Genetic control of multiple sclerosis: increased production of lymphotoxin and tumor necrosis factor-alpha by HLA-DR2+ T cells.
Lymphotoxin (LT) and tumor necrosis factor-alpha (TNF-alpha) play an important role in the pathogenesis of multiple sclerosis (MS). MS is associated with the HLA-DR2, Dw2, DQ6 HLA class II haplotype. Because both LT and TNF-alpha are encoded in the HLA region, the HLA association of MS may be related to the production of these cytokines. To test this hypothesis, we investigated the production of LT, TNF-alpha, and interferon-gamma (IFN-gamma) by CD4+ T-cell lines (TCLs) specific for myelin basic protein (MBP) or tetanus toxoid (TT) isolated from MS patients and normal controls. After stimulation with specific antigen but not mitogen, TCLs from HLA-DR2+ donors produced significantly more LT and TNF-alpha than TCLs from DR2- donors. In contrast, HLA-DR2+ and DR2- TCLs did not differ in the production of IFN-gamma, a cytokine also produced by T cells but not encoded in the HLA region. Increased secretion of LT and TNF-alpha was unrelated to the specificity (MBP vs TT), MHC restriction (HLA-DR2 vs other DR molecules), or source (MS vs normal) of the TCLs. There was no significant association of the cytokine production with individual LT or TNF-alpha alleles, indicating that the increased production of these cytokines may be linked to other polymorphic genes in this region. The results suggest that the association of MS with HLA-DR2 implies a genetically determined propensity of T cells to produce increased amounts of LT and TNF-alpha.
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004198:Disease Susceptibility; D004797:Enzyme-Linked Immunosorbent Assay; D015802:HLA-DR2 Antigen / Q000032:analysis* / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology; D008233:Lymphotoxin-alpha / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology*; D011110:Polymorphism, Genetic; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D015802:HLA-DR2 Antigen; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma