title: HLA-DR15-derived self-peptides are involved in increased autologous T cell proliferation in multiple sclerosis.
abstract: The HLA-DR15 haplotype confers the largest part of the genetic risk to develop multiple sclerosis, a prototypic CD4+ T cell-mediated autoimmune disease. The mechanisms how certain HLA-class II molecules functionally contribute to autoimmune diseases are still poorly understood, but probably involve shaping an autoimmune-prone T cell repertoire during central tolerance in the thymus and subsequently maintaining or even expanding it in the peripheral immune system. Self-peptides that are presented by disease-associated HLA-class II molecules most likely play important roles during both processes. Here, we examined the functional involvement of the HLA-DR15 haplotype in autologous proliferation in multiple sclerosis and the contribution of HLA-DR15 haplotype-derived self-peptides in an in vitro system. We observe increased autologous T cell proliferation in patients with multiple sclerosis in relation to the multiple sclerosis risk-associated HLA-DR15 haplotype. Assuming that the spectrum of self-peptides that is presented by the two HLA-DR15 allelic products is important for sustaining autologous proliferation we performed peptide elution and identification experiments from the multiple sclerosis-associated DR15 molecules and a systematic analysis of a DR15 haplotype-derived self-peptide library. We identify HLA-derived self-peptides as potential mediators of altered autologous proliferation. Our data provide novel insights about perturbed T cell repertoire dynamics and the functional involvement of the major genetic risk factor, the HLA-DR15 haplotype, in multiple sclerosis.
authors.affiliation: Institute for Neuroimmunology and Clinical Multiple Sclerosis Research, Centre for Molecular Neurobiology Hamburg, University Medical Centre Eppendorf, 20251 Hamburg, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Mohme
authors.forename: Christian
authors.initials: C
authors.lastname: Hotz
authors.forename: Stefan
authors.initials: S
authors.lastname: Stevanovic
authors.forename: Thomas
authors.initials: T
authors.lastname: Binder
authors.forename: Jar-How
authors.initials: JH
authors.lastname: Lee
authors.forename: Michal
authors.initials: M
authors.lastname: Okoniewski
authors.forename: Thomas
authors.initials: T
authors.lastname: Eiermann
authors.forename: Mireia
authors.initials: M
authors.lastname: Sospedra
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Rammensee
authors.forename: Roland
authors.initials: R
authors.lastname: Martin
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001324:Autoantigens / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D059810:HLA-DR Serological Subtypes / Q000502:physiology*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000235:genetics / Q000473:pathology*; D010446:Peptide Fragments / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D001324:Autoantigens; D059810:HLA-DR Serological Subtypes; C106559:HLA-DR15 antigen; D010446:Peptide Fragments
keywords: HLA-DR15; autologous T cell proliferation; homeostatic proliferation; multiple sclerosis; self-peptides