiesand toxic compounds in the environment. The theinduction of allergy. IgE antibodiescan tar- repeated administrationof a particular toxin get the specificmolecular configurations of can induce the synthesisof enough enzymes toxinsthat have evaded the generaldefense to cause a measurable increase in liverweight mechanismsagainst toxins. (Breckenridge,1975; Parke, 1975). Detoxifica- tion enzymes generallytarget classes of toxic- CUES OF TOXICITY SHOULD ELICIT ALLERGY ity, so that each type of enzyme is effective Becausethe array of toxic compounds in the against a range oftoxins with similar chemical environmentis immense and ever evolving, the properties.Enzymes induced by one toxincan immunesystem usually cannot "anticipate" the thereforeincrease the detoxificationrates of specifictoxic compounds that it willencoun- certain other toxins. ter.Furthermore, the diversity of antibodies, The processof enzymatic metabolism, how- althoughimmense, is nonethelesslimited by ever,converts some exogenous compounds to a setnumber of genetic components available their toxic states. Many plants, for example, forconstructing antibodies. The immunesys- exploit the detoxificationmechanisms of her- temtherefore seems to have evolvedways to bivores in order to avoid intoxicatingthem- recognizecues of toxicity (i.e., molecular con- selveswith theirown defensivechemicals: the figurationsthat have been correlated with tox- plants manufacturecompounds that are bio- icityfor a spanof time that is significantfrom logically inertwhen firstingested by a herbi- thestandpoint of natural selection), enabling vore but that become activated to their toxic it to discriminatebetween typically harmful formsduring the firstphase of the herbivore's andharmless exogenous compounds. Once the enzymaticdetoxification process (Fowden and immunesystem has identifiedan antigenas a Lea, 1979). These toxic intermediate com- toxin,antibodies can be fine-tuned(through pounds can persistin the herbivore'scircula- a mechanismdiscussed below) to have greater tion if sufficientsecond-phase substratesare affinityfor that antigen. not immediately available for conjugation The cuesthat the immune system uses to de- (Monks and Lau, 1988). Toxic intermediates terminewhether a compoundis likelyto be

toxicappear to involvethe interactionof the (Schneider, 1983). Chemically inert low- compoundwith other molecules in thebody, molecular-weightcompounds can become al- whetherof endogenous or exogenousorigin. lergenicif they are enzymaticallyconverted to Mostplant toxins are oflow molecular weight reactivemetabolites that then bind covalently (<1,000 daltons).In orderto elicitan initial to host proteins(Chesham and Davies, 1985). immune response,a low-molecular-weightHost serum proteinsare veryeffective carriers compound(hapten) must bind to a largercar- in the induction of allergies to a wide variety riermolecule, such as a protein(Mullin et al., of haptens (Kramps et al., 1981; Baur, 1983; 1983; Laytonet al., 1986, 1987). Most low- Wass et al., 1989). molecular-weightdrugs, for example, are al- Compounds that bind covalentlyto serum lergeniconly when bound covalently to a car- proteinsare frequentlytoxic, mutagenic or carrierprotein (Kasper and Schneider,1987). An cinogenicbecause theyalso bind covalentlyand unboundlow-molecular-weight compound us- nonselectivelyto other macromolecules, in- ually can triggeran immuneresponse only cluding DNA and RNA (Albert, 1985; Oesch, if antibodieswere previouslyformed to the 1987). "Anychemical capable offorming cova- compoundwhen it was conjugatedto a car- lentbonds withDNA ofsomatic and reproduc- rierprotein. (This mayrepresent a physiolog- tive mammalian cells in vivo is a potential icalconstraint; or, the immune system may be mutagen,carcinogen, and teratogen"(Rander- designedso as notto respondto unbound low- ath et al., 1985:57). Furthermore,". . . thecova- molecular-weightcompounds, because a low- lentbinding index (CBI), definedas micromole molecular-weightcompound that rarely binds of chemical bound per mole of DNA nucleo- to proteinsis not likelyto interactwith and tide/millimoleof chemical administered per harmbodily tissues.) Two immunogenictar- kilogrambody weightof animal, exhibits a good getsthat may representcues of toxicityare: quantitiative correlation with the hepatocar- (1) exogenoushaptens covalently bound to en- cinogenicpotency of chemicals of diverse struc- dogenousor exogenouscarrier proteins; and ture"(Randerath et al., 1985:57,paraphrasing (2) exogenouscarrier proteins of potentially Lutz, 1979, 1982). Examples of naturallyoc- reactiveexogenous haptens. curring compounds that bind covalently to DNA are methyleugenol(in apples and cloves), CovalentBinding safrole (in black pepper, cinnamon, and co- Covalentbinding of a low-molecular-weightcoa), myristicin(in carrots and nutmeg), es- compoundto a protein-particularlyserum tragole (in tarragon and sweet basil), and albumin- is stronglycorrelated with toxicity, aflatoxinB (produced by a mold that parasit- mutagenicity,carcinogenicity, and allergenic- izes many species ofnuts and grains) (Rander- ity. Almost everytype of compound that ath et al., 1985). Three of these compounds- reachesthe bloodstream binds in somedegree methyleugenol,safrole, and estragole-were to serumproteins - particularlyserum albu- foundby Miller et al. (1983) to be carcinogenic min,one ofwhose main functionsis to bind in high doses in mice or rats. Among the most to circulatingcompounds (Young and Tilgh- potentallergens and carcinogensare the reac- man,1986). If the bond between a haptenand tive metabolites produced during the first a serumprotein carrier is covalent- thatis, so phase of detoxification,which bind covalently strongas tobe generallyirreversible - then the to proteins, DNA, and RNA (Hodgson and haptencannot be filteredby thekidneys and Levi, 1987; Monks and Lau, 1988). persistsin the circulation for prolonged periods, The connection between covalent binding, enablingthe immune system to form antibod- toxicity,and allergenicityis especially strong ies to it (Schneider,1983; Amos and Park, in contact allergy (a delayed, T-cell-mediated 1985).Indeed, covalent binding between a hap- skin allergy,which is described in more detail tenand a carrierprotein is usuallya require- below). The potentialof a low-molecular-weight mentfor the induction of an IgE responseto compound to be a contactallergen is highlycor- thehapten (Layton et al., 1986,1987). Some relatedwith its ability to bind covalentlyto car- low-molecular-weightcompounds that bind rier proteins (Roberts and Williams, 1982; stronglybut not covalently to proteinscan be Roberts et al., 1988). Of the hundreds of allergenic,but such compounds are rare sesquiterpene lactones (mostly produced by

This content downloaded from 141.218.001.105 on August 06, 2016 07:56:10 AM All use subject to University of Chicago Press Terms and Conditions (http://www.journals.uchicago.edu/t-and-c). 32 THE QUARTERLY REVIEW OF BIOLOGY VOLUME 66 plantsof the family Compositae) that have been ious pollenand foodproteins, can also elicit investigated,an alpha-methylene-gamma-IgE responses.The toxinhypothesis predicts lactone grouping-whichpermits covalent thatnontoxic exogenous proteins that become bindingto carrier proteins -appears tobe both allergensdo so becausethey are either carriers a necessarycondition for allergenicity and a of toxinsor reliablecorrelates of toxins. primarycondition for cytotoxicity (Mitchell An exogenouscarrier protein provides a and Dupuis, 1971;Lee et al., 1971;Rodriguez largeimmunogenic target, and antibodiescan et al., 1977;Woerdenbag, 1986). The induc- typicallyform stable complexes with a variety tion of photoallergy(light-activated allergy) ofsites on a protein(Getzoffet al., 1987).When requiresthe covalent binding of the photoaller- circulatingexogenous proteins are bound to gento a carrierprotein; photoallergens exhib- haptens,they sometimes stimulate the prolifer- itingvery different chemical structures have in ationof anti-carrier IgE antibodies(Cirstea et commonthe ability to bind covalentlyto hu- al., 1984;Layton et al., 1986,1987). Proteins manserum proteins (Barratt et al., 1987).Cova- thatare especiallyefficient carriers of a wide lentbinding to carrier proteins is so important spectrumof toxins - forexample, proteins with thatit can be used to screenpotential photo- hydrophobicpockets that readily bind lipo- allergens(Barratt and Brown,1985). Because philicsubstances - maybe themost common covalentbinding can cause both allergenici- targetsof IgE antibodies. tyand carcinogenicity,it may even be possi- Naturalselection might have favored IgE re- ble to use allergenicityto screen potential sponsesto carrierproteins if, in a naturalen- carcinogens. vironment,a protein that was coupled to a toxin The persistencein the bloodstream of an ex- on oneoccasion was likely to be coupledto that ogenouscompound bound covalentlyto a se- toxinin the future (for example, both toxin and rum proteinindicates that the compoundis proteinwere consituents of the same plant). potentiallyhighly toxic (since its chemical The carrierprotein, though not itselftoxic, structureenables it to bind covalently to tissue wouldsignify potential toxicity. The produc- macromolecules),has evaded detoxification tionof IgE antibodiesto an exogenousprotein mechanisms,and probablyposes the threat of wouldbe especiallyadaptive if the protein was futureinfiltration (since it is currentlyin the "delivering"a reversibly bound low-molecular- environment).This signifiesto the immune weightcompound capable of being converted systemthat defenses should be builtup torap- into a potenttoxin. Many secondaryplant idlyrecognize and eliminatethat compound compoundsare not very reactive until activated upon subsequentencounters. A covalently totheir toxic forms by the herbivore's enzymes; bindingtoxin binds irreversibly to tissuepro- onlythen are they capable of binding covalently teinsand othermacromolecules and thusis to tissuemacromolecules. Such a toxinin its more likelythan a non-covalentlybinding lessreactive state, if bound to a carrierprotein, (reversiblybinding) toxin to cause irreparable wouldbe boundnon-covalently, and thus would harm,perhaps cumulatively, upon each ex- be likelyto disassociatefrom the protein and posure.Therefore, ifthe toxin hypothesis iscor- be convertedto an activetoxic state. By target- rect,IgE antibodiesshould be designedto tar- inga carrierprotein that is boundto a poten- getantigenic features that signify an exogenous tiallyreactive compound, the immune system compound bound covalentlyto a serum mightcause the expulsion of the compound and protein. therebyprevent it from being released and activated.In experimentsby Layton et al. (1986, ExogenousCarrier Proteins 1987),covalently bound conjugates of haptens Althoughthousands of different exogenous and carrierproteins frequently gave rise to IgE proteinsmay invade a mammalianbody dur- antibodiesto the hapten, whereas electrostati- ing itslifetime, only a smallsubset can elicit callybound (moreweakly bound) conjugates IgE responses:viral and bacterialproteins, for frequentlygave rise to IgE antibodiesto the car- example,almost never elicit IgE responses, rierprotein. An IgE responsemounted to an whereastoxic proteins, which are commonly exogenouscarrier protein may function to rap- foundin venom,often elicit IgE responses. idlyidentify and eliminatethe protein's toxic However,many nontoxic proteins, such as var- or potentiallytoxic hapten. Furtherexperi-

