The role of endometrial B cells in normal endometrium and benign female reproductive pathologies: a systematic review

Abstract

STUDY QUESTION What are the similarities and differences in endometrial B cells in the normal human endometrium and benign reproductive pathologies? SUMMARY ANSWER Endometrial B cells typically constitute less than 5% of total endometrial CD45+ lymphocytes, and no more than 2% of total cells in the normal endometrium, and while their relative abundance and phenotypes vary in benign gynaecological conditions current evidence is inconsistent. WHAT IS KNOWN ALREADY B cells are vitally important in the mucosal immune environment and have been extensively characterised in secondary lymphoid organs and tertiary lymphoid structures (TLSs), with the associated microenvironment germinal centre. However, in the endometrium, B cells are largely overlooked, despite the crucial link between autoimmunity and reproductive pathologies and the fact that B cells are present in normal endometrium and in benign female reproductive pathologies, scattered or in the form of lymphoid aggregates (LAs). A comprehensive summary of current data investigating B cells will facilitate our understanding of endometrial B cells in the endometrial mucosal immune environment. STUDY DESIGN, SIZE, DURATION This systematic review retrieved relevant studies from four databases (MEDLINE, EMBASE, Web of Science Core Collection, CINAHL) from database inception until November 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS The search strategy combined the use of subject headings and relevant text words related to ‘endometrium’, ‘B cells’ and B cell derivatives such as ‘antibody’ and ‘immunoglobulin’. Non-benign diseases were excluded using cancer related free-text terms, and searches were limited to English language and human subjects. Only peer-reviewed research papers were included. Each paper was graded as ‘Good’, ‘Fair’, or ‘Poor’ quality based on the NEWCASTLE-OTTAWA quality assessment scale. Only ‘Good’ quality papers were included. MAIN RESULTS AND THE ROLE OF CHANCE Twenty-seven studies met the selection criteria and were included in this review: 10 cross-sectional studies investigated B cells in the normal endometrium; and 17 case-control studies compared the characteristics of endometrial B cells in control and benign female reproductive pathologies including endometritis, endometriosis, infertility, abnormal uterine bleeding, endometrial polyps and uterine fibroids. In all studies, B cells were present in the endometrium, scattered or in the form of LAs. CD20+ B cells were more abundant in patients with endometritis, but the data were inconsistent as to whether B cell numbers were increased in endometriosis and patients with reproductive pathologies. LIMITATIONS, REASONS FOR CAUTION Although only “good” quality papers were included in this systematic review, there are variations in patients’ age, diagnostic criteria for different diseases and sample collection time among included studies. Additionally, a large number of the included studies only used immunohistochemistry as the identification method for endometrial B cells, which may fail to provide an accurate representation of the numbers of endometrial B cells. WIDER IMPLICATIONS OF THE FINDINGS Histological studies found that endometrial B cells are either scattered or surrounded by T cells in LAs: the latter structure seems to be under hormonal control throughout the menstrual cycle and resembles TLSs that have been observed in other tissues. Further characterisation of endometrial B cells and LAs could offer insights to endometrial B cell function, particularly in the context of autoimmune-associated pathologies such as endometriosis. Additionally, clinicians should be aware of the limited value of diagnosing plasma cell infiltration using only CD138. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Finox Biotech. The authors have no conflicts of interests to declare. PROSPERO REGISTRATION NUMBER This systematic review was registered in PROSPERO in January 2020 (PROSPERO ID: CRD42020152915).

Multivariate Analysis of Recurrence after Hysteroscopic Diagnosis and Treatment of Endometrial Polyps following IVF-ET Failure

“…As both EM and EPs are estrogenic diseases, the correlation between their occurrence has always been a hotspot in clinical research. It has been reported that most infertile patients with EM are accompanied by EPs, suggesting that EM is related to the occurrence of EPs [ 24 ]. Evidence has shown that EM syndrome in infertile patients is positively correlated with the occurrence of EPs [ 25 ], indicating that there may be mutual promotion between the pathological changes of EM and EPs in such patients.…”

Importance of the endometrial immune environment in endometrial cancer and associated therapies

“…The function of B cells within the endometrium is not well established, as was concluded in a systematic review by Shen et al. ( 63 ). However, it is possible that the B cells within LAs function as well-placed antigen presenting cells to the surrounding T cells, as they express activation markers such as CD69, HLA-DR and CD83 to a higher degree than their peripherally derived counterparts ( 65 ).…”

“…The phagocytic cells of the innate immune system – granulocytes, monocytes and macrophages, collectively make up 25% of the CD45 + endometrial immune milieu, whereas B cells are comparably rare regardless of hormonal cycle stage, at no more than 5% ( 17 , 39 , 43 , 63 ). Endometrial B cells exist primarily within LAs, but have also been detected in the stroma ( 45 , 64 ).…”

Challenges in Clinical Diagnosis and Management of Chronic Endometritis

“…The eutopic endometrium in women with endometriosis shares several common immunological characteristics with that in CE. For example, one feature of the eutopic endometrium in women with endometriosis is unusual infiltration of CD138(+) ESPCs and CD20(+)/CD5(+)/HLA-DR(+) B cells; these are typical immunocompetent cells observed in CE, but are sparse in the nonpathological endometrium [ 4 ]. Some studies suggest that these unusual ESPCs and endometrial B cells potentially play a role in the proliferation and survival of the other endometrial cell components.…”

“…By contrast, antibody-bearing lymphocytes of the B cell lineage are a rare leukocyte subpopulation found in the nonpathological human endometrium. Under a physiological condition, endometrial B cells account for approximately 3% of all endometrial lymphocytes and no more than 2% of all endometrial cells throughout the menstrual cycle [ 4 ]. Some CD138(+) endometrial stromal plasmacytes (ESPCs) can occasionally be seen in the stromal compartments.…”