Humoral autoimmunity in multiple sclerosis

The important role of B cells and autoantibodies in the pathogenesis of MS is increasingly appreciated. The recruitment and maintenance of B cells and plasma cells in MS lesions is presumably based on local production of lymphoid chemokines and B cell activation factor of the TNF family (BAFF). The failure of the clinical trial with Atacicept targeting BAFF and its relative APRIL was a great surprise and cannot readily be explained. A role for BAFF in CNS physiology, e.g. via targeting of the Nogo-66 receptor might have to be considered. The identification of patient subgroups based on autoantibodies is a future challenge. Currently patients with neuromyelitis optica (NMO) can be identified by antibodies to aquaporin 4 and about a third of children with acquired demyelinating diseases have antibodies against conformationally correct MOG, while such antibodies are hardly found in adult MS patients. Searching for new targets of the autoimmune response in adult MS patients, we have identified two axo-glial proteins focused around the node of Ranvier, namely neurofascin and contactin-2/TAG-1. Testing the functional relevance of such an autoimmune response in animal models revealed that antibodies to neurofascin may induce axonal injury and that T cells specific for contactin-2/TAG-1 mediate preferentially gray matter injury.