CNS Autoimmune Responses in BCMA-Deficient Mice Provide Insight for the Failure of Atacicept in MS
| Autor: | Rose M. Ko, Robert C. Axtell, Agnieshka Agasing, Gaurav Kumar, James L. Quinn, Scott S. Zamvil, Zahra Maria, Uday Kohli |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Encephalomyelitis Autoimmune Experimental Multiple Sclerosis Recombinant Fusion Proteins Tumor Necrosis Factor Ligand Superfamily Member 13 Autoimmunity Inflammation Article Antibodies Atacicept Myelin oligodendrocyte glycoprotein Mice 03 medical and health sciences 0302 clinical medicine Immune system immune system diseases B-Cell Activating Factor medicine Animals Humans B-Cell Maturation Antigen B-cell activating factor B-Lymphocytes biology business.industry Experimental autoimmune encephalomyelitis medicine.disease Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Neurology Models Animal Immunology biology.protein Myelin-Oligodendrocyte Glycoprotein Neurology (clinical) Bone marrow Antibody medicine.symptom business 030217 neurology & neurosurgery |
| Zdroj: | Neurology® Neuroimmunology & Neuroinflammation article-version (Version of Record) 3 |
| ISSN: | 2332-7812 |
| DOI: | 10.1212/nxi.0000000000000973 |
| Popis: | ObjectiveB 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).MethodsEAE 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.ResultsFirst, 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.ConclusionsBCMA 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. |
| Databáze: | OpenAIRE |
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