mentsare needed to elucidate the relationship DNA (Golding et al., 1987). Somatic hyper- betweenhaptens and theircarriers in the trig- mutation accounts formuch of the immuno- geringof IgE antibody production. globulin diversity(Gojobori and Nei, 1986). Class switchingand somatic hypermutation HOW IGE SPECIFICITIES FOR TOXINS are independent processes that occur during AND CARRIER PROTEINS ARE SELECTED B-cell differentiation(French et al., 1989), and The toxinhypothesis, like any functionalhy- hypermutationcan occur both before and af- pothesisof allergy,implies that natural selec- ter class switching(Allen et al., 1987; Manser, tionhas functionallydifferentiated the IgE class 1989). When an antigen stimulates the pro- fromother classes ofantibodies. IgE antibodies liferationof hypermutated B cells,the cellsthat respondto differentkinds of antigens than other proliferatemost rapidly are those expressing classes of antibodies do; viruses and bacteria, antibodies with the greatest affinityfor the forexample, almost never trigger IgE-mediated stimulatingantigen; by this process are pro- allergy,and individualswith allergies typically duced antibodies progressivelyfinely tuned to producenormal antibody spectrums in response the stimulatingantigen (Tonegawa, 1988). to nonallergenic antigens, indicatingthat the There are at leastthree developmental stages greatlyelevated levels of IgE antibodies that at which antibodies (such as those of the IgE occur during allergy are responses to a select class) could be shaped to respond specifically group ofantigens (Hammarstrom and Smith, to particular types of antigen (such as those 1987). bearingimmunogenic determinants indicating The question of how a given class of anti- toxins or toxin-carrierconjugates): body acquires its specificityfor a particular (1) The initialrearrangement of the V-region kind of antigen or antigenic structureis sig- genesmay be developmentallyprogrammed in nificantbecause the binding sites of antibod- waysthat ensure the productionof certainan- ies of everyclass are determinedby the same tibody specificities(Schroeder et al., 1987). genes (called variable-region, or V-region, During human and mouse fetallife, preferen- genes). Millions ofdifferent antibodies are pro- tial rearrangementof certain V-region genes duced by a verylimited amount of geneticma- occurs, regulatingthe production of particu- terial;the extreme diversity of antibodies results lar antibody specificities(Schroeder et al., fromthe somaticrearrangement and mutation 1987). Such antibodyspecificities may include of the V-regiongenes (French et al., 1989). In those that target particular types of toxin or the production of a new B cell, the V-region toxin-carrierconjugates. genes are rearrangedto forma unique genetic (2) Certain antigenicstimuli appear to selec- pattern;this rearrangementis completed be- tivelyinduce class switching.Stavnezer et al. forethe B cell interactswith any antigenor be- (1988:7704) have found that "The process of comes differentiated(i.e., becomes specialized class switching,whereby B cells switch from to secreteantibodies of a particularclass). Be- productionof one class ofimmunoglobulin (Ig) fore antigenic stimulation,a B cell expresses to another, is highly regulated as different only IgM and IgD antibodies on its surface. classes are expressed in response to different Afterantigenic stimulation,a B cell can ter- antigensand at differentsites in thebody." They minally differentiateinto an IgM-secretor or found,for example, thatbacterial lipopolysac- it can switchto express and secretea different charide induces a cell line of IgM-secreting B class ofantibody, such as IgE (a process called cells to switchto IgA. It is possible that anti- class switching) (French et al., 1989). Class genic stimuliindicating toxins or toxin-protein switchingis thoughtto be regulatedprimarily conjugates selectivelyinduce IgE class switch- by helper T cells, which recognize antigens ing. [When helper T cells interactwith anti- bound to B-cell surfacemolecules and secrete gens on B-cell surfaces,they can secretea vari- factorsthat activate B-cell proliferationand dif- ety of factorsthat lead to B-cell proliferation ferentiation.An antigen-stimulatedB cell can and differentiation;one ofthese factors, inter- also undergo mutation of the rearranged V- leukin-4(IL-4), has been foundin mice to pref- region genes (a process called somatic hyper- erentially direct class switching of IgM- to mutation) at a rate 10,000 times greaterthan IgE-secretingB cells (Finkelman et al., 1988; the spontaneous mutation rate of eukaryotic Lebman and Coffinan,1988) and to increasethe

clone size ofproliferating IgE-secreting B cells an IgE-secretingcell (by, forexample, secret- (Savelkoul et al., 1988).] ing IL-4). In general,the B cell can bind to and (3) The mechanism that directs somatic processself antigens as well as nonselfantigens hypermutationof the V-region genes may selec- (Lorenz and Allen, 1988), whereas the T cell tivelyfine-tune B cells to exhibithigh affinity discriminatesbetween self and nonselfantigens for particular antigenic structures(e.g., for and regulatesB-cell activationaccordingly. (By structuresindicating certain types of toxicity). processing selfantigens, such as serum albu- Some of the same hypermutationshave been min, theB cell can expose foreignantigens that foundto occur repeatedly,indicating, accord- superficiallymimic self antigens.) ing to French et al. (1989), that"hot spots"for What is importantwith respect to under- particular types of hypermutationhave been standingthe development of allergic responses selected for. is thatthe specificitiesof the B-cell surfaceim- The abilityof the immune systemto recog- munoglobulinmolecules differmarkedly from nize that an antigen is a covalently binding the specificitiesof the T-cell antigen receptors toxin or an exogenous carrier protein of a that bind the B cell's processed antigen frag- potentiallycovalently binding toxinwould de- ments coupled to MHC class II molecules. pend on the mechanism by which B cells pro- The binding ofthe T cell to the peptide/MHC cess and present antigens to T cells. A B cell complexinduces the proliferation of B cellswith whose surfaceimmunoglobulin has recognized affinityfor a determinanton the native anti- (bound) an antigenrequires T-cellrecognition gen (ratherthan forthe peptide thatbound the ofits antigen in orderto be activatedto an IgE- T cell). Thus, ifthe T cell binds to an antigen secretingcell. B-cell recognitionof antigens, fragmentwhose source was a hapten-carrier however,differs from T-cell recognitionof an- proteinconjugate, it could induce a B-cell re- tigens(Pierce et al., 1988). The surfaceof a B sponse either to the hapten or to the carrier, cell bears manyidentical immunoglobulin mol- depending on whetherthe B-cell surface im- ecules thatcan trap antigenswhose nativecon- munoglobulin was specific for the hapten or figurationscomplement the specificconfigu- the carrier. rations of those molecules. An antigen that If T cells do indeed directclass switchingof binds to a B cell'ssurface immunoglobulin mol- B cells depending on thetype of antigenic frag- ecule is usually internalized forprocessing- mentcoupled to MHC moleculesthat they de- that is, it is taken up inside the B cell to intra- tecton theB-cell surface,then T cellsmay pref- cellular compartmentswhere enzymes cleave erentially induce switchingto the IgE class it into fragments.In the case of a proteinanti- upon recognizinga peptide covalentlybound gen, forexample, processingentails unfolding to a hapten. In order to restrictinduction of the proteinto expose its internalantigenic de- anti-carrierIgE antibodiesto (exogenous) car- terminantsand cleaving it withproteases into riers of toxic or potentially toxic haptens, a constituentpeptides (Werdelin et al., 1988; non-covalentlybound carrier-haptencomplex Chain et al., 1988). The processedpeptides are that is internalized by a B cell must, once thenbound to a set ofthe cell's own molecules, processed, be recognized by a helper T cell known as major histocompatibility(MHC) as toxic. What followsis a speculative account class II molecules, transportedto the surface of how this might occur. A non-covalently of the B cell, and presented to helper T cells bound hapten that is capable of being enzy- (Yewdell and Bennink, 1990). If a helper T cell matically activated to a reactive, covalently recognizes a peptide as nonself, by binding binding toxinmight, when internalizedby the to thepeptide/MHC complex, it secretesvari- B cell forenzymatic processing,be converted ous factorsthat activate the B cell to prolifer- by the B cell's enzymes - particularlyby the ate, to differentiateinto a particularclass, and cytochromeP-450 enzymes - to itstoxic state. to secreteantibodies of the same specificityas This activatedtoxin could thenbind covalently the B cell's surfaceimmunoglobulin (or hyper- to one of the peptides fromthe carrierprotein mutated versions of that immunoglobulin) and be transportedto and displayed on the (Abbas et al., 1990). Depending on the anti- B cell's surface. B cells contain substantial genic stimulus,the T cell may be able to pref- amounts of the cytochromeP-450 enzymes erentiallydirect the B cell to differentiateinto (Selkirk et al., 1975; Freedman et al., 1979;

Crespiet al., 1985),which catalyze the conver- formto the second carrier alone (Mitchison, sionof a wide arrayof nontoxic molecules to 1971b)(although whether these anti-carrier an- highlytoxic, covalently binding intermediate tibodies are of the IgE class has not been compoundsin thefirst phase of the detoxifica- reported). (3) A B cell whose surfaceimmuno- tionreaction. A helperT cell thatrecognizes globulin has specificityfor a certain protein thecovalently bound hapten-peptide complex might,through pinocytosis (the engulfmentof coupledto MHC moleculesmight secrete fac- substancesby the cell membrane) internalize, torssuch as IL-4 to inducedifferentiation of process, and presentto T cells a differentpro- the B cell to the IgE class. In summary,IgE teinbound to a toxichapten, resultingin T-cell antibodiesmight be generatedto proteinsthat activationof that B cell whichis specificfor the are exogenouscarriers of potentially reactive firstprotein. (Pinocytosis is one waythat B cells (potentiallytoxic) haptens in the following way: trap antigens, though it is much less efficient a B cellwith specificity for the carrier protein than immunoglobulin binding.) could bind a non-covalentlybound hapten- carrierconjugate, enzymatically convert the COMMON ALLERGENS EXHIBIT THE PROPERTIES carrier'snonreactive hapten to a reactive,cova- PREDICTED BY THE TOXIN HYPOTHESIS lentlybinding hapten, and exposethe cova- If the toxin hypothesisis correct,common lentlybound hapten-peptide complex to helper allergens should exhibitmolecular configura- T cells,which would theninduce the B cell tionsthat correlate strongly with toxicity. The to differentiateand secreteantibodies with compounds mostlikely to be allergenicare: (1) specificityfor the carrierprotein. low-molecular-weighttoxins that bind cova- Mechanismsdesigned to induce allergic re- lentlyto serum proteins; (2) nontoxic protein sponsespreferentially to proteinsbound to carriersof low-molecular-weight toxins; and (3) toxicand potentiallytoxic haptens may, in cer- specifichigh-molecular-weight toxins, such as taincircumstances, potentiate dysfunctional al- snake venom, that harmed individuals in an- lergicresponses to bystander proteins. IgE re- cestral mammalian populations fora span of sponsesto such proteinsas ovalbumin,an time significantfrom the standpoint of natu- egg-whiteprotein, can be potentiatedby ad- ral selection. Most likelythere are additional ministeringthe protein with potent inducers cues of toxicityyet to be discovered. (For ex- ofIgE antibodies,such as ricin,a toxicplant ample, theimmune system may have developed protein(Thorpe, et al., 1989).Potentiation of waysto recognizemolecular configurationsin- allergyto bystander proteins might arise in the dicativeof toxins that are lethalto nonregener- followingways: (1) A B cellwhose surface im- atingnerve cells.) By targetingonly those com- munoglobulinbinds to a proteinmight be in pounds most likely to be toxic, the immune thevicinity of a secondB cellthat happens to systemavoids hypersensitiveresponses to ev- be interactingwith a T cell, and might"in- eryexogenous compound itencounters. Thus, tercept"a signal to differentiateto an IgE- the riskyallergic response is normallymounted secretingcell that was intendedfor the second only to a compound that constitutesa toxic B cell (previouslyactivated B cells thatare threat. bystandersat thesite of T-cell activity, for ex- In a naturalenvironment allergies should fall ample,can be stimulatedto proliferateby the intoone ofthree categories: (1) a typicallyadap- T-cell-derivedfactors -Abbas etal., 1990).(2) tive,defensive response to a toxic allergen; (2) A proteinfrom one foodsource that binds to a maladaptive, side-effectresponse, such as to a toxicor potentially toxic hapten from another a bystanderprotein; and (3) a maladaptive re- foodsource in thegastrointestinal tract or the sponse to a manipulation of the mammalian bloodstreamcould induce an IgE response,just machineryof allergy by anotherorganism. [See as ifit werethe original carrier of that toxin; Ewald's (1980) evolution-mindedcategorization thisprocess could be exacerbatedby the "car- ofphysiological responses to infectiousdiseases; riereffect," inwhich a haptenconjugated to one also see Williams and Nesse (1991, Table 2).] carrierprotein (e.g., serumalbumin) induces For the allergic capacity to have been main- antibodiesthat bind to thathapten when it is tained by natural selection, the benefitscon- conjugatedto a secondcarrier protein (Mitch- ferredby adaptive allergiesthroughout mam- ison,1971a; Neveu, 1987). Antibodies can then malian evolutionaryhistory must typically have

