Characterization of reappearing CD20⁺ B cells in the bone marrow, blood and secondary lymphoid organs after transient anti-CD20 treatment in murine experimental autoimmune encephalomyelitis (EAE).

Recent trials revealed that repetitively applied anti-CD20 antibodies reduce the frequency of relapses and development of central nervous system (CNS) lesions in multiple sclerosis (MS). However, it is largely unknown whether patients with MS or related demyelinating disorders must be continuously depleted of B cells to achieve this benefit or whether alternatively anti-CD20 intervention can lastingly reset disease-driving B cell function.

C57BL/6 mice received 3 weekly subcutaneous injections of 0.2 mg murine anti-CD20 or control antibody prior to immunization with a) MOG peptide p35–55, a setting in which B cells remain naive or b) MOG protein 1–117, a setting in which B cells get activated. Reappearing B cells were phenotypically analyzed for expression of activation markers, co-stimulatory molecules, B cell receptor diversity and antigen presentation function.

In both models, a fraction of CD20⁺ antigen-experienced B cells persisted in splenic follicles despite extensive systemic anti-CD20 application. Upon treatment cessation, CD20⁺ B cells simultaneously repopulated in bone marrow and spleen before their reappearance in blood. Returning B cell population, showed a shift towards mature, differentiated phenotypes containing an increased frequency of myelin-reactive B cells with restricted B cell receptor gene diversity and enhanced capability to activate myelin-specific T cells in the model in which B cells are intrinsically activated. By contrast, in the T cell-mediated EAE model, B cells reappeared in a predominantly naïve status with a relative loss of pathogenic APC function.

These findings highlight that distinct subpopulations of B cells differ in their sensitivity to anti-CD20 treatment and suggest that differentiated B cells persisting in secondary lymphoid organs contribute to the recovering B cell pool.

Disclosure: Dr. Häusler has nothing to disclose. Dr. Häusser-Kinzel has nothing to disclose. Dr. Feldmann has nothing to disclose. Dr. Torke has nothing to disclose. Dr. Lepennetier has nothing to disclose. Dr. Bernard has nothing to disclose. Dr. Zamvil has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis, Genzyme, Teva. Dr. Zamvil has received personal compensation in an editorial capacity for AAN. Dr. Zamvil has received research support from Biogen, Teva and Celgene. 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. Lehmann-Horn has nothing to disclose. 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.