Abstract
Abstract The etiology of MS is unclear, but autoimmunity plays a significant role. The autoimmune components are defined in the EAE model yet defining a biomarker remains problematic. We described a cell subset, Th40 cells, which proved highly auto-aggressive in diabetes. We compared Th40 levels in 90 MS subjects including clinically isolated syndrome (CIS), relapsing/remitting (RRMS) and secondary progressive (SPMS) patients to non-autoimmune controls. Diagnosed MS subjects have significantly increased percentages of Th40 cells in PBL compared to controls. Th40 cells produce pro-inflammatory cytokines. HLA haplotypes of MS patients were diverse although many carry DR2 (DR15). Th40 cells were elevated in MS patients regardless of HLA haplotype. Th40 cells responded to CNS antigens in an HLA dependent fashion. TRAV 8.1.3+ cells were expanded within the Th40 population in MS subjects. We used the EAE model to better define Th40 cells. EAE induction drastically expanded Th40 cell levels prior to symptoms. Th40 cells produce IFNg and IL-17 and infiltrate both brain and spinal cord. Th40 cells transfer EAE but surprisingly CD4+CD40- T cells also did but significantly (p < 0.001) more slowly and with less severity. CD4+CD40- cells became CD40+; suggesting the disease process induces CD40 on T cells. CD40flox.CD4.Cre mice did not develop EAE even after multiple disease induction attempts. These data suggest an important role for CD40 in T cell pathogenesis of MS and EAE.
Published Version
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