This content downloaded from 141.218.001.105 on August 06, 2016 07:56:10 AM All use subject to University of Chicago Press Terms and Conditions (http://www.journals.uchicago.edu/t-and-c). 36 THE QUARTERLY REVIEW OF BIOLOGY VOLUME 66 outweighedthe costs imposed by maladaptive coveryof allergic anaphylaxis: dogs who recov- allergies.The followingsubsections review the eredwithin a fewdays from an initialsublethal commonallergens -classified by theirusual doseof toxin suffered fatal anaphylactic shock routeof entry into the body-and discussthe withinan hourof a subsequentequal or slightly reasonsfor their allergenicity. greaterdose oftoxin two to threeweeks later (Portierand Richet,1902). Though sometimes InjectedAllergens (Drugs, Venom) fatal,allergy-induced anaphylaxis often could Variousdrugs cause serious allergic responses be lifesavingby slowingthe circulationof in sensitizedindividuals, especially when ad- venom[the first-aidprocedures for treating ministeredby injection, a process that bypasses venomoussnake bite -implementing a con- thedetoxification enzymes of the primary ep- strictiveband near the bite to retard lymphatic ithelialtissues. Drugs exert biodynamic effects flow(Gifford, 1984) and immobilizingthe vic- onthe body, and so areby definition toxic sub- timto slowthe heart rate (Chapman, 1968)- stances(Brody et al., 1965).Most drugs are de- are similarlydesigned to slowthe circulation rivativesof, synthetic mimics of, or based on of venom]. prototypesof plant toxins; but they are available in concentrationsfar more potentthan IngestedAllergens (Foods) plantscan affordto manufacture. Allergies oc- Almostany food can be allergenicbecause curin responseto a wide spectrumof drugs, almostany food can containtoxins or proteins butprimarily to those,such as penicillin,that thatbind as carriersto that food's toxins. Toxins bind covalently(or whose metabolitesbind arerarely investigated as the possible allergenic covalently)to serum proteins (Schneider, 1983; culpritsof foods. Although toxins may provide Bundgaard,1983). Although covalent binding thestimulus for the development of allergies is notan absoluterequirement for allergenic- to plant-derivedfoods, the specific immuno- ity,drug allergens that do notbind covalently genictargets may include the plant's proteins are veryrare (Schneider,1983; Bundgaard, thatbind to the toxin or that are otherwise relia- 1983).If allergyis designedto defendagainst blycorrelated with the toxin. The specifical- toxinsthat evade enzymatic detoxification, al- lergenicconstituent of an allergy-producing lergicsusceptibility to drugs and abilityto foodmay be difficulttoidentify, since food con- detoxifydrugs are expectedto be inversely stituentsusually are degradedin thestomach related.Allergy is not expected to develop, how- and intestines,where they undergo conforma- ever,in response to most drugs that do notbind tionalchanges or conjugationsto othersub- covalently. stances,resulting in antigenic structures differ- The toxicvenom of various insects, snakes, entfrom those of the undigested constituents. and marineanimals is frequentlyvery harm- Nevertheless,there is strongevidence that fulwhen injected directly into a victim'sblood- manyfood allergies stem from toxins in the streamby stingersor fangs,and somevenom foodsor fromfood proteins that bind as car- neurotoxinsbind irreversiblyto theirtarget riersto toxins. receptors(see Tu, 1977). Not surprisingly, Virtuallyall plantfoods contain toxins, al- manyvenoms, such as honey-beevenom, tend thoughcooking deactivates some of them. Al- to be highlyallergenic (Evans and Summers, lergyto toxins may explain the puzzle of aller- 1986). Susceptibilityto insectvenom allergy, gic cross-reactivityto plant foods from unlikesusceptibility to pollenor foodallergy, unrelatedbotanical families: such foods may is notcorrelated with susceptibility to allergy be cross-reactivebecause they contain the same in general(Evans and Summers,1986), which toxin.A numberof studies, for example, show mayindicate that selection has designedmam- thata highpercentage of personsallergic to malianimmune systems to recognizespecific birchpollen (family Betulaceae) are also aller- insectvenom toxins. The toxicproteins in the gic to someor all ofthe followingfoods: ap- venom of such marine animals as jellyfish ples,pears, peaches, cherries, apricots, plums, can also inducetoxin-specific IgE antibodies almonds(all fromthe family Rosaceae), hazel- and cause severeallergic responses (Fisher, nuts(family Betulaceae), carrots (family Um- 1986:702). As mentionedabove, toxinsex- belliferae),potato skins (family Solanaceae), tractedfrom jellyfish tentacles led to thedis- walnuts(family Juglandaceae), Brazil nuts

(familyLecythidaceae), and, to a lesserextent, (Stich et al., 1981; Hanham et al., 1983). The celery, oranges, peanuts, tomatoes, onions, foods listed secondarilyin the cross-reactivity parsley,and coconuts (Hannuksela and Lahti, literatureas allergenichave lower,but stillsig- 1977; Eriksson, 1978; Lahti and Hannuksela, nificant,amounts of caffeicacid and its deriv- 1978; Eriksson et al., 1982; Dreborg and Fou- atives(orange: Reschke and Herrmann, 1981; card, 1983; Lowenstein and Eriksson, 1983; tomato: Schuster et al., 1986; celery: Herr- Eriksson, 1984; Halmepuro et al., 1984). The mann, 1978; peanut: Dabrowski and Sosulski, most common allergic symptoms caused by 1984; coconut: Macfarlane et al., 1988; onion: eating these foods are swellingand itchingof Schmidtlein and Herrmann, 1975; parsley: the lips, mouth, and tongue, laryngealdistur- Stoehr and Herrmann, 1975). In the cinnamic bances, rhinitis,and hives (Hannuksela and acid studies cited above, only two common Lahti, 1977). Chemical analyses reveal that foods [radish and red cabbage (Shafers and birchpollen and the edible partsof every plant Herrmann,1982a; Winteret al., 1987)] thatare food listed above contain high amounts of the sometimeseaten raw (cooking degrades these phenolic acids known as cinnamic acids (al- toxins)are reportedto containmodest concen- though the data on Brazil nuts and coconuts trationsof caffeicor chlorogenicacids yetare measured total quantities of phenols rather not mentioned in the literatureas part of this than quantities of individual phenolic com- cross-reactivegroup. Since many herbs and pounds). In particular,birch pollen and every spiceshave extremelyhigh levels of these toxins fruitand vegetable in the primarylist contain (up to 19,000 parts per million fordried basil) veryhigh quantities (up to 700 parts per mil- (Schulz and Herrmann, 1980), theywould be lion freshweight) of caffeicacid or its quinic expected to elicit an allergic response in per- acid esters, chlorogenic acid and neochloro- sons withallergies to the above clusterof foods genic acid (birch and hazel pollen: Meurer et if eaten uncooked in substantial quantites. al., 1986, Meurer et al., 1988; apple and pear: The hypothesisthat caffeic and chlorogenic Mosel and Herrmann, 1974a,b;peach, apricot, acids are the allergenic constituents of the plum, and cherry: Moeller and Herrmann, above-mentioned cross-reactivefoods is also 1983; potato: Schmidtlein and Herrmann, supportedby evidence thatthese toxins are the 1975; carrot: Sarkar and Phan, 1974, Stoehr allergenicconstituents of certain other plants. and Herrmann, 1975). Chlorogenicacid has been reportedto be highly Caffeic and chlorogenic acids are phenolic allergenicto manypeople exposed occupation- toxinsthat oxidize easily,forming reactive qui- ally to the dust of green coffeebeans (Freed- nones, which can covalentlybind to proteins man et al., 1962; Bariana et al., 1965), which (Stich et al., 1981;Hurrell et al., 1982). Caffeic contain this acid in very high concentrations acid, furthermore,has been reported to be (up to 5 % ofthe dryweight of the green coffee mutagenic,carcinogenic (Ito and Hirose, 1987; bean is chlorogenicacid- Baltes, 1977). [The Fung et al., 1988; Ito et al., 1990), and clasto- allergenicityof chlorogenic acid has been chal- genic (breaks chromosomes) (Hanham et al., lengedby Layton et al. (1966, 1968), who main- 1983). The nuts in the primarylist, although tain thatproteins are theallergenic constituents found in one studyto have veryhigh concen- of coffeebeans. Freedman (pers. commun.), trationsof phenolic compounds (Macfarlane points out, however,that many of his original et al., 1988), were found in another study to experimentsdemonstrating the allergenicity of have relativelylow concentrationsof cinnamic chlorogenicacid in people withcoffee-bean al- acids (Senter et al., 1983). This latter study, lergyused syntheticallyprepared chlorogenic however,measured the acids in themeat ofthe acid, whichcould not have been contaminated nuts,and did not include the edible seed coats, with coffeeproteins.] Various phenolic com- which would be likely to contain the highest pounds have been reportedto produce immedi- concentrationof these acids; furthermore,the ate symptomsof allergy(e.g., wheal-and-flare high allergenicpotential of nuts may resultin responses in skinprick tests of sensitizedindi- part fromtheir high concentrationsof certain viduals) (Brostoff,1987), and caffeicacid es- metals, including some of the transitionmet- tersof propolis (the bee-glue frompoplar buds) als (Furr et al., 1979), which considerablyen- have been foundto cause strongcontact allergy hance the genotoxicityof the cinnamic acids (Hausen and Wollenweber,1988; Hashimoto

