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

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(+) T cells and B cells as antigen-presenting cells are involved in MS pathogenesis, we characterized the immunopeptidomes of...

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Detalles Bibliográficos
Autores principales: Wang, Jian, Jelcic, Ivan, Mühlenbruch, Lena, Haunerdinger, Veronika, Toussaint, Nora C., Zhao, Yingdong, Cruciani, Carolina, Faigle, Wolfgang, Naghavian, Reza, Foege, Magdalena, Binder, Thomas M.C., Eiermann, Thomas, Opitz, Lennart, Fuentes-Font, Laura, Reynolds, Richard, Kwok, William W., Nguyen, Julie T., Lee, Jar-How, Lutterotti, Andreas, Münz, Christian, Rammensee, Hans-Georg, Hauri-Hohl, Mathias, Sospedra, Mireia, Stevanovic, Stefan, Martin, Roland
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707104/
https://www.ncbi.nlm.nih.gov/pubmed/33091337
http://dx.doi.org/10.1016/j.cell.2020.09.054
Descripción
Sumario: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(+) 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, are abundant on B cells and thymic antigen-presenting cells. Furthermore, we identified autoreactive CD4(+) T cell clones that can cross-react with HLA-DR-derived self-peptides (HLA-DR-SPs), peptides from MS-associated foreign agents (Epstein-Barr virus and Akkermansia muciniphila), and autoantigens presented by DR2a and DR2b. Thus, both HLA-DR15 allomorphs jointly shape an autoreactive T cell repertoire by serving as antigen-presenting structures and epitope sources and by presenting the same foreign peptides and autoantigens to autoreactive CD4(+) T cells in MS.