Dataset Information

HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis

ABSTRACT: Autoimmune diseases are often associated with HLA molecules. Multiple sclerosis (MS) is a prototypical example with the HLA-DR15 haplotype as strongest genetic factor. How it contributes to MS is not clear, but key to understand this and other autoimmune diseases. Autoreactive CD4+ T cells and proinflammatory B cells are central pathogenetic factors, and since HLA-DR molecules present peptides to CD4+ T cells, we characterized the peptidomes of the two HLA-DR15 allomorphs DR2a and DR2b on B cells. Self-peptides from HLA-DR α- and β-chains themselves are abundantly presented on B cells. We identified autoreactive CD4+ T cell clones, which recognize HLA-DR-derived self-peptides and peptides from the MS-related infectious agents EBV and Akkermansia and the autoantigen RAS guanyl-releasing protein 2. Our data demonstrate how the two MS-associated HLA-DR15 allomorphs function as antigen-presenting structures and source of peptides during peripheral maintenance of autoreactive T cells and activation by MS-associated pathogens.

INSTRUMENT(S): LTQ Orbitrap XL

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Monocyte, Blood

DISEASE(S): Multiple Sclerosis

SUBMITTER: Lena Mühlenbruch

LAB HEAD: Stefan Stevanović

PROVIDER: PXD015249 | Pride | 2020-10-22

REPOSITORIES: Pride

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Publications

HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis.

Wang Jian J Jelcic Ivan I Mühlenbruch Lena L Haunerdinger Veronika V Toussaint Nora C NC Zhao Yingdong Y Cruciani Carolina C Faigle Wolfgang W Naghavian Reza R Foege Magdalena M Binder Thomas M C TMC Eiermann Thomas T Opitz Lennart L Fuentes-Font Laura L Reynolds Richard R Kwok William W WW Nguyen Julie T JT Lee Jar-How JH Lutterotti Andreas A Münz Christian C Rammensee Hans-Georg HG Hauri-Hohl Mathias M Sospedra Mireia M Stevanovic Stefan S Martin Roland R

Cell 20201021 5

The HLA-DR15 haplotype is the strongest genetic risk factor for multiple sclerosis (MS), but our understanding of how it contributes to MS is limited. Because autoreactive CD4<sup>+</sup> T cells and B cells as antigen-presenting cells are involved in MS pathogenesis, we characterized the immunopeptidomes of the two HLA-DR15 allomorphs DR2a and DR2b of human primary B cells and monocytes, thymus, and MS brain tissue. Self-peptides from HLA-DR molecules, particularly from DR2a and DR2b themselves ...[more]

PMID: 33091337

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Project description:HLA-DR molecules are highly expressed in synovial tissue (ST), the target of the immune response in chronic inflammatory arthritides, including in rheumatoid arthritis (RA) and Lyme arthritis (LA). In the current study, we identified HLA-DR-presented self-peptides (T cell epitopes) in ST, synovial fluid mononuclear cells (SF), and peripheral blood mononuclear cells (PB) from five patients with RA and eight with LA. Altogether, from 22 samples, 1,532 non-redundant HLA-DR-presented peptides were identified that were derived from 778 source proteins. Moreover, as the study progressed, application of newer, high sensitivity LC-MS instruments resulted in the identification of larger numbers of HLA-DR-presented peptides. Surprisingly, the source proteins for HLA-DR-presented peptides were as likely to have intracellular as extracellular locations. Although the number of peptides identified was greater in ST than in SF or PB, 68% of the peptides identified in SF were found in ST, and 55% of the peptides in PB were found in ST. Two RA patients had the same HLA-DR genotype (DRB1*0401 and 0101), and 44% of the peptides identified in these two patients were the same. In contrast, among the patients with RA or LA who had no shared HLA-DR alleles, only 6% of the peptides were the same. In the RA patients, HLA-DR-presented peptides were identified from source proteins that are thought to serve as potential autoantigens: collagen, enolase, fibrinogen, fibronectin, immunoglobulin and vimentin. Interestingly, peptides from these same source proteins were also commonly found in LA patients. However, citrullinated T cell epitopes were not identified in any patient. Thus, LC-MS/MS techniques are now sensitive enough to identify large numbers of T cell epitopes from tissue or fluids in individual patients. Importantly, analysis of SF or PB allowed us to identify a broader range of HLA-DR-presented self-peptides from individual patients and from patients seen earlier in the disease.

Dataset Information

HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis

Publications

HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis.

Similar Datasets

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