et al., 1988). Brostoff(1987) has even suggested Two smaller clustersof cross-reactiveplant thatplant phenolicsmay be the allergeniccon- foods and pollens include: (1) ragweed pollen, stituentsof various foods, pollens, and dusts. watermelon,banana, cantaloupe, and honey- Anotherindication that toxins - particularly dew; and (2) mugwortpollen, celery,and vari- the cinnamic acids, such as caffeicand chloro- ous spices (Dreborg, 1988). Whetherthe allergenic acids -are likelyto be the common al- gic cross-reactivityof the plants in each ofthese lergensin the above-listedcross-reactive foods clustersis due to a common toxin remains to is thatthe allergenicityof these foods is quickly be investigated. attentuatedwith storage time (especially ifthe Examples of high-molecular-weightaller- foodhas been finelychopped) or by heat,which genic toxins fromplant foods are various lec- is whypeople withapple allergies can tolerate tins,which probably are evolutionarilyancient. apple sauce or apple cake (Eriksson, 1978; Dre- Dietary lectins are not always degraded by borg and Foucard, 1983). According to Lahti cooking or digestion; ifthey are absorbed into and Hannuksela (1978:146), "themost confus- the bloodstream, theycan cause blood cells to ing factor"about the cross-reactivityof botan- agglutinateand proliferate.According to Freed icallyunrelated foods is the extremelability of (1987), some lectins can bind to virtuallyall the allergens, which "would seem to speak in typesof mammalian cells and induce allergy, favourof enzymes and othereasily destroyable and themost cytotoxic lectins are the ones most compounds" as the allergenic culprits. Chlo- likely to cause food allergy (Freed, 1987). rogenic acid is so easily destroyedby cooking Wheat, a common allergen in modern socie- or roastingthat people who are allergic to the ties,contains the lectin, wheat germagglutinin, chlorogenicacid in green coffeebeans are able whichbinds particularlystrongly to human tis- to drinkordinary roasted coffee(Freedman et sues (Freed, 1987). al., 1962). Chlorogenicacid is degraded so rap- Some toxinsin allergenicplant foods are pro- idly because it oxidizes easily, which is what duced byparasitic fungi. Aflatoxins fromAsper- causes the fruitsand vegetablesthat contain it gillusspores, forexample, are potent carcino- to turn brown when cut and exposed to air gens (Randerath et al., 1985) that commonly (Schafers and Herrmann, 1982b). contaminate peanuts and grain and that can According to Calkhoven et al. (1987:382), cause food poisoning (Rockwell, 1988). Many "The nature ofthe componentsresponsible for mold speciescause IgE-mediatedallergy (Karls- the cross-reactivityhas not yet been estab- son-Borga et al., 1989), although whetherthis lished." Plant toxins, however,have not been allergy is specificallytriggered by the toxins investigatedas thepossible culprits. Rather, the in the mold needs to be investigated.Allergy allergens in these cross-reactivefoods have to peanuts, forexample, may representan IgE generallybeen assumed to be proteins,and the response to the aflatoxinor to the peanut pro- loss ofallergenicity with storage time of apples, teins that have been associated with the afla- forexample, has been thoughtto result from toxin on previous exposures. the binding of oxidized phenols to plant pro- Allergenic foods of animal origin also can teins,resulting in changed conformationof the contain potent toxins. Many species of aller- proteins (Bjorksten et al., 1980). (Bjorksten genic fish are frequently contaminated by et al. were able to prepare apple extractsthat toxinsproduced by algae or plankton(Wright maintained theirallergenicity by adding to the and Robertson, 1987; Concon, 1988a). Shell- apple extract various compounds, including fish,particularly mussels, clams, oystersand one to inhibitthe oxidation of phenols. Since scallops, are common transvectorsof paralytic the resultingcentrifuged extract was not tested toxins from the planktonic dinoflagellate forthe presence of phenols, however,it is not Gonyaulax,particularly during red tide (Saa- knownwhether its allergenic constituents were vedra-Delgado and Metcalfe, 1984). Clupeo- unoxidizedphenols, such as theneochlorogenic toxin,possibly produced bydinoflagellates, ap- acid that is present in apples in high concen- pears sporadically in herring, anchovy and trations,or apple proteins,as the authors sug- sprat.Ciguatoxin, whichcauses ciguaterapoi- gested.) Proteins fromfoods containing these soning, is thought to be produced by toxic phenolic toxins may very well become aller- microalgae and contaminatesover 300 species genic as a result of their association with the of marine fish,including swordfishand vari- toxins. ous snappers,basses, flounders,eels, and mack-

erels (Saavedra-Delgado and Metcalfe, 1984; O'Neill and Kinsella, 1987). Soy protein,an- Concon, 1988a). Fish also can be contaminated othercommon allergen,also binds wellto a va- by toxic metals; cod, for example, one of the rietyof compounds (Damodaran and Kinsella, most allergenicfish in Scandinavian waters,is 1981). In short,egg, milk,and soyproteins are frequentlycontaminated by a formof mercury effectivecarriers of a varietyof haptens. that is highlytoxic to mammalian nerve and Since milk and eggs are not toxic, allergic brain tissue (Concon, 1988b). responses to them are probably maladaptive. The toxinhypothesis predicts that the aller- For mostof human evolutionaryhistory, adults gies to seafoods arise fromcontamination of did not drinkmilk and probably did not con- seafoods by toxins. Both the toxins and the sume eggs (or egg products) nearlyas oftenas seafood proteins to which the toxins are con- manymodern humans do. Many adulthumans jugated could induce theproduction of IgE an- lack sufficientenzymes, such as lactase, to de- tibodies. Many planktonictoxins are of fairly grade milk proteins (Sategna-Guidetti et al., low molecular weight(see Ragelis, 1984) and 1989). Although the proteinsof a given plant would have to bind to proteinsin order to be- would tend to be reliably associated with the come immunogenic. The allergenic cod pro- plant'stoxins, animal proteinsthat become al- tein (allergenM), whose main knownfunction lergenic by binding to low-molecular-weight is to bind calcium ions (King, 1976; Aas, 1987), plant toxinsfrom the diet would notbe reliably mightbe expected also to bind planktonic or associated withany particulartoxins, hence al- metallic toxins with high affinity.Individuals lergiesto such proteinswould be maladaptive. who are allergic to a particular species of aquatic animal could be tested forsensitivity InhaledAllergens (Pollen, Animal Dander) to the toxinsthat commonly contaminate that Respiratoryallergies can be caused by in- species. haling any of a varietyof substances, such as Among themost commonly allergenic foods a wide range of occupational toxins, fungal for humans, however, are cows' milk and spores, pollen, and animal dander and hair. chickens'eggs, which are not themselvestoxic Repeated exposure to toxic occupational sub- (althoughthey are sometimescontaminated by stances is a common cause of respiratoryal- toxin-producingbacteria, by antibioticsor, in lergy:for example, farmerscan acquire respi- thecase ofmilk, by plant toxinsingested by the ratoryallergy to insecticides,metal refinersto cow). The major allergens thathave been iso- metals,dyers to reactivedyes, and pharmaceu- lated fromeggs are the nontoxicegg-white pro- tical workersto various antibioticsand other teins ovalbumin, ovomucoid, and ovomucin; drugs (Davies et al., 1984). One notorious oc- the major milk allergensare the nontoxicpro- cupational respiratoryallergy is extrinsical- teins bovine serum albumin, alpha-lactalbu- lergicalveolitis (EAA), also knownas farmer's min, beta-lactoglobulin, and casein (King, lung disease, whichoccurs as a delayedreponse 1976). These proteinsmay become allergenic to the fungal spores on moldy hay dust. IgE by binding as carriers to plant toxins in the antibodies to the mold can oftenbe detected digestivetract or bloodstream. There is evi- in patients with EAA (Gari et al., 1986), al- dence that these proteinscan be effectivecar- though the onset of symptoms is usually riersof low-molecular-weight toxins. Ovalbu- delayeduntil 6 to 8 hours afterexposure. Mold min, forexample, has been shown to bind to allergies are not uncommon: Karlsson-Borga various food odorants (Maier, 1969) (many et al. (1989) detectedIgE antibodiesto 16 differ- foododorants, such as allyl-isothiocyanate,the entmold generaamong patientswith suspected pungent carcinogen synthesizedby cabbage, mold allergy.The fungalantigens of moldy hay are low-molecular-weighttoxins) and to many are so allergenicthat, according to Platts-Mills metals (Arora et al., 1984; Goux and Venkata- (1984), in some regions 50 percent of the ex- subramanian,1986). In fact,ovalbumin is com- posed population suffersfrom EAA (but see monly used in experimentsin which an effec- Malmberg et al., 1988). The fungifrequently tivecarrier for haptens is required. Of themilk isolated frommoldy hay are ofthe genus Peni- proteins, beta-lactoglobulin, alpha-lactalbu- cillium,which is thought to produce at least min, and casein bind readily to various vola- 97 differenttoxic metabolites, and of the ge- tile flavorcompounds (Maier, 1969; Franzen nus Aspergillus,which is thoughtto produce 64 and Kinsella, 1974; Yabumoto et al., 1975; differenttoxic metabolites (Emanuel et al.,

1975). Intoxication by these fungal toxins tivein modernindustrial environments is un- causes pulmonary mycotoxicosis,a sudden, clear.Pollen allergies appear to be morepreva- acute infectionthat is clinicallyvery different lent and severeamong people in industrial fromthe allergycaused by the fungi(Emanuel societiesthan they are amongpeople in nonin- et al., 1975). EAA and pulmonary mycotoxi- dustrialsocieties, although it seemsunlikely cosis appear to be mutuallyexclusive afflictions: thatthe former suffer greater exposure to pol- patients with EAA do not have active fungal lens. Possiblereasons forheightened sensi- infectionsof the lungs (Platts-Mills,1984), and tivityto respiratoryallergens in industrialso- patientswith pulmonary mycotoxicosis do not cietiesare discussedin a latersection. have EAA (Emanuel et al., 1975). Since intox- Individualswith allergies to thedander or ication seems to occur only in the absence of hairof dogs, cats, mice, rats, or horses are usu- allergyto thetoxins, allergy may protecta large allysensitized to theanimal's serum albumin, percentageof the population exposed to fungi althoughother constituents ofdander have also against the toxic effectsof fungalmetabolites. been implicatedas allergens(King, 1976; Inhalation of pollen grains can cause hay- McKey,1979). Allergies to animal dander and fever,when thenasal passages are affected,and haircould result from contact of the animal's asthma, when the lungs are affected.(Respi- furwith plant oils whosetoxins then bind to ratoryallergies to pollen usually involvewind- danderand hairproteins. (More speculatively, pollinatedrather than insect-pollinatedplants, itis also possiblethat the allergenicity of non- presumably because the air contains vastly human mammalianserum proteinsresults larger quantities of the former.)Pollen grains fromtheir structural resemblance to homolo- contain a wide spectrumof toxins - forexam- gous human serum proteinsconjugated to ple, phenolicacids, sesquiterpenelactones, and toxichaptens.) Allergy to animalsis probably alkaloids (Stanley and Linskens, 1974; Ohm- a maladaptiveresult of the evolutionarily novel oto et al., 1977; Mabry and Gill, 1979; Fisher situationof living with them in closed quarters. and Mitchell, 1986; Herminghaus et al., 1988; Meurer et al., 1988). Ewald (pers. commun.) SkinAllergens suggeststhat plants may produce pollen toxins Many planttoxins and theirsynthetic ana- as either antibrowsingor antitramplingde- logscause allergicskin reactions such as hives fenses. A connection between respiratoryal- (urticaria)and eczema. Allergiccontact der- lergyand pollen toxicitywas postulated early matitisto a plantis so commonlycaused by in thecentury by Noon (1911),who believedthat the plant'slow-molecular-weight toxins that hayfeveris intoxicationby pollen toxins, and writingson plantcontact allergens read like who used pollen extractsto tryto stimulatethe handbooksof natural toxins (e.g., Fisherand production of pollen antitoxin,analogous to Mitchell,1986). The allergicresponse to skin innoculation against bacterial toxins. Never- allergens,which includes inflammation and theless, the main pollen allergens that so far itching,may be immediate(primarily medi- have been isolated and identifiedare nontoxic atedby IgE antibodies)or delayed(primarily water-solubleproteins. (Proteins, however, are mediatedby T cells). probablythe onlypollen constituentsthat have Delayedhypersensitivity tocontact allergens been testedfor allergenicity.) These pollen pro- occursprimarily to low-molecular-weightan- teinsare reliablyassociated with low-molecular- tigensthat can bindcovalently to endogenous weight pollen toxins and probably bind the proteins(and aretherefore toxic) (Roberts and toxinsto some extent,which could account for Williams,1982). According to Belsito(1989), theirallergenicity. Platts-Mills (1984:4), add- thedelayed hypersensitivity response is as fol- ing to the workof Berrens (1974), has hypothe- lows:The antigensare trappednear thesur- sized that "irritantmaterials" in pollen could face of the skinby Langerhanscells, bone- have adjuvant (stimulating)effects on the IgE marrow-derivedepidermal cells which, like B antibodyresponses to the nonirritantproteins. cells,process antigens and presentantigenic Indeed the "irritant"toxins in pollen may in- fragments(coupled to MHC Class II mole- duce IgE antibody responses to nontoxic pro- cules)to helper T cells.The antigensare usually teins that bind these toxins boundcovalently to proteinsfrom the Lange- Whetherpollen allergiesare typicallyadap- rhanscell surface,the skin, or theserum be-

