Premium
Genetic control of multiple sclerosis: Increased production of lymphotoxin and tumor necrosis factor‐α by HLA‐DR2 + T cells
Author(s) -
Zipp Frauke,
Weber Frank,
Huber Susanne,
Sotgiu Stefano,
Czlonkowska Anna,
Holler Ernst,
Albert Ekkehard,
Weiss Elisabeth H.,
Wekerle Hartmut,
Hohlfeld Reinhard
Publication year - 1995
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410380506
Subject(s) - lymphotoxin , immunology , tumor necrosis factor alpha , cytokine , lymphotoxin alpha , human leukocyte antigen , major histocompatibility complex , biology , myelin basic protein , antigen , pathogenesis , toxoid , multiple sclerosis , myelin , endocrinology , central nervous system , immunization
Abstract Lymphotoxin (LT) and tumor necrosis factor‐α (TNF‐α) 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‐α 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‐α, and interferon‐γ (IFN‐γ) 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‐α, than TCLs from DR2 − donors. In contrast, HLA‐DR2 + and DR2 − TCLs did not differ in the production of IFN‐γ, a cytokine also produced by T cells but not encoded in the HLA region. Increased secretion of LT and TNF‐α 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‐α 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‐α.