Characterization of H+,K+-ATPase T cell epitopes in human autoimmune gastritis.
Human autoimmune gastritis (AIG) is an organ-specific inflammatory disorder leading to gastric atrophy and pernicious anemia. Gastric H+,K(+)-ATPase was identified as the autoantigen in both human disease and experimental murine AIG (EAIG). Studies of EAIG significantly contributed to current knowledge of human AIG, but to what extent EAIG mimics AIG is still debated, and the autoantigenic epitopes in AIG are yet unknown. This study aimed to identify the H+,K(+)-ATPase epitopes recognized by gastric T cell clones from AIG patients, to define their TCR Vbeta usage and epitope-induced cytokine response. Sixteen H+,K(+)-ATPase-reactive CD4+ gastric T cell clones of four AIG patients were tested for proliferation to overlapping 15-mer peptides spanning the a and beta chains of H+,K(+)-ATPase. We identified 6 epitopes in the a chain and 5 in the beta chain; TCR Vbeta usage was not restricted. Four (36%) of the 11 H+,K(+)-ATPase epitopes recognized in AIG were found to overlap with epitopes that are relevant in EAIG, including a previously described gastritogenic epitope. Gastric T cell recognition of the peptide epitopes resulted in secretion of Th1 cytokines. Our data suggest a striking similarity between human AIG and EAIG, at the epitope level, with regard to cytokine secretion and likely also with regard to pathogenic mechanisms.
Bergman
Mathijs P
MP
Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands.
Amedei
Amedeo
A
D'Elios
Mario M
MM
Azzurri
Annalisa
A
Benagiano
Marisa
M
Tamburini
Carlo
C
van der Zee
Ruurd
R
Vandenbroucke-Grauls
Christina M
CM
Appelmelk
Ben J
BJ
Del Prete
Gianfranco
G
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology / Q000302:isolation & purification; D001327:Autoimmune Diseases / Q000201:enzymology / Q000276:immunology*; D002999:Clone Cells / Q000276:immunology; D016384:Consensus Sequence; D000939:Epitopes / Q000276:immunology*; D005260:Female; D005753:Gastric Mucosa / Q000201:enzymology / Q000276:immunology; D005756:Gastritis / Q000201:enzymology / Q000276:immunology*; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006801:Humans; D018928:Immunity, Mucosal; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D006180:Proton-Translocating ATPases / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000378:metabolism
D001324:Autoantigens; D000939:Epitopes; D010446:Peptide Fragments; D015847:Interleukin-4; D007371:Interferon-gamma; D006180:Proton-Translocating ATPases