foreprocessing and presentation.On firstex- guez et al., 1977;Woerdenbag, 1986; Gaspar posure to the covalentlybinding antigens, et al., 1986; Thastrupet al., 1987). Langerhanscells migrate to local lymph nodes, Prolongedexposure to occupationalmate- wherethey come into contact with many T cells. rialsderived from plants (all ofwhich contain HelperT cellswith specificity for the processed toxins)also can cause allergy.For example, antigensrelease a varietyof factors, initiating bookbinderssometimes become sensitized to the inflammationof skintissues and the de- theresins of their binding materials, carpenters structionof skin cells that may have been con- to wood,and surgeonsto therubber of surgi- taminatedby the antigens.Mast cells are cal gloves (Fregert,1981). Many synthetic thoughtto be activatedas well,releasing their chemicalsthat are foundin manyhousehold inflammatorychemicals. The T cellsthen pro- and industrialproducts are also allergenic liferateand circulate,so thatif the individual (Foussereauet al., 1982;Fisher and Mitchell, is reexposedto the antigensthe Langerhans 1986),particularly ifthey are lipophilic, of low cellswill not need to migratefar to finda T molecularweight and, thus,analogs of plant cellcapable of recognizing the antigen and in- toxins. ducingthe appropriate inflammatory response. Metals,which can be verytoxic, often pro- The protectionconferred by delayed T-cell- vokeskin (and respiratory)allergies, and can mediatedallergy is similarto thatconferred be mediatedeither by T cells (Belsito,1989) by immediateIgE-mediated allergy: inflam- or by IgE antibodies(Novey et al., 1983). mationof the infected area, which contains the Metallicsalts can cause contactallergy even toxin,and itching,which leads to theremoval thoughthey form non-covalent complexes with oftoxin-contaminated skin cells via scratching. proteins(Belsito, 1989). Trace amountsof But because delayedresponses are localized many metals are presentnaturally in soil, and occuron a slowertime scale, the riskof plants,and animaltissues, and are required anaphylactic shock associated with IgE- forproper nutrition; human serum even con- mediatedallergy is avoided.When toxins are tainsa specialprotein to bindnickel (Kaspr- boundto proteinsnear the site of entry-and, zak, 1987).Excessive amounts of metals, how- hence,are not freeto circulatein theblood- ever,are harmful and sometimeslethal. Many streamand bind to vulnerableinternal tis- metalsare genotoxicor carcinogenicto mam- sues-the damage can be containedlocally, maliancells by inducingDNA strandbreaks and so the riskyIgE responsepresumably (Furst,1987). Nickel,perhaps the most aller- wouldnot be warranted. genicmetal (Fisher, 1986), is also one of the Examplesof toxic contact allergens include mostcarcinogenic (Kasprzak, 1987). Epidemi- theurushiols from poison oak and poisonivy, ologicalstudies have shown that individuals ex- many of the mutagenicor otherwisetoxic posedoccupationally to largeamounts of cer- oleoresinsfrom vegetables and spices,such as tain nickelcompounds have a significantly capsicumpepper and nutmeg(Damhoeri et al., increasedrisk of cancer (Kasprzak, 1987). 1985;Fisher, 1986), and toxinsfrom such com- Eisenbud(1987) notes that of the 15 metals on mon vegetablesas garlic,onion, and celery whichstudies of carcinogenicity and allerge- (Fenwickand Hanley,1985; Berkeleyet al., nicityhave been performed,the fourmetals 1986).Among the most allergenic of the plant thatare unambiguouslycarcinogenic in hu- toxinsare certain sesquiterpene lactones in the mans or animals (arsenic,beryllium, chro- pollenof ragweed and parthenium weed, plants mium,and nickel)are also stronglyallergenic whosepollen causes widespread contact allergy inhumans. Thus, the link between allergenic- as well as respiratoryallergy, although not ityand carcinogenicityis especially striking in necessarilyin the same person(Fisher and metals. Mitchell,1986:439). As previouslydiscussed, many sesquiterpenelactones are allergenic, Helminths mutagenic,and cytotoxicto mammals,and Parasiticworms (helminths) frequently in- thosethat are allergenicare thosethat bind duce substantialIgE proliferationand some- covalentlyto proteinsand thatare, therefore, times even fatal anaphylaxis(Ogilvie and potentialmutagens and carcinogens(Rodri- Jones,1973). Various researchers have viewed

This content downloaded from 141.218.001.105 on August 06, 2016 07:56:10 AM All use subject to University of Chicago Press Terms and Conditions (http://www.journals.uchicago.edu/t-and-c). 42 THE QUARTERLY REVIEW OF BIOLOGY VOLUME 66 thepresence of IgE antibodiesduring helminth antigensof many helminths, such as Schistosoma infectionsas indicatingthat the functionof al- mansoni(Maddison, 1986)- notoriousfor elicit- lergyis to protectagainst such infections(God- ing IgE responses- Onchocercavolvulus (Mac- frey,1975); some researchersgive examples of Kenzie et al., 1986), and Wuchereriabancrofti possible IgE involvementin the expulsion of (Ambroise-Thomasand Peyron,1986). These and resistance to helminths (Dessaint and antigensmay be toxinsthat either are synthe- Capron, 1989). Other researchers, however, sized by the wormsor are absorbedby the note that IgE antibodies do not seem to be wormsfrom the host's diet and thenexcreted necessaryto expel worms(Mitchell, 1979;Jas- or secretedinto the host's circulation. Various sim et al., 1987). According to Jassim et al. studiesindicate that some of the antigens ex- (1987), high levels of IgE antibodies to adult cretedor secreted by helminths are toxic to host worm antigensin helminth-infestedindividu- cells:extracts of many metazoal parasites have als do not decrease susceptibilityto subsequent cytotoxicor inhibitory effects on host lymphoid helminthinfection, and helminth-infestedin- cells(Mitchell, 1979); the helminth Angiostron- dividuals withlow IgE levelsto adult worman- gyluscantonensis secretes soluble antigens that tigens do not appear to be immunologically can depresscertain host immunological activi- compromised in their defenses against the ties(Dobson and Yong,1987); pork tapeworm worms. According to Ikeda and Tani (1988), (Taeniasolium) cysts release substances at death the IgE response to the helminthParagonimus thatare toxicto thehost's central nervous sys- ohiraiconfers little protection against reinfec- tem(Alcock, 1983:128); and cestodes,in their tion. Protection against helminths has been earlystages, secrete enzymes that help them shownto involvemany parts of the immune sys- to penetratehost tissues (Ogilvie and Jones, tem, including T cells, which in mice can con- 1973). ferimmunity to some helminthswhen thecells Helminthsmay sequestertoxic secondary are passivelytransmitted to offspringthrough plantcompounds from the host's diet and re- lactation(Kumar et al., 1989); neutrophilsand lease theminto the bloodstreamas weapons eosinophils,which bombard helminths with ox- againstthe host, just as certaininsects sequester ygen radicals (Kazura et al., 1985) and toxic planttoxins as an antipredatordefense. On the proteins(Gleich and Adolphson, 1986); mac- otherhand, helminthsmay simplyabsorb rophages, which secrete factorsthat are cyto- toxinsalong with nutrients from the host's diet toxic to some helminthlarvae (James et al., and thenexcrete or secretethe toxins into the 1990); and, possibly,various classes ofantibod- bloodstreamas wasteproducts. Host hypersen- ies, which are produced during helminthin- sitivityto these dietary toxins might be exacer- fections(Lopes et al., 1990). The risk of fatal bated by helminthabsorption of hostserum anaphylaxisin a potentiallychronic and gener- proteinsand subsequentexcretion of these pro- ally unavoidable disease seems to be a high teinsconjugated to dietarytoxins. The excre- price to pay forthe tenuous benefitsobtained tory/secretoryproducts of the helminth Brugia bymounting IgE responsesto helminths.Thus, pahangi,for example, include host serum albu- the high costs and dubious benefitsof allergic min(Maizels etal., 1985);in one study,a third responses to helminths,coupled with the fact ofhelminth excretory/secretory products con- thatthe vast majorityof allergies have nothing sistedof host serum albumin (MacKenzie et to do withhelminth infections, imply that the al., 1986). Dietarytoxins that become con- functionof allergy is not to protectagainst hel- jugated to excreted/secretedworm proteins minths. could also triggerIgE responsesto theworm An alternativehypothesis to explain thehigh proteins.If sequestereddietary toxins are the levels ofIgE antibodies surroundinghelminth allergensin helminth infections, then perhaps infectionsis thathelminths release toxins into IgE-mediatedinflammation could be partially the host's tissues and bloodstream, and it is alleviatedby eliminatingfrom the diet those these toxins,rather than the helminthsthem- foodsthat contain the toxinsmost often se- selves,that IgE antibodies target.The IgE re- questeredby the helminths. (The relationship sponses to helminthinfections are usually to betweenallergies to helminth excretions/secre- substances excretedor secretedby the worms. tionsand allergiesto foodsamong helminth- IgE antibodies targetthe excretory/secretory infestedindividuals is unknown.)

Helminths may even manipulate the host's opted certain of these mechanisms to expel machinery of allergy for their own ends by helminths. If so, one might expect to find releasing toxins that elicit allergic responses. separatesubpopulations of mast cells, basophils, For example, Mitchell (1979) has hypothesized and, possibly,IgE antibodies, involvedin de- thathelminths may deliberatelytrigger allergy fending against the two classes of antigens, in order to feed on the nutritiousserum pro- so that the dangerous chemicals that are im- teinsthat accumulate in theresulting inflamed portantonly fordefense against toxins would tissues. More speculatively,helminths may se- not be released duringhelminth infections. In crete toxins as decoys that divertthe immune particular,whereas mast cells specialized to de- system'seosinophils and basophils fromattack- fend against toxins should be selected to con- ing helminthsto attacking allergens. Eosino- tain high concentrationsof chemicals, such as phils and basophils are granule-containing histamine,that can lowerblood pressure,mast white blood cells (leukocytes) in vertebrate cells specialized to defend against helminths blood and connectivetissue that possess spe- should not. Mast cells and basophils do display cificreceptors for IgE and IgG antibodies and heterogeneity(Cohan et al., 1989): rodents,for thatare activein immune responsesto various example, have two types of mast cells, which antigens, including common allergens, hel- appear to differin morphology,biochemistry, minths, and possibly certain tumors (Gleich and function(Irani and Schwartz, 1989). All and Adolphson, 1986). During an allergic re- mast cells so far studied contain substantial sponse,chemicals released from mast cells sum- amounts of histamine, although the amount mon eosinophils to the site of the allergen, can vary dramatically among differenttypes where IgE antibodies cause them to degranu- of mast cells in differentlocations in the body late and release various enzymes, toxic pro- (Barrettand Metcalfe, 1987). In ratsand mon- teins,and othersubstances (Gleich and Adolph- keys,for example, thehistamine content is sig- son, 1986). nificantlylower (by 30-foldin rats) in mast cells As mobilechemical arsenals, eosinophils and of the intestinesthan in those of the lungs or basophils probablyevolved multiple defensive peritoneum(Barrett and Metcalfe,1987). Since functions,perhaps includingthe chemical de- helminthsare farmore likelyto parasitize the structionof both allergens and helminths(al- intestinesthan any otherpart of the body, the thoughthe typeof eosinophil thatcombats al- substantiallyreduced histaminecontent of the lergensmay differfrom the typethat combats intestinalmast cell may be evidence of special- helminths). Eosinophils and basophils may ization for helminthinfections; on the other help to destroyor neutralize toxic allergensby hand, the intestinalmast cell may contain re- releasing enzymes that detoxifythem (Just duced levels of histamine in order to prevent as neutrophils, related leukocytes, release anaphylactic reactions to dietary toxins re- enzymes during bacterial infectionsthat de- leased by helminthsinto the bloodstream. In- toxify toxic bacterial lipopolysaccharides- testinalmast cells ofrats and monkeyscontain Munfordand Hall, 1986). During helminthin- little or no heparin, in contrastto lung mast fections,however, the eosinophils and basophils cells (Barrettand Metcalfe, 1987). Heparin is thattravel to the siteof infection appear to help an anticoagulant which is effectivein inhibit- combat helminths by secreting various pro- ing the procoagulant activitiesof some of the teins, some of which are toxic to certain spe- many toxic enzymes in snake and insect cies ofhelminth (Gleich and Adolphson, 1986). venoms (Higginbotham and Karnella, 1971; It is possible that helminthsare able to divert Joshua and Ishay, 1973; Teng and Ko, 1988; thefocus of eosinophilic attack from themselves Melo and Suarez-Kurtz, 1988; Williams and to allergens by releasing allergenic toxins de- White, 1989). Heparin's presencein mostmast rived from the host's diet. cells may thereforehave evolvedpartly as a de- Comparing allergiesand helminth-induced fenseagainst venoms. Its absence in intestinal IgE responses leads one to speculate that IgE mast cells may promote defense against hel- antibodies may have two separate defensive minths(since heparininhibits the killing of hel- functions:one against toxins,the other against minths by toxic eosinophil proteins, such as helminths.After the basic mechanisms of al- major basic protein and eosinophil cationic lergyevolved, natural selection may have co- protein- Hamann et al., 1990) or minimizethe

