1. Gliadin-Specific CD8 + T Cell Responses Restricted by HLA Class I A*0101 and B*0801 Molecules in Celiac Disease Patients.
- Author
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Picascia S, Sidney J, Camarca A, Mazzarella G, Giardullo N, Greco L, Auricchio R, Auricchio S, Troncone R, Sette A, and Gianfrani C
- Subjects
- Adolescent, Adult, Algorithms, Carrier Proteins immunology, Carrier Proteins physiology, Celiac Disease genetics, Celiac Disease physiopathology, Child, Child, Preschool, Computational Biology, Enzyme-Linked Immunospot Assay, Epitopes, T-Lymphocyte immunology, Female, Genes, MHC Class I, Glutens immunology, HLA-A1 Antigen genetics, HLA-A1 Antigen metabolism, HLA-B8 Antigen genetics, HLA-B8 Antigen metabolism, Humans, Interferon-gamma genetics, Interferon-gamma immunology, Male, Middle Aged, Peptides metabolism, Young Adult, CD8-Positive T-Lymphocytes immunology, Celiac Disease immunology, Gliadin immunology, HLA-A1 Antigen immunology, HLA-B8 Antigen immunology, Peptides immunology
- Abstract
Initial studies associated the HLA class I A*01 and B*08 alleles with celiac disease (CD) susceptibility. Subsequent analyses showed a primary association with HLA class II alleles encoding for the HLA DQ2.5 molecule. Because of the strong linkage disequilibrium of A*01 and B*08 alleles with the DR3-DQ2.5 haplotype and a recent genome-wide association study indicating that B*08 and B*39 are predisposing genes, the etiologic role of HLA class I in CD pathogenesis needs to be addressed. We screened gliadin proteins (2α-, 2ω-, and 2γ-gliadin) using bioinformatic algorithms for the presence of peptides predicted to bind A*0101 and B*0801 molecules. The top 1% scoring 9- and 10-mer peptides ( N = 97, total) were synthesized and tested in binding assays using purified A*0101 and B*0801 molecules. Twenty of ninety-seven peptides bound B*0801 and only 3 of 97 bound A*0101 with high affinity (IC
50 < 500 nM). These 23 gliadin peptides were next assayed by IFN-γ ELISPOT for recognition in peripheral blood cells of CD patients and healthy controls carrying the A*0101 and/or B*0801 genes and in A*0101/B*0801- CD patients. Ten of the twenty-three peptides assayed recalled IFN-γ responses mediated by CD8+ T cells in A*0101/B*0801+ patients with CD. Two peptides were restricted by A*0101, and eight were restricted by B*0801. Of note, 50% (5/10) of CD8+ T cell epitopes mapped within the γ-gliadins. Our results highlight the value of predicted binding to HLA molecules for identifying gliadin epitopes and demonstrate that HLA class I molecules restrict the anti-gluten T cell response in CD patients., (Copyright © 2017 by The American Association of Immunologists, Inc.)- Published
- 2017
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