Peanut Allergy: a Growing Phenomenon

Peanut allergy: a growing phenomenon

Wesley Burks

J Clin Invest. 2003;111(7):950-952. https://doi.org/10.1172/JCI18233.

Commentary

Peanut allergy is one of the most serious of the immediate hypersensitivity reactions to foods in terms of persistence and severity and appears to be a growing problem (1). The prevalence of food hypersensitivity in adults is reportedly less common, but a recent survey in the US found that 1.3% of adults are allergic to peanuts or tree nuts (2). Recently, in a cohort of American children referred for the evaluation of atopic dermatitis, the prevalence of allergic reactivity to peanuts was nearly twice as high as that in a similar group evaluated a decade earlier (3). In spite of increased recognition and understanding of food allergies, food is the single most common cause of anaphylaxis seen in hospital emergency departments (4), accounting for about one-third of anaphylaxis cases seen. It is estimated that about 30,000 food-induced anaphylactic events are seen in American emergency departments each year, 200 of which are fatal (5). Either peanuts or tree nuts cause more than 80% of these reactions. Due to the persistence of the reaction and the lack of effective treatment, peanut-specific immunotherapy is currently being examined as a treatment option. An understanding of the molecular mechanisms is vital to ensure the eventual, effective treatment of peanut-allergic patients. Th2 polarization of cytokines The study by Turcanu et al. (6) in this issue of […]

Find the latest version: https://jci.me/18233/pdf repressing our sodium transporters in Cell. 104:545–556. not mutant WNK4. Proc. Natl. Acad. Sci. U. S. A. 3. Achard, J.M., Disse-Nicodeme, S., Fiquet-Kempf, 100:680–684. our kidney, the frequency of salt-sensi- B., and Jeunemaitre, X. 2001. Phenotypic and 9. Robert-Nicoud, M., et al. 2001. Transcriptome of tive hypertension would have been genetic heterogeneity of familial hyperkalaemic a mouse kidney cortical collecting duct cell line: even higher and hypertension even hypertension (Gordon syndrome). Clin. Exp. Phar- effects of aldosterone and vasopressin. Proc. Natl. macol. Physiol. 28:1048–1052. Acad. Sci. U. S. A. 98:2712–2716. much more severe. 4. Wilson, F.H., et al. 2001. Human hypertension 10. Nicod, M., et al. 2002. A novel vasopressin- caused by mutations in WNK kinases. Science. induced transcript promotes MAP kinase activa- Acknowledgments 293:1107–1112. tion and ENaC downregulation. EMBO J. We thank Jean-Daniel Horisberger, 5. Choate, K.A., et al. 2003. WNK1, a kinase mutat- 21:5109–5117. ed in inherited hypertension with hyperkalemia, 11. Loffing, J., and Kaissling, B. 2003. Sodium and Dmitri Firsov, and Laurent Schild for localizes to diverse Cl-transporting epithelia. calcium pathways along the mammalian distal critically reading the manuscript and Proc. Natl. Acad. Sci. U. S. A. 100:663–668. nephron: from rabbit to human. Am. J. Physiol. Nicole Skarda for secretarial work. 6. Schambelan, M., Sebastian, A., and Rector, F.C., Renal Physiol. In press. Jr. 1981. Mineralocorticoid-resistant renal hyper- 12. Rossier, B.C., Pradervand, S., Schild, L., and This work was supported by a grant kalemia without salt wasting (Type 2 pseudohy- Hummler, E. 2002. Epithelial sodium channel from the Swiss National Foundation poaldosteronism): role of increased renal chloride and the control of sodium balance: interaction (no. 31-061966.00 to B.C. Rossier). reabsorption. Kidney Int. 19:716–727. between genetic and environmental factors. 7. Yang, C.-L., Angell, J., Mitchell, R., and Ellison, Annu. Rev. Physiol. 64:877–897. D.H. 2003. WNK kinases regulate thiazide- 13. Kriz, W., and Kaissling, B. 2000. Structural organ- 1. Guyton, A.C. 1991. Blood pressure control - Spe- sensitive Na-Cl cotransport. J. Clin. Invest. ization of the mammalian kidney. In The kidney: cial role of the kidneys and body fluid. Science. 111:1039–1045. doi:10.1172/JCI200317443. physiology and pathophysiology. 3rd Edition. D.W. 252:1813–1816. 8. Wilson, F.H., et al. 2003. Molecular pathogenesis Seldin and G. Giebiesch, editors. Lippincott 2. Lifton, R.P., Gharavi, A.G., and Geller, D.S. 2001. of inherited hypertension with hyperkalemia: the Williams and Wilkins. Philadelphia, Pennsylva- Molecular mechanisms of human hypertension. Na-Cl cotransporter is inhibited by wild-type but nia, USA. 587–654.