This content downloaded from 141.218.001.105 on August 06, 2016 07:56:10 AM All use subject to University of Chicago Press Terms and Conditions (http://www.journals.uchicago.edu/t-and-c). 44 THE QUARTERLY REVIEW OF BIOLOGY VOLUME 66 damagecaused by allergic responses to dietary bly associatedwith their sources, which are toxinsreleased by helminths. conspicuousentities that mammals can usu- As yet,there is no evidencefor differences allyavoid. Contact allergens (which elicit T-cell- in thetypes of mast cells that are triggeredin mediatedallergy) are often unidentifiable (and helminthinfections and allergicresponses that thusoften unavoidable) because thedelay in occurin thesame part of the body, nor for the developingthe allergic response weakens the existenceof distinct subpopulations of IgE an- associationbetween the response and its source; tibodies. In general,however, immune re- however,contact allergy is veryrarely life- sponsesto helminthsdo differfrom immune threatening.Similarly, inhaled allergens, al- responsesto allergens; for example, neutrophils thoughto some extent avoidable (by relocation), are importantcomponents in the defense areless avoidable than ingested or injectedal- againsthelminths (Horii etal., 1988),whereas lergens,but are also muchless likely than in- neutrophilsare notsignificant in allergy(and gestedor injectedallergens to be life-threat- evenlack receptors for IgE antibodies-Walsh ening(perhaps because relatively small amounts and Kay, 1986).Although it is extremelyun- ofinhaled allergen reach the bloodstream). Al- likelythat allergy originally evolved to protect lergensin a naturalenvironment that elicit againsthelminths, it is possiblethat some of potentiallylife-threatening IgE-mediated re- themechanisms of the allergicresponse may sponses are almost alwaysidentifiable and have been co-optedor altered for defense avoidable. againsthelminths. By contrast,mammals usually cannot per- ceiveand avoidspecific viruses, bacteria, and AllergyMimics otherpathogens: since a pathogenis notpro- Trueallergies -which are immunologically duced by the sourcesin whichit is found,it mediated- shouldbe distinguishedfrom phys- is lesslikely to be reliablyassociated with any iologicalintolerances whose symptoms mimic particularsource. Furthermore, pathogens, un- allergies.Various symptoms of foodintoler- liketoxins, generally replicate inside their hosts, ance,for example, may result, not from allergy, and consequentlyparasitize their hosts for in- butfrom a toxiceffect of a substance,or from definiteperiods of time. A hostthat is exposed a protectivebut nonimmunologicalresponse on one occasionto a particularpathogen may to a toxicsubstance, or froman inabilityto ef- becomeexposed to thatpathogen chronically. ficientlydigest a substance(e.g., lactose in Thus,IgE responsesto pathogens could be ex- milk).Some plantsand insectseven provoke ceedinglydangerous and, therefore,would be symptomsthat mimic allergies by releasing selectivelydisadvantageous. With the excep- histamineinto theirpredators and victims tionof helminths, which may manipulate the (Richmanand Baer, 1986; Moneret-Vautrin, host'smachinery of allergy, pathogens gener- 1987).Moreover, since the machinery of allergy ally do not triggerimmediate-type allergies. is ancient,it wouldbe surprisingif some or- Bacteria,however, do producetoxins. Be- ganismshad notevolved counterstrategies to causebacteria colonize mammalian intestines, exploitthe dangers inherent in this machinery. mammalsare chronicallyexposed to at least Indeed,cobra venom contains a chemicalthat lowlevels of bacterial toxins. Over thecourse triggersmast-cell degranulation independently ofmammalian evolution toxin-producing bac- of IgE antibodies(Morrison et al., 1975). teriaprobably parasitized every individual that livedlong enough to reproduce.Mammalian ALLERGENS ARE USUALLY AVOIDABLE immune systemstherefore evolved mecha- BecauseIgE-mediated (immediate-type) al- nismsother than IgE antibodiesto cope with lergicresponses entail potentially serious risks, bacterialtoxins, mechanisms that take into ac- reexposureto allergenscan be dangerous.Se- countthe unavoidability and chronicity ofthese lectiontherefore would be expectedto favor the toxins.Helminths, unlike other pathogens, fre- mountingof IgE responsesprimarily to avoid- quentlyinduce the formation of IgE antibod- able toxins,hence the avoidability of allergens ies;but if the sources of helminth allergens are shouldbe an essentialaspect of any adapta- planttoxins ingested by the host, then helminth tionistaccount of allergy.Plant and insect toxins are indistinguishablefrom dietary toxins- commonallergens - tendto be relia- toxins,and theimmune system is "tricked"into

responding to an unavoidable and chronic ALLERGIES ARE MORE PREVALENT pathogenas ifit were an avoidable plant toxin. IN INDUSTRIAL SOCIETIES The immune systemappears to have evolved Many people in industrial societies suffer mechanisms to determinewhether a particu- fromallergies; epidemiologists' estimates of the lar toxin is avoidable, by using chronicityof prevalence of respiratoryallergy alone range exposure as a sign ofunavoidability, and to re- from5 to 27 percent(Weeke, 1987). Although duce the proliferationof IgE antibodies to theliterature on allergyamong preliteratepeo- unavoidable toxins. In chronic human aller- ples is sparse, allergy is generallythought to gies, the levels of the subclass IgG4 antibody occur substantiallymore frequentlyin indus- oftenrise; IgG4 antibodies compete with IgE trial than in preliteratesocieties (Black, 1980; antibodies in binding to allergens (Urbanek, Weeke, 1987). The incidence and prevalence 1988). (In certainnonhuman mammals other of allergy in industrial societies is therefore subclasses ofIgG antibodiesfunction similarly most likelya highlyskewed representationof to the TgG4 subclass in humans - Mota, 1986). the incidence and prevalence of allergy Afterprolonged exposures to an allergen,lev- throughout most of human evolutionary els of IgG4 antibodies often surpass those of history. IgE (Shakib, 1986). In chronichelminth infec- One cause of the increased incidence and tions, forexample, IgG4 levels rise markedly, prevalenceof allergy in industrialsocieties may whereas in earlyor acute infestationsIgG4 lev- be the dramatic reduction of breast-feeding els are low (Catty et al., 1986). One ofthe func- (women in hunter-gatherersocieties typically tions of IgG4 antibodies may be to block the breast-feed their children for at least three production of dangerous IgE antibodies to years). Various studies have found that the chronicallyencountered toxins. breast-feedingof infantscorrelates negatively IgG4 "blocking" antibodies are generally withthe incidence of allergy in infantsand chil- thoughtto account forthe success of desensitiz- dren (Saarinen et al., 1979; Chandra, 1979), ing innoculationsagainst pollen and venom al- but other studies have found no such correla- lergies:low levelsof allergenic extracts injected tion (Fergusson et al., 1981;Van Asperen et al., at regular intervals over a prolonged period 1984). [Van Asperen et al. (1984) reviewmany cause IgG4 levelsto risedramatically and block studies on the relationship between breast- the access of IgE antibodies to the allergens feedingand allergy.]Frick (1987) emphasizes (Nakagawa, 1986; Stanworth,1986). The pro- that preventingthe developmentof allergyin tective effectsof IgG4 antibodies have been infantsmay requireexclusive breast-feeding for demonstratedin the cases ofpollen, dust-mite, at least six months. Breast-feedingcould sup- and bee-venomallergies (Aalberse et al., 1983; pressthe developmentof allergies if the mater- Nakagawa, 1986; Stanworth,1986). This pro- nal IgA antibodies(which bind to and neutral- longed artificialimmunization with allergens ize antigensin thegastrointestinal tract without mimics chronicnatural exposure to allergens. inflamingthe surrounding tissues) in colostrum Through periodicdesensitizing injections of al- and breast milk compete withthe infant'sIgE lergenic extracts, the immune system may antibodies, therebypreventing ingested anti- be "tricked"into recognizing the allergens as gens fromstimulating excessive production of chronicand, therefore,as unavoidable. (If the IgE antibodies (Frick, 1987). If allergy and purpose ofIgG4 blocking antibodies is to pre- breast-feedingare negativelycorrelated, then ventsevere allergic responses to chronic aller- many allergicpeople in industrialsocieties can gens, then IgG4 antibodies should rise only be expected to produce an unnaturally high in response to riskylevels of allergen. Individ- and non-optimal level of IgE antibodies. uals with chronicallergies to pollen and other Respiratoryallergies, such as those to pol- inhaled allergensmay not develop IgG4 block- len, are very common in industrial societies ing antibodies spontaneouslyif the level of al- (comparativedata on hunter-gatherersocieties lergenthat reaches the bloodstreamas a result are not available). In addition to infantfeed- of inhalation is much lowerthan the level that ing practices,various factors,such as viral re- would reach the bloodstream as a result of spiratoryinfections, may increase the risk of desensitizing innoculations.) developing respiratoryallergies. Various re-

searchershave noted thatthe onset of respira- other hand, are exposed to many hidden in- toryallergies in childrencorrelates with the on- gredients in their foods (e.g., fish oil in ice set ofrespiratory infections (Frick, 1987; Busse, cream),which are introducedduring manufac- 1989). In an experimentdesigned to investigate turingor preservingprocesses (Radcliffe, 1987) this relationship, Frick and Brooks (1983) and which are not easily identifiableby sight, foundthat puppies injectedat regularintervals scent,or taste. Furthermore,an allergen may withboth pollen extractsand live viralvaccines be a common constituentof many processed mounted significantlygreater IgE responsesto foods and not easily avoidable; wheat, forex- the pollen than did puppies injected only with ample, which is a fairlycommon allergen, is pollen extracts.Most childrenin industrialso- an ingredientin many breads, cereals, pastas, cieties come into contact with large numbers crackers,and otherfoods. Skin allergies often ofpeople fromwhom theycatch numerous re- result from prolonged daily contact with spiratoryinfections; by contrast,children in substances- such as detergents,soaps, sham- hunter-gatherersocieties come into contact poos, and occupational chemicalsthat are withmany fewerpeople and thus are probably widely used in industrial societies but not in less likelyto sufferfrom a continuous series of hunter-gatherersocieties. Most skin-careprod- viral respiratoryinfections. Viral infections ucts contain an assortmentof potential aller- mightconceivably increase susceptibilityto al- gens, and it is oftenvery difficult to pinpoint lergysimply by augmentingthe numbers of cir- the specificallergenic constituents of allergenic culating T cells and B cells that are available products. to respondto allergens.Air pollutionmight also The environmentsin which thehuman ma- exacerbate allergyto airborne allergens, such chineryof allergy was shaped by natural selec- as pollen (Miyamoto et al., 1988). For exam- tiondiffer considerably from modern industrial ple, in experimentsdesigned to investigatepos- environments.Ancestral humans probablyde- sible causes forthe dramatic increase in pollen veloped allergies from time to time to sub- allergyinJapan since the 1950s, Miyamoto et stances that were generally identifiable and al. (1988) foundthat mice injectedwith a com- avoidable,whereas humans in industrialsociet- bination of diesel exhaust particlesand either ies oftensuffer chronically from allergies to sub- ovalbuminor cedar pollen produced significant stances that cannot be easily identifiedor, for levelsof anti-ovalbumin IgE or anti-cedarIgE, reasons related to occupation or hygiene,can- whereas mice injected with ovalbumin or ce- notbe avoided.(Similarly, wild mammals prob- dar pollen alone produced verylow levels of ably sufferfewer allergies than theirdomestic IgE. counterpartsdo.) Although theyare in many Respiratoryallergies to other airborne an- respects evolutionarilynovel, industrial en- tigens,such as dust mites, are probably much vironmentsoften constitute excellent testing more common among people in industrialso- grounds foradaptationist hypotheses because cieties,who establishfairly permanent homes, the patternspredicted by such hypothesesmay than they are among hunter-gatherers,who be manifested in an exaggerated fashion in lack the household materials,such as blankets these environments;for example, the mecha- and carpets, that collect dust and provide nisms that underpin the human cravings for breedinggrounds for dust mites. Furthermore, sugar, fat, and salt are manifestedmore dra- by resettlingfrequently, hunter-gatherers avoid maticallyin modernfast-food cuisine than they continual exposure to at least some of the air- are in hunter-gatherercuisine (Symons, in borne allergens of any particular locality. press). An appropriatetest of the toxin hypoth- The difficultyof identifying and avoidingthe esis is not whethera particularallergy is adap- allergenicculprits in foodsand skin-careprod- tivein an evolutionarilynovel industrialenvi- ucts has undoubtedly exacerbated the inci- ronment but, rather, whether the allergy dence and prevalence of allergy in industrial conformsto the patternpredicted by this hy- societies. A hunter-gathererwho experiences pothesis (which is based on specific assump- an immediate allergic reaction to a fruit,veg- tions about the selection pressures that op- etable, or fish,for example, can fairlyreliably erated in the environment of evolutionary identifythe offendingfood and avoid it in the adaptedness) (Symons, pers. commun.). future.People in industrial societies, on the

