Département 'Développement, Reproduction et Cancer', Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Université Paris Descartes, Sorbonne Paris Cité Paris, France.
Faculté de Médecine, Sorbonne Paris Cité, Université Paris Descartes, Paris, France.
Hum Reprod. 2019 Jul 8;34(7):1225-1234. doi: 10.1093/humrep/dez071.
What are the effects of B lymphocyte inactivation or depletion on the progression of endometriosis?
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.
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.
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.
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.
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.
B 淋巴细胞失活或耗竭对子宫内膜异位症进展的影响是什么？
使用布鲁顿酪氨酸激酶（Btk）抑制剂伊布替尼抑制激活的 B 细胞向调节性 B 细胞（Bregs）的倾斜，可防止小鼠的子宫内膜异位症进展，而使用抗 CD20 抗体耗竭 B 细胞则没有效果。
尽管抗子宫内膜自身抗体在很大一部分子宫内膜异位症患者中被描述为 B 细胞的多克隆激活，但它们在疾病机制中的确切作用仍不清楚。
研究设计、大小、持续时间：本研究比较了对照组小鼠与用抗 CD20 耗竭抗体或 Btk 抑制剂伊布替尼治疗的动物在 21 天内的子宫内膜异位症进展情况，伊布替尼可防止 B 细胞激活。
参与者/材料、设置、方法：在同种异体子宫内膜移植后，通过体积、重量、超声、组织学和病变中靶基因表达比较治疗组和对照组小鼠的子宫内膜异位症病变。通过流式细胞术对分离的脾和腹腔细胞进行激活和调节性 B 细胞、T 淋巴细胞和巨噬细胞的表型分析。通过 ELISA 测定细胞因子。
Btk 抑制剂伊布替尼可防止病变生长，降低病变中环氧合酶-2、α平滑肌肌动蛋白和 I 型胶原的 mRNA 表达，并使子宫内膜异位症小鼠的脾脏和腹腔中的激活 B 细胞向 Bregs 倾斜。此外，与抗 CD20 抗体和对照组小鼠相比，伊布替尼治疗组小鼠腹腔中的 M2 巨噬细胞数量减少。与对照组小鼠相比，使用抗 CD20 抗体耗竭 B 细胞对子宫内膜异位症病变的活性和生长以及巨噬细胞均无影响。
无。
局限性、谨慎的原因：目前尚不清楚抗 CD20 或伊布替尼对 B 细胞的耗竭是否可以预防人类子宫内膜异位症的建立和/或进展。
进一步的研究可能有助于阐明 B 细胞亚群在人类子宫内膜异位症中的作用。
研究资金/竞争利益：本研究得到法国国家健康与医学研究院和巴黎笛卡尔大学的资助。作者均无利益冲突。
