| dc.description.abstracteng | Multiple sclerosis (MS) is one of the most common causes of persisting disability in young adults. Its clinical course can be heterogeneous with a varying extent of inflammatory central nervous system (CNS) lesions, demyelination and axonal loss accumulating over time. Earlier concepts assumed that MS is primarily a T cell driven disease. Current evidence suggests that B cells may play an equally important role in MS pathogenesis. This notion was boosted by the extensive and rapid benefit of B cell depletion via anti-CD20 antibodies in recent clinical trials in patients with relapsing, remitting MS. Notwithstanding these results, it is currently not clear whether patients with MS and related disorders need to be permanently depleted of B cells to maintain clinical stabilisation. As the related mechanistic question, it is thus far unknown when B cells reappear in compartments other than the blood and in particular, in what functional status B cells return upon cessation of anti-CD20 treatment. To address these questions, we utilized two murine MS models of experimental autoimmune encephalomyelitis (EAE), one in which B cells remain naïve, and one on which B cells get actively involved in a pathogenic manner. Using these opposing models, we monitored reappearance of B cells as well as their functional phenotype in bone marrow, spleen, lymph node, blood as well as the CNS. First, and independent of the model used, we observed that B cells reappeared in bone marrow and spleen substantially prior to the blood, which indicates that monitoring B cells in the blood of patients may not be a suitable strategy to assess B cell reappearance. Second, we observed that despite extensive anti-CD20 treatment, a population of CD20+ B cells remained un-depletable in the spleen of mice with EAE. These B cells were found to be differentiated and antigen-experienced germinal center B cells, while naïve B cells were rarely detected. Of note, this finding was pronounced in the EAE model in which B cells are activated. Upon recovery from anti-CD20 treatment, this population strongly expanded in vivo in parallel to de novo generation of naïve B cells in the bone marrow. I consequence, we observed that upon return of B cells, mice which had received the B cell-involving EAE induction regimen contained a higher ratio of antigen-activated / naïve B cells when compared to the EAE model in which B cells remain naïve. Functionally, this translated into an enhanced antigen-presenting function of reappearing B cells in the B cell-EAE model. These findings indicate that in a B cell activating milieu, remaining antigen-experienced B cells can expand in secondary organs after anti-CD20 treatment, which may result in a relative shift towards pro-inflammatory B cell function when compared to the status of B cells prior to depletion.
Recent findings suggest that besides B cells, a small population of differentiated human T cells express CD20. To date it is not clear whether these T cells play a pathogenic role in MS. Following this observation mechanistically, we could detect that mice with EAE indeed contain a population of CD20+ T cells, which is rapidly depleted upon anti-CD20 treatment. Paralleling the compartment-specific repletion of B cells, CD20+ T cells sequentially reoccurred in spleen, lymph nodes and blood after anti CD20 treatment. Further studies aim to dissect to what extent depletion of these T cells may possibly contribute to the clinical benefit of anti-CD20 treatment independent of B cells. | de |