B cells and multiple sclerosis.

Clonal expansion of B cells and the production of oligoclonal IgG in the brain and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) have long been interpreted as circumstantial evidence of the immune-mediated pathogenesis of the disease and suggest a possible infectious cause. Extensive work on intrathecally produced antibodies has not yet clarified whether they are pathogenetically relevant. Irrespective of antibody specificity, however, the processes of antibody synthesis in the CNS of patients with MS are becoming increasingly clear. Likewise, targeting B cells might be therapeutically relevant in MS and other autoimmune diseases that are deemed to be driven predominantly by T cells. Accumulating evidence indicates that in MS, similar to rheumatoid arthritis, B cells aggregate into lymphoid-like structures in the target organ. The process of aggregation is mediated through the expression of lymphoid-homing chemokines. In the brain of a patient with MS, ectopic B-cell follicles preferentially adjoin the pial membrane within the subarachnoid space. Recent findings indicate that substantial numbers of B cells that are infected with Epstein-Barr virus (EBV) accumulate in these intrameningeal follicles and in white matter lesions and are probably the target of a cytotoxic immune response. These findings, which await confirmation, could be an explanation for the continuous B-cell and T-cell activation in MS, but leave open concerns about the possible pathogenicity of autoantibodies. Going beyond the antimyelin-antibody dogma, the above data warrant further work on various B-cell-related mechanisms, including investigation of B-cell effector and regulatory functions, definition of the consistency of CNS colonisation by Epstein-Barr virus-infected B cells, and understanding of the mechanisms that underlie the formation and persistence of tertiary lymphoid tissues in patients with MS and other chronic autoimmune diseases (ectopic follicle syndromes). This work will stimulate new and unconventional ways of reasoning about MS pathogenesis.