Primary Care Respiratory Journal (2004) 13, 65—67

EDITORIAL The hypothesis: promises and pitfalls

The popular hygiene hypothesis for and hypothesis [6]. The strongest evidence is usually has been riding on a swell of provocative developed from prospective cohort studies where evidence over the past decade. Broadly stated, nat- the development from cause to subsequent effect urally occurring andmicrobial exposures can be examined carefully. Indeed, randomized might confer protection against the development controlledtrials are an optimizedvariant of longi- of asthma andallergic andautoimmune diseases. tudinal prospective studies. Common microbial exposures–—viral andbacterial We have foundit helpful to studybacterial en- infections, gastrointestinal tract colonization, and dotoxin as a prototypical microbial adjuvant and exposure to certain microbial components such as exposure [1]. Briefly, endotoxin is a lipopolysac- bacterial endotoxin–—are potent inducers of im- charide that comprises most of the outer cell wall mune memory, Th1 immune responses, andregula- of all gram-negative . It is a ubiquitous tory immune responses. They are implicatedin this andpotent inducerof immune memory, Th1 im- scheme. Murine atopic asthma models have con- mune development, and also of regulatory immune sistently revealedthat microbial infections (e.g., mechanisms that keeps immune responses appro- BCG, M. pneumoniae), killedbacterial organisms priately containedandcontrolled.Th1 immune (e.g., heat-killedlisteria), bacterial immune stim- development is believed to mitigate the devel- ulatoryCopyright components (e.g., General bacterial endotoxin Practice or opment of allergic Airways diseases and asthmaGroup through CpG motif DNA), or the Th1-type cytokines they a number of pathways. The classic paradigm is induce (e.g., IFN-g, IL-12)Reproduction can all prevent induc- that Prohibited Th1 down-modulates Th2 development and tion of the allergic asthma phenotype (reviewedin . Th1 immune responses also induce multiple [1]). The relevance of this concept in humans has anti-viral mechanisms that keep respiratory been supportedby observations from natural his- from proliferating in the respiratory epithelium tory studies and detailed population studies which and spreading down the airways. Th1 immune re- have begun to explore the causal relationships sponses during airways injury and inflammation also between these microbial exposures andthe subse- inhibit aberrant repair processes that underlie tis- quent development of the , allergy sue changes in asthma. For example, IFN-g inhibits andasthma. mucous glandandsmooth muscle hyperplasia, fi- I wouldlike to commendandthank Drs. Gore, brotic repair processes, andmast cell activation, Custovic, van Schayck, andKnottnerus for a lively through direct and indirect mechanisms. andthoughtful debateon this hygiene hypothe- Endotoxin is therefore considered to be a pro- sis [2—5]. I join them in that much of the current totypical pathogen-associatedmolecular pattern epidemiological data are not strong enough to (PAMP), which are fundamental components of mi- infer causation. Quantity andlay appeal of stud- crobes that the immune system relies heavily on ies does not equal quality, and ultimately quality to recognize them. From this scientific basis, along will be needed to prove it. However, randomized with clinical investigations of endotoxin exposure, controlledtrials of high quality, although ideal, primarily in occupational settings, we have envis- are not always feasible in proving causation. This agedendotoxinexposure to be both harmful and challenge in not unique to the hygiene hypothesis, helpful–—harmful in that, at high exposure levels, and is common in the study of disease causation. some people will develop an occupational form Specific epidemiological criteria have been estab- of asthma (i.e., byssinosis). Also, if asthma or al- lishedthat can prove a strong causal relation, and lergic diseases are ongoing, then endotoxin–—an can be usedto weigh the evidencefor the hygiene adjuvant–—is like gas on a flame and will increase

