CNS Autoimmune Responses in BCMA-Deficient Mice Provide Insight for the Failure of Atacicept in MS. Issue 3 (May 2021)

• Record Type: Journal Article
• Authors: Kumar, Gaurav; Maria, Zahra; Kohli, Uday; Agasing, Agnieshka; Quinn, James L.; Ko, Rose M.; Zamvil, Scott S.; Axtell, Robert C.
• Is Part Of: Neurology. Volume 8:Issue 3(2021)
• Publication Date: 2021-05
• Subjects: Neuroimmunology -- Periodicals; Neurology -- Periodicals; 616.8
• DOI: 10.1212/NXI.0000000000000973
• Languages: English
• ISSNs: 2332-7812

Abstract

Abstract : Objective: B cells have emerged as a therapeutic target for MS. Anti-CD20 antibodies, which deplete B cells, are effective therapies for MS. However, atacicept (TACI-Fc), which blocks BAFF and APRIL and reduces B cells, unexpectedly exacerbates MS. We tested the hypothesis that B cell maturation antigen (BCMA), a receptor for BAFF and APRIL, plays a role in the paradoxical effects of anti-CD20 antibody and TACI-Fc using experimental autoimmune encephalomyelitis (EAE). Methods: EAE was induced in wild-type (BCMA +/+ ) and BCMA-deficient (BCMA −/− ) mice with an immunization of rodent myelin oligodendrocyte glycoprotein (MOG)35–55 peptide. Treatment with anti-CD20 antibody, TACI-Fc, and isotype controls was administered by intraperitoneal injections. CNS infiltration was evaluated by histology; immune cell phenotypes were evaluated by flow cytometry; MOG-specific antibodies were determined by ELISA. Mixed bone marrow chimeras and cell culture assays were used to identify the specific subsets of immune cells affected by BCMA deficiency. Results: First, we found that BCMA −/− mice had more severe EAE compared with BCMA +/+ mice and the increased disease was associated with elevated anti-MOG B-cell responses. Second, we found that anti-CD20 therapy attenuated EAE in BCMA −/− mice but not in BCMA +/+ mice. Third, TACI-Fc attenuated EAE in BCMA +/+ mice but not in BCMA −/− mice. Mixed bone marrow chimeric and cell culture experiments demonstrated that BCMA deficiency elevates inflammatory B-cell responses but inhibits inflammatory responses in macrophages. Conclusions: BCMA has multifaceted roles during inflammation that affects therapeutic efficacies of anti-CD20 and TACI-Fc in EAE. Our results from BCMA-deficient mice provide insights into the failure of atacicept in MS.