Modulation of allergenicity of major house dust mite allergens Der f 1 and Der p 1 by interaction with an endogenous ligand.
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.
Takai
Toshiro
T
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan. t-takai@juntendo.ac.jp
Kato
Takeshi
T
Hatanaka
Hideki
H
Inui
Kyoko
K
Nakazawa
Takuya
T
Ichikawa
Saori
S
Mitsuishi
Kouichi
K
Ogawa
Hideoki
H
Okumura
Ko
K
D000485:Allergens / Q000008:administration & dosage / Q000097:blood / Q000502:physiology*; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000008:administration & dosage / Q000097:blood / Q000276:immunology*; D060829:Arthropod Proteins; D020134:Catalytic Domain / Q000276:immunology; D055312:Cystatin A / Q000008:administration & dosage / Q000097:blood / Q000502:physiology*; D003545:Cysteine / Q000008:administration & dosage; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000502:physiology*; D040001:Dermatophagoides farinae / Q000276:immunology* / Q000378:metabolism; D040002:Dermatophagoides pteronyssinus / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008808:Mice, Inbred CBA; D010084:Oxidation-Reduction; D011485:Protein Binding / Q000276:immunology; D019163:Reducing Agents / Q000008:administration & dosage; D014611:Vaccination
D000485:Allergens; D039741:Antigens, Dermatophagoides; D060829:Arthropod Proteins; D055312:Cystatin A; D015853:Cysteine Proteinase Inhibitors; D008024:Ligands; D019163:Reducing Agents; D007073:Immunoglobulin E; C026407:CSTA protein, human; D003546:Cysteine Endopeptidases; C451159:Dermatophagoides farinae antigen f 1; C451162:Dermatophagoides pteronyssinus antigen p 1; D003545:Cysteine