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*Atopy (Allergy) Research Center,
Department of Dermatology, and
Department of Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan;
Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan;
¶Database Center for Life Science, Research Organization of Information and Systems, Tokyo, Japan; and
||Department of Materials and Biological Sciences, Faculty of Science, Japan Women’s University, Tokyo, Japan
Although many allergens bind endogenous molecules other than Abs in the human body, whether the interaction can modulate allergenicity has been unknown. Here, we investigated the effect of the interaction of recombinant major mite group 1 allergens (Der f 1 and Der p 1), which belong to the papain-like cysteine protease family, with an endogenous protease inhibitor, cystatin A, on their allergenicity. Cystatin A bound reduced forms of the allergens, in which the cysteine residue at the catalytic center of the protease activity was reduced by treatment with L-cysteine, but did not bind oxidized forms. Cystatin A partially inhibited the binding of IgE in mite-allergic volunteers’ sera to the reduced forms, but unexpectedly enhanced the basophil histamine-releasing activity. A catalytic site-mutant of Der f 1 behaved in terms of histamine release, similarly to the reduced form. Molecular modeling showed that cystatin A interacts with the allergens within a narrow area. The results indicate that interaction with cystatin A reduces the limited number of IgE epitopes of the allergens but enhances their biological activity to release histamine, suggesting a new concept, that interaction between allergens and their endogenous ligands modulates the allergenicity even toward enhancement in the effector phase. On the other hand, i.p. immunization without alum of mice with cystatin A-treated reduced Der f 1 induced less serum Der f 1-specific IgE than immunization with reduced Der f 1 alone, suggesting that endogenous protease inhibitors suppress the induction of allergen-specific IgE, which is dependent on the enzymatic activity of cysteine protease-allergens, in the sensitization process.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by a Health and Labour Sciences Research Grants for Research on Allergic Disease and Immunology from the Ministry of Health, Labour and Welfare, Japan and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to T.T.).
2 Address correspondence and reprint requests to Dr. Toshiro Takai, Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail address: t-takai{at}juntendo.ac.jp
3 Abbreviations used in this paper: rDer f 1 and rDer p 1, unglycosylated recombinant Der f 1 and Der p 1; rDer f 1-WT and rDer p 1-WT, hyperglycosylated rDer f 1 and rDer p 1; rDer f 1-C35S, a catalytic site mutant of rDer f 1; PBST, PBS containing 0.05% Tween 20.
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