See the related article beginning on page 1065. studies have been complicated and not easily interpreted. Human T cells, Peanut allergy: a growing phenomenon when repeatedly stimulated in vitro, will often develop a Th2 phenotype regardless of their origin (7, 8). Wesley Burks In this study, the authors compare peanut-allergic individuals, individu- University of Arkansas for Medical Sciences, Arkansas Children’s Hospital, Little Rock, als who have outgrown peanut aller- Arkansas, USA gy, and those who had always tolerat- J. Clin. Invest. 111:950–952 (2003). doi:10.1172/JCI200318233. ed peanuts (6). Peripheral blood lymphocytes in the peanut-allergic individuals demonstrated a Th2 Peanut allergy is one of the most seri- of anaphylaxis seen in hospital emer- polarization of cytokine production ous of the immediate hypersensitivity gency departments (4), accounting for by peanut-specific cells with low levels reactions to foods in terms of persist- about one-third of anaphylaxis cases of IFN-γ and TNF-α and high levels of ence and severity and appears to be a seen. It is estimated that about 30,000 IL-4, IL-5, and IL-13. In the individu- growing problem (1). The prevalence food-induced anaphylactic events are als who had outgrown their peanut of food hypersensitivity in adults is seen in American emergency depart- allergy and the nonallergic controls, reportedly less common, but a recent ments each year, 200 of which are fatal the cytokines showed a Th1 bias with survey in the US found that 1.3% of (5). Either peanuts or tree nuts cause high levels of IFN-γ and TNF-α and adults are allergic to peanuts or tree more than 80% of these reactions. low levels of IL-4, IL-5, and IL-13. An nuts (2). Recently, in a cohort of Amer- Due to the persistence of the reac- interesting part of the study investi- ican children referred for the evaluation and the lack of effective treat- gated individuals who were allergic to tion of atopic dermatitis, the preva- ment, peanut-specific immunotherapy eggs, using similar laboratory and lence of allergic reactivity to peanuts is currently being examined as a treat- cloning techniques. As in the peanut- was nearly twice as high as that in a ment option. An understanding of the specific cells, the egg-allergic individ- similar group evaluated a decade earli- molecular mechanisms is vital to uals’ peripheral blood lymphocytes er (3). In spite of increased recognition ensure the eventual, effective treat- had a Th2 skewing of their ovalbu- and understanding of food allergies, ment of peanut-allergic patients. min-specific T cells (Figure 1). food is the single most common cause This evidence that peanut antigens Th2 polarization of cytokines do not in themselves induce a Th2 The study by Turcanu et al. (6) in this cytokine response is not surprising, Address correspondence to: Wesley Burks, Department of Pediatrics, Division of Allergy issue of the JCI uses a novel approach, since all food allergy patients share and Immunology, Arkansas Children’s that of CFSE staining to separate similar clinical symptoms in the skin, Hospital, 1120 Marshall Street, Little Rock, peanut-specific lymphocytes by flow gastrointestinal tract, and respiratory Arkansas 72202, USA. cytometry and subsequent cloning. tract. The results of the present study Phone: (501) 364-1060; Fax: (501) 364-3173; E-mail: [email protected]. Due to technical difficulties arising (6) will help in the evaluation of Conflict of interest: The author owns stock from the low frequency of allergen- future immunomodulatory treat- and/or stock options in SEER Inc. specific cells in the blood, previous ments for food allergy and in studies

950 The Journal of Clinical Investigation | April 2003 | Volume 111 | Number 7 mechanism of the food hypersensitivity response that can be studied as patients with food allergy are placed on food-specific immunotherapy. One of the more exciting recent developments in the treatment of food allergy is novel immunotherapeutic strategies designed to alter the immune system’s response to food allergens. These strategies are now being examined in animal models as potential treatment modalities (11). They include cytokine-modulated immunotherapy, immunostimulatory sequence–modulated immunotherapy, plasmid DNA immunotherapy, allergen-peptide immunotherapy, and “engineered” (mutated) allergen protein immunotherapy. All of these methods strive to elicit a Th1-type response or tolerance from the immune system in response to a specific food allergen.