ALLERGY IS EXPECTED TO BE bodies depends on a multitude of factors,ac- HIGHLY VARIABLE AMONG INDIVIDUALS countingfor much ofthe variability of allergies. One ofallergy's most salient characteristics Because allergies stem fromso many factors is itsapparent capriciousness. Allergy should thatare not readilyapparent to the allergicin- be expectedto be highlyvariable among indi- dividual or to investigators'ofallergy, allergies viduals,however, since, according to the toxin may appear capricious even though theyusu- hypothesis,it was designedby naturalselec- allyrepresent responses to definitetoxic threats. tionto function as a lastline of defense against toxins,and thereforeto respondto the variabil- ALLERGY-CANCER CORRELATIONS ityin individual phenotypes and environments. Althoughallergy is not specificallydesigned Individualdifferences in theoccurrence of al- to preventcancer, it may help to do so by ex- lergiesarise fromindividual differences in pelling or destroyingmutagenic and carcino- geneticpredispostion to allergy;exposure to genictoxins. At least 22 epidemiologicalstudies particulartoxins; effectiveness ofprimary de- have measured the correlation between defensesagainst toxins, including such factors as velopingallergy and developingcancer. [Most quantityand typeof detoxificationenzymes of these studies are reviewed by Vena et al. and permeabilityof epithelial surfaces to toxic (1985); studies not in Vena et al. include Al- antigens;and lifehistory (e.g., whether or not legra et al. (1976), Hallgren et al. (1981), an individualwas breast-fed). Moussa et al. (1985), McDuffie et al. (1988), Geneticdifferences account for some of the and McWhorter (1988).] Of the 22 studies, 16 individualvariation in allergy,and individu- found a negative correlationbetween allergy als who are especiallysusceptible to allergies and cancer (i.e., individuals with a historyof oftenhave family histories of allergy.Inheri- allergy were less likely to develop cancer), 3 tanceof particularalleles of the major histo- found no correlation,and 3 found a positive compatibilityregion of the genome predisposes correlation.Clear relationshipsbetween types individualsto certainallergies (de Wecket al., ofallergy and typesof cancer, however, cannot 1977). be abstractedfrom these heterogeneous studies: The degreeof susceptibility to a particular some ofthe studies analysed only a small sub- toxindepends largely on theavailability of en- set of cancer types; many did not control for zymescapable of detoxifyingthat toxin. "All smoking, age, and sex; and most did not theseenzymes differ in quantity,subcellular differentiateallergy fromnon-IgE-mediated localizationand sometimesalso in substrate allergy-likesymptoms (asthma and hives, for specificitybetween organs, development stages, example, are usually regarded in the medical sexesand species.They therefore represent an literatureas havingboth allergicand nonaller- importantcontributing factor to differences in gic etiologies).Although the preponderance of susceptibilities[to toxinsand carcinogens]" studies reportingan inverse relationship be- (Oesch, 1987:174).The setof genes coding for tween allergy and cancer may appear to sup- detoxificationenzymes exhibits an unusually port the toxin hypothesis,such correlational highdegree of polymorphism(Meyer et al., studies should be interpretedcautiously. 1988;Johnson et al., 1988),and susceptibility Among the studies that found a negative to certainallergies is in parta functionof en- correlationare thefollowing: Vena et al. (1985), zyme phenotype(Brostoff, 1987). Further- in a retrospectivestudy of 13,665 cancer pa- more,because each individual has a uniquedi- tientsand 4079 controlsmatched forage and etary and environmentalhistory, each has sex, found that men with a historyof allergy induceddifferent levels of enzymes. Since en- had a lowerrisk of cancers ofthe mouth, lung, zymeinduction significantly influences suscep- larynx,digestive system, urinary system, and tibilityto toxins, it probably also influences sus- of all sites combined, and that women had a ceptibilityto allergy. lower risk of cancers of the digestive and The immunesystem must be able tomount reproductivesystems -particularly cancers of IgE responsesto an immensearray of toxins thecervix-and ofall sitescombined. Hallgren and carrierproteins. Which toxins will succeed et al. (1981), in a studyof 217 bronchial carci- inpermeating epithelial tissues, evading detox- noma patients and 389 noncancer controls, ificationenzymes, and stimulatingIgE anti- reportedan incidence of allergy5 timeshigher

among the controls.Cockroft et al. (1979), in toms of allergy are acute or chronic. Allergy a studyof 392 cancerpatients and 303 controls, inflames tissues, and chronic allergies do so foundthat allergiesoccurred more than twice chronically.Chronic inflammationfrom any as oftenin controlsas in patientswith cancers cause is a riskfactor for cancer because itleads of endodermal origin, such as cancers of the to chronic cell proliferationand the produc- lungs and digestivetract, tissues that are heav- tion ofoxygen radicals, both ofwhich promote ilyexposed to carcinogens.Ure (1969),in a study carcinogenesis(Ames, 1989). Chronic allergies of 140 patientsof a gynecologicalward, found may increasethe riskof cancer even ifsporadic that the women who sufferedfrom hay-fever- allergies lower the risk. type allergies (20%) and the women who suf- Furtherepidemiological and experimental feredfrom malignancies (28%) constitutedmu- studiesto determinethe relationships between tuallyexclusive groups. By contrast,McWhorter toxins,particular types of allergy,and partic- (1988), in a follow-upstudy of 6108 people sur- ular typesof cancer mightshed lighton theeti- veyedbefore 1976, found thatpeople who had ology ofcertain cancers. For example, it is pos- been diagnosed as havingallergies had a higher sible thatthe (apparently)higher incidences of riskof cancer; a historyof hives was a particu- gynecologicalcancers in women withoutaller- lar risk factor for lymphatic-hematopoietic gies resultfrom higher concentrations of toxin cancers. that have been circulated to the highlyvascu- The authorsof most of the studiesthat found larized uterinelining or deposited in the cer- negativecorrelations cautiously suggest that al- vix during menstrual shedding of the uterine lergymay protectagainst cancer. Rosenbaum lining. Most human cancers arise fromepithe- and Dwyer (1977) even propose that IgE anti- lial tissues,such as the gutlining, skin or lungs bodies and the pharmacological substances (Wrightand Alison, 1984), which are heavily released duringallergic responses may directly exposed to environmental carcinogens and promote tumor resistance. A key question in whichare lined bymast cells and IgE antibod- interpretingallergy-cancer correlations, how- ies. By targetingcovalently binding toxins, IgE ever,is whethera particularallergy occurs be- antibodies may help to protect these tissues cause the individual has heightened allergic fromcarcinogenic transformation. capability,heightened exposure to a particular toxin,or heightenedsusceptibility to a par- ticulartoxin. The toxinhypothesis would pre- THE TOXIN HYPOTHESIS, BUT NOT THE dict a negativecorrelation between allergy and HELMINTH HYPOTHESIS, ACCOUNTS FOR THE cancer only if the variabilityin allergy repre- MAIN PHENOMENA OF ALLERGY sentedvariability in the immunologicalcapac- If allergy had evolved primarilyto protect ity to target and eliminate toxins. As Ewald againsthelminths, it would representastonish- (pers. commun.) has pointed out, positive inglypoor design by natural selection.(As dis- correlationsbetween allergy and cancer would cussed above, however,it is possible thatsome be expected ifpeople withallergies simply had of the mechanisms of allergy have been co- less effectiveprimary detoxificationmecha- opted or alteredfor defense against helminths.) nisms or were exposed to higherdoses oftoxins To support this assertion, 12 phenomena that than people without allergies. a successfultheory of allergy should account Furthermore,the fact that allergy-cancer forwill be discussed. These phenomena con- correlations have been determined only in stitutethe most distinctive or puzzling features evolutionarilynovel industrial environments ofallergy. Some ofthe phenomena are ofmore creates additional problems ofinterpretation. concernin one partof the allergy literature than As a hypotheticalexample, ifnot being breast- in other parts; forexample, covalent binding fed turned out to be a risk factorfor cancer, is discussed widelyin theliterature on drug al- thena positivecorrelation between allergy and lergybut not in theliterature on pollen allergy. cancer would not necessarilyindicate a causal The first4 phenomena can be accounted for connection, since not being breast-fedis ap- both by the toxin hypothesis(TH) and by the parentlya riskfactor for allergy (Symons, pers. helminthhypothesis (HH); the remaining 8, commun.). Moreover, the effectof allergyon however,can be accounted foronly by the toxin cancer riskmay depend on whetherthe symp- hypothesis.