1471-4418/$30.00 © 2004 General Practice Airways Group. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.pcrj.2004.03.004 66 Editorial inflammation anddiseaseseverity. On the other ticular was associatedwith less atopic , side, endotoxin could help to promote health- less foodallergy, andless allergen sensitization at ful immune responses to microbial pathogens and 1 year of age [13]. Interestingly, ownership was other ubiquitous environmental exposures such as also associatedwith increasedIL-10 production allergens. Most importantly, the determinants for from peripheral bloodcells (a biomarker of immune harmful or healthful outcomes include: timing and regulatory responses). Furthermore, the effect of dosage of exposure, environmental co-factors, and dog ownership on was strongest genetics. These have been the focus of careful in- for those children with a high-responder polymor- vestigations in recent years. To summarize, current phism in their CD14 promoter region (which is a evidence suggests that early timing, moderate ex- receptor/enhancer binding protein for endotoxin). posure levels, environmental co-exposures such as Although the mechanism(s) for this potential pro- other PAMPs andallergens, andgenetic polymor- tective influence are unclear, one possibility is phisms that influence response to exposure, are that greater microbial (e.g., endotoxin and other all important determinants of healthful or harmful PAMPs) exposure occurs with animal contact and/or outcomes due to endotoxin exposure. animal/pet-keeping in the home. Recent studies In support of these relationships is the com- have reportedthat indoorpets are a major factor pelling work of European investigators of several associated with higher indoor endotoxin levels in farm/non-farm communities, who have reported metropolitan homes [1,14]. the following associations between greater endo- In closing, as the authors have espoused, a word toxin exposure andasthma andallergy outcomes in of caution when seeking to extrapolate these early school-age children: investigative clues into action. The hygiene hypoth- esis argument for the prevention of allergy, asthma 1. Farm children are exposed to more endotoxin (as and autoimmune diseases has not been developed measured in house dust, barn dust, and mattress strongly enough to provide any course of action for dust) [7,8]; either prevention or therapy. The current evidence, 2. Greater endotoxin exposure is associated with however, is intriguing andcan well substantiate an less allergen sensitization, hay fever symptoms, investigative blueprint from which essential stud- and atopic asthma, in a dose-dependent manner ies can be targetedanddeveloped,andcausation [8]; between microbial exposures andsubsequent al- 3. The bloodcells of farmer’s childrenexpressed lergy, asthma, andautoimmunity can be tested. higher amounts of CD14 andToll-like receptor 2, In the meantime, what is well understood about Copyrightwhich are innate immune General receptors for microbial Practice Airways Group interventions that optimize human health should compounds that include endotoxin [9]; prevail. 4. Recollection of earlyReproduction life exposures to farm barns Prohibited andunpasteurizedmilk hadthe strongest associ- ations with low asthma andallergy prevalences [10]; and 5. High levels of endotoxin exposure were associ- References atedwith an increasedprevalence of non-atopic wheeze [8]. [1] Liu AH. Endotoxin exposure in allergy and asthma: recon- ciling a paradox. J Allergy Clin Immunol 2002;109(3):379— Therefore, natural endotoxin exposure may pro- 92. mote early Th1-type immune development, thereby [2] Gore C, Custovic A. Protective parasites andmedicinal preventing the development of allergen sensitiza- microbes? The case for the hygiene hypothesis. Prim Care Respir J 2004;13(2):68—75. tion, allergic airways conditions, and asthma. As [3] van Schayck CP, Knottnerus JA. No clinical evidence base well, high levels of endotoxin exposure may bring to support the hygiene hypothesis. Prim Care Respir J out endotoxin-sensitive asthma in the vulnerable, 2004;13(2):76—9. similar to occupational forms of endotoxic asthma. [4] Gore C, Custovic A. Response to ‘No clinical evidence base Coulda similar phenomenon be true for pet to support the hygiene hypothesis’ by CP van Schayck and JA Knottnerus. Prim Care Respir J 2004;13(2):80—2. animal exposures in typical metropolitan homes? [5] van Schayck CP. Response to ‘Protective parasites and Sticking with well-performed, longitudinal studies, medicinal microbes? The case for the hygiene hypothesis’ two recent birth cohort studies in US metropolitan by C Gore andA Custovic. Prim Care Respir J 2004;13(2):83. communities have foundless subsequent asthma [6] Liu AH, Murphy JR. Hygiene hypothesis: fact or fiction? J in children raised with pet [11], andless Allergy Clin Immunol 2003;111(3):471—8. subsequent allergen sensitization with increasing [7] Gereda JE, Leung DYM, Liu AH. House-dust endotoxin is higher in rural homes in developing countries and numbers of pet cats and/or dogs in early life [12]. farm homes, where asthma is less prevalent. JAMA In a third birth cohort study, dog ownership in par- 2000;284(13):1652—3. Editorial 67

[8] Braun-Fahrlander C, Riedler J, Herz U, Eder W, Waser M, [13] Gern JE, Reardon CL, Hoffjan S, Nicolae D, Li Z, Roberg KA, Grize L, et al. Environmental exposure to endotoxin and et al. Effects of dog ownership and genotype on immune its relation to asthma in school-age children. N Engl J Med development and atopy in infancy. J Allergy Clin Immunol 2002;347(12):869—77. 2004;113:307—14. [9] Lauener RP, Birchler T, Adamski J, Braun-Fahrlander C, [14] Gereda JE, Klinnert MD, Price MR, Leung DYM, Liu AH. Bufe A, Herz U, et al. Expression of CD14 andToll-like Metropolitan home living conditions associated with indoor receptor 2 in farmers’ andnon-farmers’ children.Lancet endotoxin levels. J Allergy Clin Immunol 2001;107:790—6. 2002;360(9331):465—6. [10] Riedler J, Braun-Fahrlander C, Eder W, Schreuer M, Waser Andrew H. Liu M, Malsch S, et al. Exposure to farming in early life and development of asthma and allergy: a cross-sectional sur- Division of Allergy & vey. Lancet 2001;358:1129—33. Department of Pediatrics [11] Remes ST, Castro-Rodriguez JA, Holberg CJ, Martinez FD, National Jewish Medical and Research Center Wright AL. Dog exposure in infancy decreases the subse- University of Colorado Health Sciences Center quent risk of frequent wheeze but not of atopy. J Allergy 1400 Jackson Street (K1023) Clin Immunol 2001;108:509—15. [12] Ownby DR, Johnson CC, Peterson EL. Exposure to dogs and Denver, CO 80206, USA cats in the first year of life andrisk of allergic sensitization Tel.: +1-303-398-1143; fax: +1-303-398-1225 at 6 to 7 years of age. JAMA 2002;288(8):963—72. E-mail address: [email protected] (A.H. Liu)

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