Natural history of peanut allergy It will be even be more interesting to Figure 1 Foods enter the gastrointestinal tract and undergo protein digestion and then antigen (Ag) pro- elucidate why only a few food allergens cessing. Some Ag enters the blood stream to be distributed at distal sites throughout the body induce the type of Th2 response early (particularly the skin and respiratory mucosa along with sites in the gastrointestinal mucosa). As in life that is demonstrated in this the antigen-presenting cell presents Ag to the T cell, specific cytokines are produced. In the peanut- study (6), and why certain people out- allergic individual, the T cells will secrete increased amounts of IL-4, IL-5, and IL-13, among other grow their food allergy. In this study, mediators, and reduced amounts of IFN-γ and TNF-α when compared to that in an individual who individuals allergic to peanuts and is not allergic to peanuts. The T cell in turn regulates eventual peanut-specific IgE production by B individuals allergic to eggs had a simi- cells. Peanut-specific IgE is attached to mast cells in the gastrointestinal tract, skin, and respira- lar Th2-skewed cytokine response. tory tract mucosa. Subsequently, on ingestion of peanuts, in the peanut-allergic individual, the However, the natural history of the protein is digested and the Ag binds peanut-specific IgE on the mast cell, causing activation of the clinical symptoms of peanut allergy is mast cell with mediator release at the mucosal site. Clinical symptoms ensue. quite different from that of the symptoms of egg allergy. Peanut allergy is infrequently outgrown (12), while egg that examine the natural history of patients with insect-sting hypersensi- allergy is typically outgrown in the food allergic reactions. tivity when they have experienced sig- first 4–5 years of life. nificant systemic symptoms (9). The novel approach used by these Peanut-specific IgE Because allergen immunotherapy can authors to identify antigen-specific T The sequence of events necessary to downregulate the specific-IgE re- cells will likely have important implica- produce allergen-specific IgE suggests sponse and the cellular response to tions for future studies of allergic dis- several potential avenues for immuno- allergens, it is now being studied as a ease, as well as autoimmune disorders. modulatory intervention. These ap- possible option for patients with life- proaches can be placed into two gen- long food allergies (10). The goal of 1. Sampson, H.A. 2002. Clinical practice. Peanut allergy. N. Engl. J. Med. 346:1294–1299. eral categories: (a) strategies designed peanut-specific immunotherapy would 2. Sicherer, S.H., Munoz-Furlong, A., Burks, A.W., to inhibit IgE or the interaction of not be to allow patients to eat peanuts and Sampson, H.A. 1999. Prevalence of peanut mediators important to IgE produc- at will, but rather to give them some and tree nut allergy in the US determined by a random digit dial telephone survey. J. Allergy tion, and (b) strategies designed to protection in case of accidental inges- Clin. Immunol. 103:559–562. alter T cell activation. The second cat- tion. Given the partial rate of response 3. Sampson, H.A. 1996. Managing peanut allergy. egory includes induction of T cell and high rate of adverse reactions to BMJ. 312:1050–1051. 4. Yocum, M.W., et al. 1999. Epidemiology of ana- anergy by use of allergen-specific pep- traditional food immunotherapy in phylaxis in Olmsted County: a population- tides (T cell epitopes), and modulation previous studies, and the frequent based study. J. Allergy Clin. Immunol. of Th cell development by means that occurrence of accidental peanut inges- 104:452–456. 5. Bock, S.A., Munoz-Furlong, A., and Sampson, favor a Th1 cytokine response and/or tion, alternative forms of immuno- H.A. 2001. Fatalities due to anaphylactic reac- by prevention of T cell proliferation. therapy are necessary for this poten- tions to foods. J. Allergy Clin. Immunol. Allergen immunotherapy is an effec- tially fatal allergy. The findings by 107:191–193. 6. Turcanu, V., Maleki, S.J., and Lack, G. 2003. tive therapeutic modality to prevent Turcanu et al. (6) provide additional Characterization of lymphocyte responses to further anaphylactic episodes in laboratory data about the possible peanuts in normal children, peanut-allergic chil-

The Journal of Clinical Investigation | April 2003 | Volume 111 | Number 7 951 dren, and allergic children who acquired toler- acquire a Th2 phenotype upon repetitive stimu- ment of peanut allergy with rush immunother- ance to peanuts. J. Clin. Invest. 111:1065–1072. lations in neutral conditions. Eur. J. Immunol. apy. J. Allergy Clin. Immunol. 90:256–262. doi:10.1172/JCI200316142. 25:2722–2725. 11. Burks, A.W., Bannon, G.A., and Lehrer, S.B. 7. Cohen, S.B., Webb, L.M., and Feldmann, M. 9. Valentine, M.D., et al. 1990. The value of 2001. Classic specific immunotherapy and new 1996. The method of deriving human T-cell immunotherapy with venom in children with perspectives in specific immunotherapy for food clones alters the proportion of IL-10-producing allergy to insect stings. N. Engl. J. Med. allergy. Allergy. 67:121–124. cells. Immunology. 87:343–347. 323:1601–1603. 12. Skolnick, H.S., et al. 2001. The natural history 8. Demeure, C.E., et al. 1995. Human naive CD4 T 10. Oppenheimer, J.J., Nelson, H.S., Bock, S.A., of peanut allergy. J. Allergy Clin. Immunol. cells produce interleukin-4 at priming and Christensen, F., and Leung, D.Y. 1992. Treat- 107:367–374.

