Specific histamine release capacity of peptides selected from the modelized der P I protein, a major allergen of Dermatophagoides pteronyssinus

doi:10.1016/0161-5890(92)90184-Y

Molecular Immunology

Volume 29, Issue 6, June 1992, Pages 739-749

https://doi.org/10.1016/0161-5890(92)90184-Y Get rights and content

Abstract

Dust mite allergens are considered as a major cause of allergic disease and as a risk factor for asthma. Der p I, a 222 amino-acid residue globular glycoprotein, is one of the major allergens from Dermatophagoides pteronyssinus (Dpt) mites. In this study, we have used predictive conventional algorithms (i.e. hydrophilicity, mobility, accessibility) and a three-dimensional model of Der p I derived from comparison to actinidin and papain to select continuous amino acid sequences as potential B cell epitopes. Four peptides, 52–71, 117–133, 176–187, 188–199 were synthesized. Their antigenic reactivity was investigated, mainly by measuring their capacity to induce in vitro histamine release. Results indicated that only Dpt-sensitive patients react specifically to Der p I-derived peptides and more frequently to 52–71 and 117–133. For each peptide, the intensity of response was dependent on the patient tested and on the peptide concn. The capacity of peptides to induce histamine release was demonstrated to be correlated with the serum level of anti-Der p I IgE (r = 0.86; p < 10⁻²).

Taken together these data emphasize, in Dpt-sensitive patients, the heterogeneity of the specific response to synthetic Der p I-derived peptides and underline the possible variety of epitopes belonging to the allergen Der p I.

