Human endometriosis is associated with plasma cells and overexpression of B lymphocyte stimulator

Hevér, Anikó; Roth, Richard B.; Hevezi, Peter; Marin, M. Esther Valverde; Acosta, José A.; Acosta, Héctor; Rojas, José M.; Herrera, Rosa; Grigoriadis, Dimitri E.; White, E.C.; Conlon, Paul; Maki, Richard A.; Zlotnik, Albert

doi:10.1073/pnas.0703451104

Cited by 209 publications

(177 citation statements)

References 52 publications

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“…By contrast, injection of AdCre in MUC1Kras mice was followed by notable changes in the ovarian surface epithelium and neoformation of endometriotic glands, which triggered persistent high levels of MUC1-specific IgM and IgG1. We postulate that the isotype switch from IgM to IgG1 that was observed during disease development was because of a Th2 bias; this is in agreement with previous reports in humans (Antsiferova et al, 2005;Podgaec et al, 2007) showing increased autoantibody levels (Gleicher et al, 1987) and signs of B-cell activation (Hever et al, 2007). However, it has been argued that chronic exposure to antibodies can promote tumors: antibodies can extravasate into the stroma and form immune complexes that can initiate inflammatory cascades associated with tissue destruction (Johansson et al, 2008).…”

Section: Disease Models and Mechanisms Dmmsupporting

confidence: 79%

A conditional mouse model for human MUC1-positive endometriosis shows the presence of anti-MUC1 antibodies and Foxp3+ regulatory T cells

Budiu

Diaconu

Chrissluis

et al. 2009

Disease Models &Amp; Mechanisms

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SUMMARYEndometriosis is defined by the presence of tissue implants resembling endometrial glands outside of the uterus, at ectopic sites, frequently on the ovarian surface. The ectopic lesions are often invasive, resistant to therapy, and may predispose to endometrioid and clear cell ovarian tumors. The complex mechanisms leading to chronic endometriosis are mediated partly by impaired immune surveillance in the host. Although innate immunity has been addressed previously, the response of adaptive immune effectors to specific antigens has not been characterized, mostly because very few endometriosis antigens have been defined to date. We postulated that the mucin 1 (MUC1) glycoprotein, which is normally present on eutopic human endometrial glands and overexpressed in endometrioid and clear cell ovarian tumors, is also present in ectopic lesions of ovarian endometriosis. Furthermore, changes in MUC1 expression in endometriosis could promote adaptive anti-MUC1 immunity that might play a role in the malignant progression. To test our hypothesis, we crossed MUC1 transgenic mice, which express human MUC1 under the endogenous promoter, with the loxP-Stop-loxP-Kras G12D/+ (Kras) mice, in which endometriosis can be induced through Cre-loxP recombination. The double transgenic MUC1Kras mice develop benign, MUC1-positive ovarian lesions, closely resembling human endometriosis. Subsequent to disease induction, the mice generate high titers of IgM and IgG antibodies that are specific for MUC1. Antibodies appear early in disease and the predominance of the IgG1 subclass suggests Th2-driven immunity. Immune phenotyping revealed an accumulation of Foxp3+ CD4 regulatory T cells (Tregs) in the draining lymph nodes at late-stage disease. Furthermore, our observations in human endometriosis showed a similar recruitment of FOXP3+ CD4 T cells. Overall, our results reveal a Th2/Treg-dominant natural immunity in endometriosis with potential implications for cancer progression.

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Section: Disease Models and Mechanisms Dmmsupporting

confidence: 79%

A conditional mouse model for human MUC1-positive endometriosis shows the presence of anti-MUC1 antibodies and Foxp3+ regulatory T cells

Budiu

Diaconu

Chrissluis

et al. 2009

Disease Models &Amp; Mechanisms

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“…Regarding overproduction, BAFF is excessive in autoimmune disorders [27][28][29][30][31] , and studies on endometriotic lesions indicate that areas of pathological cell growth are filled with plasma cells due to excessive production of BAFF by macrophages. 32 If BAFF and/or APRIL is important to programming trophoblast functions, relationships between underproduction and failure of trophoblast migration such as occurs in pre-eclampsia could be envisioned. If important to programming placental macrophage functions, immunity in the placenta might be compromised, leading to infectionassociated preterm labor and delivery.…”

Section: Discussionmentioning

confidence: 99%

Signaling Pathways for B Cell-Activating Factor (BAFF) and a Proliferation-Inducing Ligand (APRIL) in Human Placenta