See the related article beginning on page 989. induces conformational changes in the reactive center loop of the serpin that Heparan sulfate: Antithrombotic or not? accelerate the rate at which antithrombin inhibits its target proteases by two to three orders of magnitude. Jeffrey I. Weitz Although heparin is found in granules of human mast cells, it is not the Henderson Research Centre, Hamilton, Ontario, Canada physiological counterpart of medicinal J. Clin. Invest. 111:952–954 (2003) doi:10.1172/JCI200318234. heparin. Recent studies indicate that mast cell heparin regulates the types and amounts of positively-charged Tissue factor exposed at sites of vascu- protein C pathway. Mice totally defi- proteases stored in mast cell granules. lar injury initiates coagulation result- cient in thrombomodulin die in utero Thus, mast cells deficient in heparin- ing in thrombin generation. In addi- (3), whereas ablation of endothelial synthesizing enzyme have altered mor- tion to converting fibrinogen to fibrin, thrombomodulin causes early onset phology (9) and their granules contain thrombin amplifies its own generation thrombosis (4). Likewise, patients with reduced amounts of tryptase, chymase, by activating platelets and by activating protein C or protein S deficiency are and carboxypeptidase A (10). Not only factors V and VIII, key cofactors in prone to thrombosis, as are those with are protease levels reduced, but their coagulation. Consequently, tight regu- the factor V Leiden mutation, a point activity may also be limited because lation of thrombin activity is essential mutation that renders activated factor heparin enhances the activity of some to prevent excessive thrombosis (1). V Leiden relatively resistant to inacti- mast cell proteases (11). vation by activated protein C (5). Current thinking is that the physio- Regulation of thrombin Antithrombin also is critical for the logical counterpart of medicinal Two naturally occurring anticoagu- regulation of coagulation. A member of heparin is heparan sulfate, a glycos- lant pathways serve to regulate throm- the serine proteinase inhibitor (serpin) aminoglycan found on the surface of bin; the protein C pathway and superfamily, antithrombin inhibits most eukaryotic cells and in the extra- antithrombin. The protein C pathway thrombin and other clotting enzymes cellular matrix. Anchored to the cell is initiated when thrombin binds to in a slow, progressive fashion. The surface by its proteoglycan core, the thrombomodulin, a thrombin recep- importance of antithrombin is high- functional units of heparan sulfate are tor expressed by endothelial cells (2). lighted by the fact that patients with found on its branching glycosamino- Once bound to thrombomodulin, heterozygous antithrombin deficiency glycan side-chains (Figure 1). Cultured thrombin undergoes a conformation- have a thrombotic tendency (5, 6). endothelial cells synthesize heparan al change at its active site that converts Complete deficiency of antithrombin is sulfate and 1% to 10% of the molecules it from a procoagulant enzyme into a likely to be incompatible with life, a have anticoagulant activity because potent activator of protein C. Activat- concept supported by the observation they contain the 3-O-sulfated glu- ed protein C, in concert with its cofac- that knocking out the antithrombin cosamine residue that is the hallmark tor protein S, serves as an anticoagu- gene in mice results in intrauterine of the antithrombin-binding pen- lant by degrading and inactivating death from massive thrombosis (7). tasaccharide (11). activated factors V and VIII (2). Antithrombin binds to cultured Several lines of evidence highlight Heparan sulfate endothelial cells and binding is reduced the physiological importance of the The activity of antithrombin is en- when the cells are pretreated with hanced by heparin. Antithrombin pos- heparinase (12), suggesting that this sesses a heparin binding site that inter- interaction is mediated by heparan sul- Address correspondence to: Jeffrey I. Weitz, Henderson Research Centre, 711 Concession acts with a unique pentasaccharide fate. When radiolabeled antithrombin Street, Hamilton, Ontario L8V 1C3, Canada. sequence found on one-third of the is used, over 90% of the antithrombin Phone: (905) 574-8550; Fax: (905) 575-2646; chains of unfractionated heparin. Key to that binds to cultured endothelial cells E-mail: [email protected]. high-affinity binding of antithrombin to or to the surface of perfused aortic seg- Conflict of interest: The author has declared this pentasaccharide sequence is 3-O-sul- ments can be localized to the suben- that no conflict of interest exists. Nonstandard abbreviations used: serine fated glucosamine, the middle saccha- dothelial matrix (13). Exposure of cul- proteinase inhibitor (serpin); ride unit of the pentasaccharide (8). Pen- tured endothelial cells to IL-1 or tumor 3-O-sulfotransferase-1 (3-OST-1). tasaccharide binding to antithrombin necrosis factor reduces heparan sulfate

952 The Journal of Clinical Investigation | April 2003 | Volume 111 | Number 7