B lymphocytes inactivation by Ibrutinib limits endometriosis progression in mice

Luiza Gama Coelho Riccio, L G C Riccio, Jeljeli M, Mohamed Jeljeli, M Jeljeli, Piétro Santulli, Santulli P, P Santulli, Chouzenoux S, S. Chouzenoux, Sandrine Chouzenoux, L Doridot, Ludivine Doridot, C Nicco, Carole Nicco, Reis FM, Fernando M. Reis, F. M. Reis, Abrão MS, Maria Silvia Abrão, M S Abrão, Charles Chapron, Chapron C, C. Chapron, F. Batteux, Batteux F, Frédéric Batteux
Human Reproduction · 2019 · vol. 34(7) , pp. 1225–1234 · doi:10.1093/humrep/dez071 · PMID:31247078 · W2953858475
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Ibrutinib prevented endometriosis progression in mice by shifting activated B cells toward regulatory B cells, while anti-CD20 antibody depletion of B cells had no effect.

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Abstract

STUDY QUESTION: What are the effects of B lymphocyte inactivation or depletion on the progression of endometriosis? SUMMARY ANSWER: Skewing activated B cells toward regulatory B cells (Bregs) by Bruton's tyrosine kinase (Btk) inhibition using Ibrutinib prevents endometriosis progression in mice while B cell depletion using an anti-CD20 antibody has no effect. WHAT IS KNOWN ALREADY: A polyclonal activation of B cells and the presence of anti-endometrial autoantibodies have been described in a large proportion of women with endometriosis though their exact role in the disease mechanisms remains unclear. STUDY DESIGN, SIZE, DURATION: This study included comparison of endometriosis progression for 21 days in control mice versus animals treated with the anti-CD20 depleting antibody or with the Btk inhibitor Ibrutinib that prevents B cell activation. PARTICIPANTS/MATERIALS, SETTING, METHODS: After syngeneic endometrial transplantation, murine endometriotic lesions were compared between treated and control mice using volume, weight, ultrasonography, histology and target genes expression in lesions. Phenotyping of activated and regulatory B cells, T lymphocytes and macrophages was performed by flow cytometry on isolated spleen and peritoneal cells. Cytokines were assayed by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: Btk inhibitor Ibrutinib prevented lesion growth, reduced mRNA expression of cyclooxygenase-2, alpha smooth muscle actin and type I collagen in the lesions and skewed activated B cells toward Bregs in the spleen and peritoneal cavity of mice with endometriosis. In addition, the number of M2 macrophages decreased in the peritoneal cavity of Ibrutinib-treated mice compared to anti-CD20 and control mice. Depletion of B cells using an anti-CD20 antibody had no effect on activity and growth of endometriotic lesions and neither on the macrophages, compared to control mice. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: It is still unclear whether B cell depletion by the anti-CD20 or inactivation by Ibrutinib can prevent establishment and/or progression of endometriosis in humans. WIDER IMPLICATIONS OF THE FINDINGS: Further investigation may contribute to clarifying the role of B cell subsets in human endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by a grant of Institut National de la Santé et de la Recherche Médicale and Paris Descartes University. None of the authors has any conflict of interest to disclose.

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Condition tags

endometriosis

MeSH descriptors

Agammaglobulinaemia Tyrosine Kinase B-Lymphocytes Endometriosis Pyrazoles Pyrimidines Adenine Adenine Agammaglobulinaemia Tyrosine Kinase Animals B-Lymphocytes Cytokines Cytokines Disease Progression Drug Evaluation, Preclinical Endometriosis Endometriosis Endometriosis Female Mice, Inbred BALB C Piperidines

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