Immunostimulatory and immunomodulatory peptides derived from the alpha1 domain of HLA-B27 in experimental autoimmune diseases in Lewis rats.
Peptides derived from amino acid sequence 60-80 of HLA-B27 (B27PA, aa 60-72 and B2702PA, aa 60-80) mimic cytokeratin and are able to induce in vitro proliferation of human peripheral blood lymphocytes as well as arthritis in Lewis rats. Here we show that the pathogenic epitope recognized by autoaggressive rat T cells is located at the N-terminus of the sequence, between aa 60 and 72. A C-terminally elongated 25mer peptide (B2702.60-84) showed increased pathogenicity, indicating either a second arthritogenic epitope or an immunomodulatory region within this peptide. B2702.60-84 has been described to inhibit murine and human CD8 + cytotoxic T cells (CTL) and was even successfully used for the treatment of allograft rejection. In addition to pathogenicity we have investigated the immunomodulatory effect of peptide B2702.60-84 in our rat model of experimental autoimmune uveitis (EAU), induced with retinal S-Antigen peptide PDSAg. We found that disease exacerbated following coimmunization of PDSAg with B2702.60-84. In vitro, the B27-peptide enhanced the proliferation of CD4+ T cell lines specific for retinal autoantigen peptides during coincubation of B2702.60-84 with the respective antigen. Oral tolerance induction, an effective mechanism to prevent uveitis in Lewis rats, is abrogated by cofeeding peptide B2702.60-84 with the tolerogen PDSAg. In rat EAU, naturally occurring regulatory T cells and orally induced gamma deltaTCR+ suppressor cells are CD8+ which might be impeded by peptide B2702.60-84. As a consequence of their abrogated suppressive capacity disease was exacerbated. We propose a similar role of HLA-B27 in man: disturbing the mechanisms down-regulating self-responses might lead to autoimmune diseases. This could explain the high association of HLA-B27 with a variety of autoimmune diseases targeting different organs or tissues.
Diedrichs-Möhring
Maria
M
Section of Immunobiology, Department of Ophthalmology, Ludwig-Maximilians-University, Mathildenstr. 8, 80336 Munich, Germany. maria.diedrichs-moehring@med.uni-muenchen.de
Wildner
Gerhild
G
D000595:Amino Acid Sequence; D000818:Animals; D001168:Arthritis / Q000139:chemically induced; D001327:Autoimmune Diseases / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000276:immunology* / Q000494:pharmacology; D007108:Immune Tolerance / Q000276:immunology; D007633:Keratins / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D014605:Uveitis / Q000139:chemically induced
D015796:HLA-B27 Antigen; D010446:Peptide Fragments; D007633:Keratins