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CNS Autoimmune Responses in BCMA-Deficient Mice Provide Insight for the Failure of Atacicept in MS

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 ant...

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Autores principales: Kumar, Gaurav, Maria, Zahra, Kohli, Uday, Agasing, Agnieshka, Quinn, James L., Ko, Rose M., Zamvil, Scott S., Axtell, Robert C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954465/
https://www.ncbi.nlm.nih.gov/pubmed/33649164
http://dx.doi.org/10.1212/NXI.0000000000000973
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author Kumar, Gaurav
Maria, Zahra
Kohli, Uday
Agasing, Agnieshka
Quinn, James L.
Ko, Rose M.
Zamvil, Scott S.
Axtell, Robert C.
author_facet Kumar, Gaurav
Maria, Zahra
Kohli, Uday
Agasing, Agnieshka
Quinn, James L.
Ko, Rose M.
Zamvil, Scott S.
Axtell, Robert C.
author_sort Kumar, Gaurav
collection PubMed
description 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.
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spelling pubmed-79544652021-03-15 CNS Autoimmune Responses in BCMA-Deficient Mice Provide Insight for the Failure of Atacicept in MS Kumar, Gaurav Maria, Zahra Kohli, Uday Agasing, Agnieshka Quinn, James L. Ko, Rose M. Zamvil, Scott S. Axtell, Robert C. Neurol Neuroimmunol Neuroinflamm Article 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. Lippincott Williams & Wilkins 2021-03-01 /pmc/articles/PMC7954465/ /pubmed/33649164 http://dx.doi.org/10.1212/NXI.0000000000000973 Text en Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (http://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
spellingShingle Article
Kumar, Gaurav
Maria, Zahra
Kohli, Uday
Agasing, Agnieshka
Quinn, James L.
Ko, Rose M.
Zamvil, Scott S.
Axtell, Robert C.
CNS Autoimmune Responses in BCMA-Deficient Mice Provide Insight for the Failure of Atacicept in MS
title CNS Autoimmune Responses in BCMA-Deficient Mice Provide Insight for the Failure of Atacicept in MS
title_full CNS Autoimmune Responses in BCMA-Deficient Mice Provide Insight for the Failure of Atacicept in MS
title_fullStr CNS Autoimmune Responses in BCMA-Deficient Mice Provide Insight for the Failure of Atacicept in MS
title_full_unstemmed CNS Autoimmune Responses in BCMA-Deficient Mice Provide Insight for the Failure of Atacicept in MS
title_short CNS Autoimmune Responses in BCMA-Deficient Mice Provide Insight for the Failure of Atacicept in MS
title_sort cns autoimmune responses in bcma-deficient mice provide insight for the failure of atacicept in ms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954465/
https://www.ncbi.nlm.nih.gov/pubmed/33649164
http://dx.doi.org/10.1212/NXI.0000000000000973
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