Immunological phenotyping identifies a subgroup of MS patients experiencing a proinflammatory immune cell activation upon therapeutic B cell removal

Objective: To study how anti-CD20 treatment of multiple sclerosis (MS) patients affects activation and cytokine production of myeloid antigen-presenting cells (APC) and T cells and whether a pre-existing regulatory B cell phenotype correlates with the extent of immune cell activation upon therapeutic B cell removal. Background: In MS, B cell-depleting anti-CD20 antibodies efficiently reduce relapses and central nervous system lesion formation by abrogating APC function and pro-inflammatory cytokine secretion of B cells. However, B cells are moreover capable of regulating immune cells via anti-inflammatory cytokines, e.g. interleukin-10, a property which may be concomitantly eradicated by anti-CD20. Design/Methods: To study the influence of B cells on other immune cells, we co-cultured murine macrophages, B and T cells in various settings. To investigate the effects of anti-CD20, we collected peripheral blood mononuclear cells of MS patients before and after treatment initiation and assessed phenotype and cytokine signature of B, T and myeloid cells by flow cytometry and ELISPOT. Results: We identified a triangle of B, T and myeloid cells, in which B cell-derived interleukin-6 enhanced myeloid APC and T cell activation. Conversely, B cell-produced interleukin-10 regulated the APC-T cell axis in an anti-inflammatory manner. Reflecting these interactions, we identified distinct subgroups of MS patients with a pro-versus anti-inflammatory differentiation of monocytes and T cells after therapeutic removal of B cells. Conclusions: The B cell-generated cytokine milieu is capable of shaping the activity of other immune cells. While in most MS patients, anti-CD20 treatment resulted in a desirable immunological outcome, others displayed an accentuated immune cell activation. We hypothesize that the latter situation reflects the loss of pre-existing B cell regulation, which we are currently evaluating. In context with clinical data, these investigations aim to generate immunological biomarkers to identify individual patients in whom B cells should not be unselectively eradicated. Disclosure: Dr. Hausser-Kinzel has nothing to disclose. Dr. Nissimov has nothing to disclose. Dr. Hajiyeva has nothing to disclose. Dr. Brueck has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Bayer Vital, Biogen, Merck Serono, Teva Pharma, Genzyme, Sanofi-Aventis and Novartis. Dr. Brueck has received personal compensation in an editorial capacity for Neuropathology and Applied Neurobiology, Multiple Sclerosis International and Therapeutic Advances in Neurological Disorders. Dr. Brueck has received research support from Teva Pharma, Biogen, Novartis and Genzyme. Dr. Weber has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen-Idec, Merck Serono, Novartis, Roche, TEVA, Bayer and Genzyme. Dr. Weber has received research support from Deutsche Forschungsgemeinschaft, Novartis, TEVA, Biogen-Idec, Roche, Merck and the ProFutura Program of the Universitatsmedizin Gottingen.