Clonal expansions of CD4+ B helper T cells in autoimmune myasthenia gravis

The weakness in myasthenia gravis (MG) is mediated by T helper cell (Th)-dependent autoantibodies against neuromuscular epitopes. So far, analyzing Th phenotypes or antigen specificities has yielded very few clues to pathogenesis. Here we adopt an alternative antigen-independent approach, analyzing T cell receptor (TCR) V beta usage/expansions in blood from 118 MG patients. We found major expansions (>= five standard deviations above the mean of 118 healthy, individually age- and sex-matched controls) in diverse V beta in 21 patients (17.6%, p < 0.001) among CD4(+) T cells, and in 45 patients (38.1%, p < 0.001) among CD8(+) T cells. In informative probands, the expanded CD4(+) cells consistently showed a Th cell phenotype (CD57(+)CXCR5(+)) and expressed Th1 cytokines. Furthermore, their expression of markers for activation, lymphocyte trafficking and B cell-activating ability persisted for >= 3 years. Surprisingly, we noted a selective decline in the expansions/their CD57 positivity while the probands' MG was improving. CDR3 spectratyping suggested mono- or oligoclonal origins, which were confirmed by the prevalent TCRV beta CDR3 sequences of Th cells cloned from repeat bleeds. Thus, our data provide evidence for persistent clonally expanded CD4(+) B helper T cell populations in the blood of MG patients. These unexpected CD4(+) expansions might hold valuable clues to MG immunopathogenesis.