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In our study, it was shown that D57, L58 and E92 residues are also part of epitopes. Jeannin et al. [42] have mentioned in their study that 118CQIYPPNVNKIREALAQ133 sequences might correspond to B-cell epitopes of Der p 1 which partially overlaps with the predicted epitope in our study (Y121–N126). They have also reported 188VRNSWTNWGDNGY201 as Der p 1 epitope.
Mite allergens are one of the major allergens; however, their structures and epitopes have not been thoroughly studied. In the present study, we predicted the tertiary structures of several mite allergens and also identified the B-cell epitopes, which can be suggested as potential epitopes for allergen immunotherapy. Twenty-five mite allergens, from six mite allergen groups, were investigated; homology modeling and structure refinement were performed for seventeen allergens with unknown structures. Furthermore, various servers were employed to predict linear and conformational B-cell epitopes and consensus B-cell epitopes were identified (172 linear and 64 conformational epitopes). Conservation and epitope identity were also determined among the allergens of the same group and some conserved epitopes were identified. Some regions of the predicted epitopes were identified as novel epitope regions. The predicted consensus epitopes can be applied as suitable candidates to design immunotherapeutic vaccines.
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One of the major allergenic molecules of Dpt is the glycoprotein Der p 1, and some potential epitopes have been predicted by bioinformatic methods. Using a three-dimensional model, Der p 1 (222-amino acids based protein) has been mapped, four potential B cell epitopes have been selected and their IgE-dependent biological activities demonstrated (Greene and Thomas 1992; Jeannin et al. 1992; Duez et al. 2001). One of these epitopes (peptide p52-71) was used as a model epitope in the present study.
House dust mites Dermatophagoides pteronyssinus (Dpt) are among the most frequent causes of allergy symptoms in Europe. Der p 1 is one of the major allergenic compounds of Dpt and the pathological Der p 1-specific B cells play a key role as producers of allergen-binding antibodies. The selective elimination of these cells by artificial protein molecules which inhibit the production of Dpt-recognizing IgE antibodies is a perspective therapeutic goal of allergy.
A protein engineered chimeric molecule has been constructed, which binds Der p 1-specific B cells via their BCR and suppresses selectively the production of anti-Der p 1 antibodies via CR1. The synthetic peptide Der p 1 p52-71 and an anti-CD35 monoclonal antibody were used for the construction of Der p 1 chimera. The functional effects of engineered antibodies were analyzed in vitro using PBMCs from allergy patients.
Significant inhibition of allergen-specific proliferation and reduction of Der p 1-IgE antibody production were observed after treatment of PBMCs from allergic patients with Der p 1-peptide chimera. Culturing of these PBMCs in the presence of the chimeric molecule increased the percentage of apoptotic (Annexin V-positive) B lymphocytes, but not T lymphocytes.
Mimotopes identify conformational B-cell epitopes on the two major house dust mite allergens Der p 1 and Der p 2
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House dust mite allergy occurs in 10–20% of the population. Improvement of the present immunotherapy requires detailed knowledge about the structure of the allergens. Mimotopes selected from phage peptide libraries imitate the conformational epitopes of a natural allergen. The aim of our study was to generate epitope mimics for the two major allergens of house dust mite. When the monoclonal anti-Der p 1 and anti-Der p 2 antibodies were used for biopannings, mimotopes were selected which bound also specific IgE from human allergic patients’ sera. The conformational matching of these mimotopes on the 3D structure of the natural allergens determined discontinuous epitopes in both cases, representing conformational B-cell epitopes relevant for binding of human IgE. Therefore, these mimotopes are potential candidates for the directed induction of blocking antibodies and epitope-specific immunotherapy of mite allergy.
Three-dimensional structure and IgE-binding properties of mature fully active Der p 1, a clinically relevant major allergen
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Located 14 Å from the catalytic site, Mg++ is unlikely to play a major role, if any, in Der p 1 activity, as confirmed by maintenance of peptidolytic activity in presence of EDTA (data not shown), but its location close to the allergen surface could alter or stabilize the conformation of IgE epitopes, including the 52-56 stretch (Fig 3, D). Such epitopes have been described.10 Interestingly, in the Der p 1.0110 isoform, Glu 44 is replaced by an Asp (see this article's Table E2 in the Online Repository at www.jacionline.org).
Der p 1 is a 25-kd allergen with cysteine protease activity. Sensitization to Der p 1 affects a large proportion of individuals with allergy, resulting in rhinitis, asthma, and/or atopic dermatitis.
We determined the Der p 1 crystallographic structure to understand the relationships among structure, function, and allergenicity.
Recombinant pro–Der p 1 was produced in Pichia pastoris and allowed to mature spontaneously before purification by a 2-step procedure. Protease activity was checked by using a fluorogenic peptide substrate. Allergenicity was analysed by IgE binding assays and basophil activation test. The determination of the 3-dimensional structure was obtained by X-ray crystallography at 1.9 Å resolution.
The recombinant protein is fully active and expresses an allergenicity equivalent to its natural counterpart. Der p 1 exhibits a cysteine protease fold typical of the papain family, has a magnesium binding site, and forms dimers with a large interface. The crystal lattice shows that the dimers are tightly packed in a compact double layer of proteins. Such an assembly likely exists in dry fecal pellets, the natural form of allergen exposure, and appears ideal to interact with cell surface and trigger allergic inflammation.
We present here the 3-dimensional structural features of mature fully active Der p 1, one of the main allergens involved in human allergic diseases. This opens the possibility to evaluate the importance of enzymatic activity in pathology and possible new therapeutic interventions.
Determinant analysis of IgE and IgG4 antibodies and T cells specific for bovine α<inf>s1</inf>-casein from the same patients allergic to cow's milk: Existence of α<inf>s1</inf>-casein-specific B cells and T cells characteristic in cow's-milk allergy
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In an effort to clarify the etiology of milk allergy from the standpoint of allergen-specific immune reactions, we investigated the determinants of IgE, IgG4, and T cells specific for bovine α_s1-casein from the same individual patients by using its synthetic peptides and cyanogen bromide–digested fragments. α_s1-Casein is a major allergen in cow's milk, and its unique conformation enabled us to investigate the determinants of antibodies without consideration about missing the reactivities because of conformational changes. Nine patients were selected as subjects from among 129 milk-sensitive infants screened by ELISA to assess the anti-α_s1-casein IgE levels in their sera. By using ELISA for epitope mapping, a C-terminal region of α_s1-casein was identified as a common binding site for IgE from all of these patients, whereas those for anti-α_s1-casein IgG4 were located in multiple regions of α_s1-casein. We determined the specificities of seven α_s1-casein–specific T-cell lines established from peripheral blood mononuclear cells of two of the patients. These T cells have been shown to secrete IL-4. All of the T-cell lines had different specificities to α_s1-casein. However, a common amino acid residue use was found among the determinants of various T-cell lines from each patient. The results suggest that patients allergic to cow's milk have characteristic B cells recognizing a limited region of α_s1-casein and secreting α_s1-casein–specific IgE. These B cells may interact particularly with T cells recognizing determinants with a common structure. (J Allergy Clin Immunol 1998;101:660-71)
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Specific histamine release capacity of peptides selected from the modelized der P I protein, a major allergen of Dermatophagoides pteronyssinus

Abstract

J. molec. Biol.

J. Allergy Clin. Immun.

Chest

J. Immun. Meth.

J. Allergy Clin. Immun.

Molec. Immun.

J. molec. Biol.

J. Allergy Clin. Immun.

J. Allergy Clin. Immun.

J. Immun. Meth.

Clin. Immun. Immunopathol.

J. Allergy Clin. Immun.

TIPS

J. Allergy Clin. Immunol.

The antigenic structure of protein

Ann. Rev. Immun.

Knowledge-based prediction of protein structure and the design of novel molecules

Nature

Platelets in asthma

Platelets as effectors in immune and hypersensitivity reaction

Int. Arch. Allergy Appl. Immun.

Human basophil releasability. VI. Changes in basophil releasability in patients with allergic rhinitis or bronchial asthma

Am. Rev. Resp. Dis.

Measurement of IgG, IgA, and IgE partially purified fraction of mite extract (F4P1)

Clin. Exp. Immun.

Purification and characterization of the allergen from Dermatophagoides pteronyssinus-antigen PI

J. Immun.

Monoclonal antibodies as structural probes for mite, cat, and cockroach allergens

Adv. Biosciences

Sequence analysis of cDNA coding for a major house dust mite allergen. Der pI

J. exp. Med.

The nature of the accessible and buried surfaces in proteins

J. molec. Biol.

A basophil activating factor from human T-lymphocytes

Immunology.

Complement-induced histamine release from human basophils

J. Immun.