Lancet Neurol. 2015 Dec 23. pii: S1474-4422(15)00334-8.
Identification of the target antigens of pathogenic antibodies and T cells is of fundamental importance for understanding the pathogenesis of multiple sclerosis, and for the development of personalised treatments for the disease. Myelin-specific CD4+ T cells emerged long ago as a key player in animal models of multiple sclerosis. Taking a forward-translational approach, autoreactive CD4+ T cells have been studied extensively in patients with multiple sclerosis, and there is evidence, but as yet no direct proof, that autoreactive CD4+ T cells are a key player in the pathogenesis of the disorder. Several therapies that selectively target myelin-specific CD4+ T cells have been investigated in clinical trials up to phase 3. So far, however, none of these (mostly underpowered) therapeutic trials have provided definitive evidence of clinical efficacy. One major obstacle to personalised, highly selective immunotherapy is the absence of standardised and reliable assays to assess antigen-specific human T-cell responses. Such assays would be essential for stratification of patients with multiple sclerosis according to their individual target antigens.
The search for the target antigens of multiple sclerosis, part 2: CD8+ T cells, B cells, and antibodies in the focus of reverse-translational research.Hohlfeld R, Dornmair K, Meinl E, Wekerle H. Lancet Neurol. 2015 Dec 23. pii: S1474-4422(15)00313-0.
Interest in CD8+ T cells and B cells was initially inspired by observations in multiple sclerosis rather than in animal models: CD8+ T cells predominate in multiple sclerosis lesions, oligoclonal immunoglobulin bands in CSF have long been recognised as diagnostic and prognostic markers, and anti-B-cell therapies showed considerable efficacy in multiple sclerosis. Taking a reverse-translational approach, findings from human T-cell receptor (TCR) and B-cell receptor (BCR) repertoire studies provided strong evidence for antigen-driven clonal expansion in the brain and CSF. New methods allow the reconstruction of human TCRs and antibodies from tissue-infiltrating immune cells, which can be used for the unbiased screening of antigen libraries. Myelin oligodendrocyte glycoprotein (MOG) has received renewed attention as an antibody target in childhood multiple sclerosis and in a small subgroup of adult patients with multiple sclerosis. Furthermore, there is growing evidence that a separate condition in adults exists, tentatively called MOG-antibody-associated encephalomyelitis, which has clinical features that overlap with neuromyelitis optica spectrum disorder and multiple sclerosis. Although CD8+ T cells and B cells are thought to have a pathogenic role in some subgroups of patients, their target antigens have yet to be identified.