Langat

Wheaton

Platt

et al. 2008

The American Journal of Pathology

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The tumor necrosis superfamily (TNFSF) contains two soluble ligands that are involved in B lymphocyte development, BAFF (B cell activating factor, BlyS, TALL-1, CD257, TNFSF13B) and APRIL (a proliferation inducing ligand, CD256, TNFSF13). These two ligands signal through three receptors: the exclusive BAFF receptor (BAFF-R, CD268, TNFRSF17) and two receptors that recognize both BAFF and APRIL, TACI (transmembraneactivator-1 and calcium-modulator-and cyclophilin ligand-interactor CD267, TNFRSF13B) and BCMA (B cell maturation antigen, CD269, TNFRSF13C). All but BAFF-R are known to be synthesized in term placentas. In this study, expression of the ligands and receptors were distinguished in two embryologically discrete subpopulations of placental cells, villous cytotrophoblast (vCTB) cells and mesenchymal cells (MCs). Real-Time PCR showed that vCTB cells contain low levels of BAFF and APRIL transcripts whereas MCs contain high levels. Both Real-Time PCR and immunohistochemistry identified BAFF-R and BCMA mRNA and proteins in vCTB cells but essentially no TACI. By contrast, MCs contained readily detectable levels of all three receptors. These results illustrating potential autocrine and paracrine pathways for BAFF and APRIL signaling in human placentas suggest that lineage-specific regulation of placental cell viability, differentiation and/or other activities may be novel functions of these proteins. (Am J Pathol

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“…The data were obtained from the NCBI Gene Expression Omnibus (GSE6364). The third data set, published by Hever et al (25), compared paired endometriosis and normal endometrium. The data were obtained from the NCBI Gene Expression Omnibus (GSE7305).…”

Section: Methodsmentioning

confidence: 99%

Proteomics Identification of Annexin A2 as a Key Mediator in the Metastasis and Proangiogenesis of Endometrial Cells in Human Adenomyosis

Zhou

et al. 2012

Molecular & Cellular Proteomics

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Adenomyosis is a common estrogen-dependent disorder of females characterized by a downward extension of the endometrium into the uterine myometrium and neovascularization in ectopic lesions. It accounts for chronic pelvic pain, dysmenorrhea, menorrhagia, and infertility in 8.8 -61.5% women worldwide. However, the molecular mechanisms for adenomyosis development remain poorly elucidated. Here, we utilized a two-dimensional polyacrylamide gel electrophoresis/MS-based proteomics analysis to compare and identify differentially expressed proteins in matched ectopic and eutopic endometrium of adenomyosis patients. A total of 93 significantly altered proteins were identified by tandem MS analysis. Further cluster analysis revealed a group of estrogen-responsive proteins as dysregulated in adenomyosis, among which annexin A2, a member of annexin family proteins, was found up-regulated most significantly in the ectopic endometrium of adenomyosis compared with its eutopic counterpart. Overexpression of ANXA2 was validated in ectopic lesions of human adenomyosis and was found to be tightly correlated with markers of epithelial to mesenchymal transition and dysmenorrhea severity of adenomyosis patients. Functional analysis demonstrated that estrogen could remarkably up-regulate ANXA2 and induce epithelial to mesenchymal transition in an in vitro adenomyosis model. Enforced expression of ANXA2 could mediate phenotypic mesenchymal-like cellular changes, with structural and functional alterations in a ␤-catenin/T-cell factor (Tcf) signaling-associated manner, which could be reversed by inhibition of ANXA2 expression. We also proved that enforced expression of ANXA2 enhanced the proangiogenic capacity of adenomyotic endometrial cells through HIF-1␣/VEGF-A pathway. In vivo, we demonstrated that ANXA2 inhibition abrogated endometrial tissue growth, metastasis, and angiogenesis in an adenomyosis nude mice model and significantly alleviated hyperalgesia. Taken together, our data unraveled a dual role for ANXA2 in the pathogenesis of human adenomyosis through conferring endometrial cells both metastatic potential and proangiogenic capacity, which could serve as a potential therapeutic target for the treatment of adenomyosis patients.

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Human endometriosis is associated with plasma cells and overexpression of B lymphocyte stimulator

Cited by 209 publications

References 52 publications

A conditional mouse model for human MUC1-positive endometriosis shows the presence of anti-MUC1 antibodies and Foxp3+ regulatory T cells

A conditional mouse model for human MUC1-positive endometriosis shows the presence of anti-MUC1 antibodies and Foxp3+ regulatory T cells

Signaling Pathways for B Cell-Activating Factor (BAFF) and a Proliferation-Inducing Ligand (APRIL) in Human Placenta

Proteomics Identification of Annexin A2 as a Key Mediator in the Metastasis and Proangiogenesis of Endometrial Cells in Human Adenomyosis

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