PhenomenaExplained Both by the Toxin TH: Helminth excretions and secretions, Hypothesisand bythe Helminth Hypothesis which are the primarytargets of IgE anti- likely (1) The manifestationsof allergy include vomit- bodies duringhelminth infections, are host's ing, diarrhea,coughing, sneezing, scratching, to contain toxins absorbed fromthe the and tearing. diet; it is these toxins that are probably out, TH: These manifestationsare means ofrap- allergens.As Mitchell(1979) has pointed the host's idly expelling dangerous toxinsbefore they helminthsmay even manipulate in- reach target organs. machineryof allergyin order to feed on flamed host tissues. HH: A similar argument could be made: some ofthese manifestations could be means HH: IgE antibodiesare induced to helminth of expelling helminths. Platts-Mills (1987) excretionsand secretionsin order to com- notesthat coughing might dislodge helminth bat the helminths. larvae fromthe respiratorytract and diarrhea mighthinder helminths from penetrat- PhenomenaExplained Only by ing the gatrointestinaltract. theToxin Hypothesis in a strong allergic (2) Chronic allergies are frequentlyaccompa- (5) Blood pressure drops nied by high levels of IgG4 "blocking" anti- response. bodies. Accordingto the toxinhypothesis, the drop the TH: Chronicityof exposure to a particular in blood pressure, which is caused by allergensignifies to the immune systemthat histamine released from mast cells and at which the allergen is unavoidable. IgG4 antibod- basophils,functions to slowthe rate ies accompany chronic allergies in order to toxins are circulated to target organs. block IgE antibodies and protect against The helminthhypothesis literature does not anaphylactic shock caused by unavoidable confrontthis issue. allergens. (6) Anticoagulants are released during an al- HH: A similar argument could be made: lergic response. is an anticoagulant. Many snake IgG4 antibodies appear to partially block Heparin venoms containenzymes that are IgE responsesto helminthsin chronicinfec- and insect because of their coagulant properties tions (Hussain and Ottesen, 1985; 1986). toxic et al., 1989; Williams and White, Jassimet al. (1987) and Hussain and Ottesen (Yarleque Heparin inhibits many of the (1988) have pointed out that high levels of 1989). and certain other toxins of IgG4 antibodiesmay inhibitpotentially dan- procoagulants snake and insectvenom (Higginbothamand gerous IgE responses to helminths. One 1971;Sun and Walker,1986; Teng might reasonably ask, however,why natu- Karnella, and Karnella ral selectionwould have designed IgE anti- and Ko, 1988). Higginbotham suggestthat mast cellsof the skin, bodies to defend against a pathogen that is (1971)even amounts ofhepa- so oftenchronic. which contain significant rin, may be uniquely adapted for defense (3) Eosinophilshave receptorsfor IgE antibod- against bee venom. Heparin therapyfor the ies and degranulateduring an allergicresponse. treatmentof bites by the Russell's viper, a TH: Eosinophils are mobile chemical wea- snake whose venom kills more than 1000 ponriesthat probably have multipledefense people in Burma everyyear, is currentlyun- functions,perhaps includingboth the enzy- dergoingexperimental trials (Than-Than et matic detoxificationof toxins and the de- al., 1988). structionof helminths. Since heparin also inhibits certain eosino- HH: The functionof eosinophil degranula- phil proteinsthat are toxic to helminths,in- tion in IgE responses is the destructionof cluding major basic proteinand eosinophil helminths(even though most allergens are cationic protein(Hamann et al., 1990) and, not helminths). to some extent, eosinophil-derived neu- helminth (4) Helminth infectionsoften induce IgE anti- rotoxin(Molina et al., 1988), the bodies. hypthesiscannot account forthe release of

heparinduring allergic responses. Intestinal may need to be augmented (particularlyif mastcells, unlike mast cells of the lungs, for the riskfrom the toxinis cumulative). That example,have little or no heparin(Barrett the severityof an allergic response tends to and Metcalfe,1987); since helminthspri- increasewith repeated exposures implies that marilyparasitize the intestines,selection allergens are avoidable; and most toxin- mayhave reduced the heparin content of in- containingsubstances are, indeed, avoidable testinalmast cells so thathelminth infections (e.g., mammals can modifytheir behavior wouldnot cause the release of this potentially to avoid disturbingvenomous bees or ingest- dangerouschemical and so thateosinophil ing particular allergenic plants). defensesagainst helminths would not be thwarted. This phenomenon is incompatiblewith the (7) Covalentbinding of low-molecular-weight helminthhypothesis. A mechanismdesigned substances(haptens) to carrierproteins fre- to produce an increasingly dangerous re- quentlytriggers allergy. sponse to each successive contact with a Covalentbinding of haptens to proteins sig- pathogen that is usually unavoidable and nifiestoxicity and potentialDNA damage chronic, as helminthsare, makes no adap- and, thus,is expectedto triggerallergy. tive sense. [Africanchildren with helminth infectionssometimes die suddenly-appar- The helminthhypothesis literature does not ently due to anaphylactic shock caused by confrontthis issue. IgE responses to the worms (Ogilvie and Jones, 1973).] (8) IgE-mediatedallergy is risky(potentially lethal). The dangerof IgE-mediated responses im- (10) Allergies occur to many foods, pollens, plies thatallergy was designedto counter venoms, metals, and drugs. threats,such as toxins,that can cause seri- The toxinhypothesis easily accounts forthe ous harmwithin minutes of entering the cir- allergenicityof plant foods,pollens, venoms, culation. metals, and drugs: these substances either contain toxins or are toxic. Immuneresponses to nonhelminthpatho- gens,such as virusesand bacteria, are rarely Some proponentsof the helminthhypothe- as riskyas IgE-mediatedresponses. Since sis have accounted forIgE responsivenessto helminths,like other pathogens, do notseri- the thousands of nonhelminth allergenic ouslyharm theirhosts within minutes of substances by the followingline of reason- parasitizingthem, the risk entailed by IgE ing. (1) Allergies to these substances are responsesto themseems dysfunctional. Of merelyby-products of modernization. (2) In themyriad dangerous pathogens, why would preindustrialenvironments, widespread al- helminthsalone requiresuch urgency and lergies to nonhelminthantigens would not risk?This questionhas notbeen addressed have occurredbecause antihelminthIgE an- by proponentsof the helminth hypothesis. tibodies would have saturated all available (9) Symptomsof allergicresponses often be- mast cells, leaving no mast cells freeto bind comemore severe with repeated exposures to IgE antibodiesspecific for nonhelminth anti- an allergen. gens. (3) In industrial environments,how- This phenomenonis compatiblewith the ever,where helminth infections are compar- toxinhypothesis: the risk from multiple ex- ativelyrare, IgE antibodies lack helminths posuresto a toxinis sometimescumulative to bind and so instead bind innocuous tar- and,thus, the severity of the response to the gets,such as pollen and food proteins(God- toxinmight reasonably be expectedto in- frey,1975). (Of course,this line ofreasoning creasewith subsequent exposures; in addi- tendsto underminethe helminth hypothesis: tion, the initialallergic response may be IgE antibodiesand mastcells are permanent- suboptimal,as is oftenthe case withother ly at war with helminthsprecisely because immuneresponses; and it is also possible that theyare not effectivein expellinghelminths.) thedeterrent effect of the allergic response Substantial evidence; however,is inconsis-

tentwith the above account. Many helminth- The apparent capriciousness of allergy is infestedindividuals mount strong IgE re- perhaps the biggest stumblingblock to the sponses to nonhelminthantigens (Teo et al., acceptance of any adaptationist account of 1985), although not necessarilyto the same allergy.The toxinhypothesis, however, leads antigensthat are commonlyencountered by to the expectation of wide variabilityin al- individuals at higher socioeconomical lev- lergyamong individualsand populationsbe- els (Lynch, DiPrisco-Fuenmayor,and Soto, cause, as discussed above (p. 47) allergy is 1983; Lynch, Lopez, Isturiz, and Tenias- a last line of defense,rather than a primary Salazar, 1983). Among nativesof the south- defense, against toxins. ern maldives, forexample, high IgE levels caused by helminthinfections do not pre- The helminthhypothesis cannot account for vent asthma, which is common (Wolsten- the variabilityof the IgE response to any al- holme, 1979). Among South Africans,in- lergen, including helminths. dividuals withhigh levels of IgE antibodies (12) Allergiccross-reactivity occurs among cer- to helminthshave higher levels of IgE to tain foods and pollen fromunrelated botani- common inhaled allergensthan do individ- cal families. uals without IgE antibodies to helminths According to the toxin hypothesis,cross- (Joubert et al., 1980). Among children of reactivityoccurs because certain unrelated Caracas, Venezuela, thereis a veryhigh in- plants contain the same toxins. cidence of allergy,even though many of the allergic children have helminth infections The helminthhypothesis cannot account for (Lynch and DiPrisco-Fuenmayor, 1984). allergiccross-reactivity to plants(or, indeed, The Waorani Indians of eastern Ecuador, for any allergic reactivityto plants). who have veryhigh IgE levels and high inci- In summary,the helminth hypothesis suffers dences ofhelminth infection, can be readily fromsevere limitations: it cannot account for sensitizedto pollen allergens(Larrick et al., most of the salient phenomena of allergy,and 1983). In rats,high IgE levelsresulting from the evidence that allergieshelp to combat hel- helminthsdo not appreciablyprotect against minthinfections is tenuous. The toxinhypoth- other allergies (Jarret and MacKenzie, esis, by contrast,accounts foror is compatible 1980), except in the case of rats bred to be with all of the salient phenomena of allergy. low IgE-responders (Turner et al., 1985). Furthermore,whether human populations UNDERSTANDING THE FUNCTION OF ALLERGY manifestlow or high prevalence of allergy MAY FACILITATE THE PREVENTION, depends, in general,on whetherthey are ru- DIAGNOSIS, AND TREATMENT OF ALLERGIES ral or urban, not on whetherhelminth in- fectionsare presentor absent (Lynch et al., Understandingthe relationshipbetween al- 1984). lergiesand toxinsmay lead to novelapproaches to the prevention,diagnosis, and treatmentof Proponentsof the helminthhypothesis have allergy. The development of food allergies noted thata large percentage ofthe IgE an- mightbe preventedor mitigated,for example, tibodiesproduced in helminthinfections ap- by cooking foods sufficientlyto degrade their pear to be "irrelevant" i.e., not specificfor toxic constituents,or by diversifyingthe diet helminthantigens (Turner et al., 1982). The to preventexcessive exposure to any particu- IgE antibodiessynthesized during helminth lar toxinand to induce detoxificationenzymes infections,however, may not be designed to to a wide varietyof toxins. counterworm antigens at all but, rather,to The diagnosis of allergy, which includes countertoxins that helminths sequester from isolating and identifyingallergens, might be thehost's diet and thenrelease into the blood- aided by focusingon toxins and their carrier stream,often conjugated to thehost's serum proteinsin allergenicsubstances; the treatment albumin. The supposedly "irrelevant"IgE ofallergy, in turn,would benefitfrom more ac- antibodies may, therefore,have been ap- curatediagnoses. Conventionaldesensitization propriatelyinduced to toxins. immunotherapy,for example, might be im- (11) Allergy appears to be capricious. provedif the identificationof specificallergens

facilitatedthe development of purer allergenic chineryof allergy; or (3) a maladaptive, side- extracts.Treatments to prevent or mitigate al- effectresponse to an innocuous substancethat lergicattacks might include the use ofspecific benefitsneither the allergy sufferer nor a toxin- detoxificationand digestiveenzymes to de- producing organism. Allergic responses that gradeparticular allergens. Individuals with re- representmanipulations and maladaptive side spiratoryallergies, for example, might use in- effectsmay be safelysuppressed, but non-life- halants containingenzymes that degrade threateningand non-debilitatingallergic re- particularpollen toxinsor pollen proteins, sponses to toxinsmay be betterleft untreated. whileindividuals with food allergies might in- As Rosenbaum and Dwyer (1977:17)have writ- gesttablets containing enzymes that degrade ten, "the somewhat disreputable IgE may yet particularfood toxins or foodproteins. Vari- make the list of immunobiological heroes." ous researchershave notedthat the presence of digestiveenzymes can mitigateallergy by ACKNOWLEDGMENTS degradingspecific allergens, such as cows'milk Many peoplehelped in someway with revisions proteins(Stanworth, 1985; Knikerand Rod- of this paper. Above all, I am indebtedto Don riguez,1987; Spragueand Milam, 1987). Symons,whose generous contributions are woven Ewald's(1980) evolution-minded guidelines throughoutthe paper; his tremendous help in edit- forthe treatment of infectious diseases may also ing thepaper, elucidating many of theideas, and be of use in decidingwhether or not to sup- keepingmy spirits up is greatlyappreciated. I would pressan allergicresponse; see also Williams also liketo thankPaul Ewald,Maryellen Ruvolo, and GeorgeWilliams for many excellent comments and Nesse (1991,Table 2). This decisionwill and suggestions.And I wouldlike to thankthe fol- depend upon whetherthe allergicresponse lowingpeople for helpful discussions, criticisms, or represents(1) an adaptationto defend against references:Bruce Ames, Samuel Freedman,Balz a toxin;(2) an adaptationof an organism,such Frei,Jeff Kitzler, Mark Shigenaga,Lou Tartaglia, as a helminth,to manipulatethe victim's ma- and twoanonymous reviewers.

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