B lymphocytes inactivation by Ibrutinib limits endometriosis progression in mice.

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.

• Authors: L G C Riccio, M Jeljeli, P Santulli, S Chouzenoux, L Doridot, C Nicco, F M Reis, M S Abrão, C Chapron, F Batteux
• Journal: Human reproduction (Oxford, England) (Hum Reprod) Vol. 34 Issue 7 Pg. 1225-1234 (07 08 2019) ISSN: 1460-2350 [Electronic] England
• PMID: 31247078 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Cytokines
• Piperidines
• Pyrazoles
• Pyrimidines
• ibrutinib
• Agammaglobulinaemia Tyrosine Kinase
• Adenine

Topics

• Adenine (analogs & derivatives)
• Agammaglobulinaemia Tyrosine Kinase (antagonists & inhibitors)
• Animals
• B-Lymphocytes (drug effects)
• Cytokines (blood)
• Disease Progression
• Drug Evaluation, Preclinical
• Endometriosis (blood, drug therapy, immunology)
• Female
• Mice, Inbred BALB C
• Piperidines
• Pyrazoles (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• T-Lymphocytes (drug effects)