Myelin Autoreactivity in Multiple Sclerosis: Recognition of Myelin Basic Protein in the Context of HLA-DR2 Products by T Lymphocytes of Multiple- Sclerosis Patients and Healthy Donors

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 87; no. 20; pp. 7968 - 7972
• Main Authors: Pette, Martin, Fujita, Kyoko, Wilkinson, David, Altmann, Daniel M., Trowsdale, John, Giegerich, Gerhard, Hinkkanen, Ari, Epplen, Jorg T., Kappos, Ludgwig, Wekerle, Hartmut
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.10.1990; National Acad Sciences
• Subjects: Adult; Animals; Antigens; Biological and medical sciences; Cell lines; Data lines; Epitopes; Epitopes - analysis; Female; Haplotypes; HLA-DR2 Antigen - genetics; HLA-DR2 Antigen - immunology; HLA-DR2 Antigen - isolation & purification; Humans; L cells; L Cells (Cell Line) - immunology; Major Histocompatibility Complex; Male; Medical sciences; Mice; Molecules; Multiple sclerosis; Multiple Sclerosis - immunology; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Myelin; Myelin Basic Protein - immunology; Neurology; Reference Values; T lymphocytes; T-Lymphocytes - immunology; Transfection; Human; Antigen presentation; Multiple sclerosis; Nervous system diseases; Antigenic determinant; Radiolabelling; Myelin; T-Lymphocyte; Autoantibody; Autoimmune disease; HLA»-System
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.87.20.7968

A panel of 20 human myelin basic protein (hMBP)-specific T-lymphocyte lines was generated from the peripheral blood of eight multiple sclerosis (MS) patients and two healthy donors, most of them expressing the HLA-DR2 haplotype, which is associated with an increased susceptibility to MS. Using HLA-DR gene-transfected mouse L-cell lines as antigen-presenting cells, we established that of the 20 hMBP-specific T-lymphocyte lines, 7 were restricted by the DR2a gene products of the DR2Dw2 haplotype. Four T-cell lines recognized hMBP in the context of the DR2b products of the DR2Dw2 haplotype. DR2b-restricted T-cell responses were demonstrable only in T-cell lines derived from MS patients. The hMBP epitopes presented by the DR2a heterodimer were mapped to peptides covering amino acid residues 1-44, 76-91, 131-145, or 139-153 and to a region spanning the thrombin-cleaved bond at Arg130-Ala131. DR2b-restricted T-cell lines recognized epitopes within amino acids 80-99 and 148-162. Peptide 139-153 was also presented in the context of HLA-DR1 molecules. Our data show that (i) in MS patients both the DR2a and DR2b products of the DR2Dw2 haplotype function as restriction elements for the myelin autoantigen hMBP, (ii) the DR2a molecule presents at least five different epitopes to hMBP-specific T lymphocytes, and (iii) anti-hMBP T-cell lines derived from individual donors can differ in their antigen fine specificity as well as in their HLA restriction.