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

Abstract

Endometriosis affects 10-20% of women of reproductive age and is associated with pelvic pain and infertility, and its pathogenesis is not well understood. We used genomewide transcriptional profiling to characterize endometriosis and found that it exhibits a gene expression signature consistent with an underlying autoimmune mechanism. Endometriosis lesions are characterized by the presence of abundant plasma cells, many of which produce IgM, and macrophages that produce BLyS/BAFF/TNFSF13B, a member of the TNF superfamily implicated in other autoimmune diseases. B lymphocyte stimulator (BLyS) protein was found elevated in the serum of endometriosis patients. These observations suggest a model for the pathology of endometriosis where BLyS-responsive plasma cells interact with retrograde menstrual tissues to give rise to endometriosis lesions.

Fig. 1.

IPA was used to identify pathways altered in endometriosis compared with normal endometrium, and the two most significant networks associated with immune responses are shown (merged). The significance values of each were Network 1, P = 10⁻³⁸, and Network 2, P = 10⁻²⁶. For explanation of significance values, see Materials and Methods.

Fig. 2.

Endometriosis lesions contain macrophages and plasma cells. (a) Staining with H&E showing plasma cells in endometriosis lesions (arrows). (Magnification: ×10.) (b) Immunohistochemical analysis shows that some of the plasma cells express IgM (arrows). (Magnification: ×40.) (c) H&E staining revealed many macrophages with hemosiderin in the lesions of ovarian endometriosis. (Magnification: ×10.) (d) Staining with anti-CD68 confirmed the presence of macrophages in these lesions. (Magnification: ×40.)

Fig. 3.

BLyS and its receptor BCMA are significantly altered in endometriosis. (a) Qualitative RT-PCR (TaqMan) confirmed the overexpression of BLyS mRNA in endometriosis vs. control endometrium, as originally identified through microarray analysis. Relative expression values are expressed as mean of 2^(40−Ct) ± SEM: endometrium, 100 ± 15 (n = 16); endometriosis, 886 ± 263 (n = 13). (b) BCMA mRNA was also found to be overexpressed in endometriosis vs. control endometrium by quantitative RT-PCR (TaqMan). Relative expression values are expressed as mean of 2^(40−Ct) ± SEM: endometrium, 43 ± 13 (n = 16); endometriosis, 290 ± 89 (n = 13). (c) Immunohistochemical staining revealed that BlyS is produced by macrophages in endometriotic lesions. (Magnification: ×100.) (d) Individual serum BlyS protein levels in 21 healthy control females and 31 patients with endometriosis were measured by ELISA. The data show the mean pg/ml values of each group ± SEM: control, 523 ± 74; endometriosis, 1,695 ± 188.