Regulatory B cells in multiple sclerosis - functional characterization and therapeutic implication
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). For decades, T cells have been believed to be the key effector cells in MS. Nowadays however, B cells are known to be equally important disease drivers: they act as antigen-presenting cells for auto-reactive T cells, and serve as source of proinflammatory cytokines and CNS-reactive antibodies, altogether nourishing chronic CNS inflammation. Thus, anti-CD20 antibody-mediated depletion of B cells enables an excellent therapeutic control of acute relapses in people with MS. However, besides these proinflammatory features, B cells also possess opposing anti-inflammatory properties: they express inhibitory cytokines and surface molecules, which potentially slow down MS progression, but are inevitably eliminated by many current therapies, such as CD20-mediated pan B cell-depletion. Within the scope of this DFG project, we hence aimed to characterize anti-inflammatory features of B cells in people with MS to elaborate whether they might be worth to be maintained when developing new MS therapies. First, we investigated whether B cell immune phenotyping identifies people with MS with pathogenic B cell involvement and whether the B cell phenotype before therapy initiation correlated with the effects of anti-CD20-mediated B cell depletion. Based on the relative occurrence of naïve versus memory B cells in the blood of our study participants, we stratified our MS cohort into two groups: the memory/balanced or the naïve B cell type. Correlating these groups with the effect of anti-CD20 treatment, we observed that people with a memory/balanced B cell type showed relatively extended differences in the T cell phenotype upon B cell depletion, suggesting a loss of T cell stimulation by differentiated B cells. On the other hand, patients with a naive B cell phenotype showed partially opposite changes in the T cell compartment. Regarding myeloid cells, pan B cell depletion was associated with an upregulated activity of myeloid cells in the blood. In contrast to T cells, these changes were not determined by the preexisting B cell phenotype. In conclusion, these immunological alterations most likely represent the loss of B cell regulatory properties, which in our conception inevitably occurs upon nonselective B cell depletion. In this context, we then identified IL-10 as a key factor in controlling pro-inflammatory activity of both peripheral myeloid cells and CNS microglia. Depleting B cells via anti-CD20 in a mouse model of MS unleashed the activity of myeloid cells and microglia and accelerated disease severity; in contrast, adoptive transfer of IL-10-providing B cells restored in vivo control of CNS macrophages and microglia and reversed clinical exacerbation. In conclusion, these findings suggest that B cells exert meaningful regulatory properties, e.g. via IL-10, which we suggest to be considered when designing novel B cell-directed agents.
Publications
-
Immunological phenotyping identifies MS patients with accentuated immune cell activation upon anti-CD20 treatment. 34th Congress of the European committee for treatment and research in multiple sclerosis, October 10th–12th 2018, Berlin, Germany, Oral presentation
Häusser-Kinzel S., Nissimov N., Torke S., Pellkofer H., Brück W. & Weber M.S.
-
Immunophenotyping identifies a subgroup of MS patients that experiences pro-inflammatory immune cell activation upon B cell-depleting therapy. 35th Congress of the European committee for treatment and research in multiple sclerosis, September 11th–13th 2019, Stockholm, Sweden, Poster presentation
Häusser-Kinzel S., Nissimov N., Hajiyeva Z., Brück W. & Weber M.S.
-
In multiple sclerosis patients, B cells repopulate immature yet more activated upon anti-CD20 antibody therapy. 27th Annual Meeting of the European Charcot Foundation, November 21st–23th 2019, Baveno, Italy, Poster presentation
Nissimov N., Hajiyeva Z., Brück W., Häusser-Kinzel S. & Weber M.S.
-
B cells reappear less mature and more activated after their anti-CD20–mediated depletion in multiple sclerosis. Proceedings of the National Academy of Sciences, 117(41), 25690-25699.
Nissimov, Nitzan; Hajiyeva, Zivar; Torke, Sebastian; Grondey, Katja; Brück, Wolfgang; Häusser-Kinzel, Silke & Weber, Martin S.
-
B cells regulate chronic CNS inflammation in an IL-10-dependent manner. 8th Joint Conference of the European and American committee for treatment and research in multiple sclerosis, September 11th–13th 2020, Virtual meeting, Oral presentation
Geladaris A., Häusler D., Brück W. & Weber M.S.
-
The role of B cell-derived IL-10 in regulation of chronic CNS inflammation. 37th Congress of the European committee for treatment and research in multiple sclerosis, October 13th–15th 2021, Virtual meeting, Oral presentation
Geladaris A., Häusler D., Brück W. & Weber M.S.
-
Regulatory B cells ameliorate chronic CNS inflammation in an interleukin-10-dependent manner. 15th Congress of the International Society of Neuroimmunology, November 8th–12th 2021, Nice, France, Virtual meeting, Oral and poster presentation
Häusser-Kinzel S., Geladaris A., Häusler D., Brück W. & Weber M.S.
-
Interleukin-10 secreting B cells regulate myeloid phagocytes and microglia, ameliorating chronic central nervous system inflammation. 38th Congress of the European committee for treatment and research in multiple sclerosis, October 26th–28th 2022, Amsterdam, The Netherlands, Oral presentation
Häusser-Kinzel S., Geladaris A., Pretzsch R., Nissimov N., Lehmann-Horn K., Häusler D. & Weber M.S.
-
IL-10-providing B cells govern pro-inflammatory activity of macrophages and microglia in CNS autoimmunity. Acta Neuropathologica, 145(4), 461-477.
Geladaris, Anastasia; Häusser-Kinzel, Silke; Pretzsch, Roxanne; Nissimov, Nitzan; Lehmann-Horn, Klaus; Häusler, Darius & Weber, Martin S.
