B Cell Lineage in the Human Endometrium: Physiological and Pathological Implications

Abstract

Immunocompetent cells of B lineage function in the humoral immunity system in the adaptive immune responses. B cells differentiate into plasmacytes upon antigen-induced activation and produce different subclasses of immunoglobulins/antibodies. Secreted immunoglobulins not only interact with pathogens to inactivate and neutralize them, but also involve the complement system to exert antibacterial activities and trigger opsonization. Endometrium is a mucosal tissue that lines the mammalian uterus and is indispensable for the establishment of a successful pregnancy. The lymphocytes of B cell lineage are a minority in the human cycling endometrium. Human endometrial B cells have therefore been understudied so far. However, the disorders of the female reproductive tract, including chronic endometritis and endometriosis, have highlighted the importance of further research on the endometrial B cell lineage. This review aims to revisit lymphopoiesis, maturation, commitment, and survival of B cells, shedding light on their physiological and pathological implications in the human endometrium.

Keywords: B cells; chronic endometritis; endometriosis; endometrium; infertility; plasma cells.

Figure 1

Current models of B cell lymphopoiesis, maturation, and commitment. B cells originate from the bone marrow hematopoietic precursor cells. Recombination-activating gene (RAG) 1/2–induced rearrangement from the germline initiates at the pro-B-cell stage. V-gene segment rearrangement follows in the early pre-B cell stage. Pre-B cell receptor (BCR)–associated signals silence RAG gene expression, suppress the rearrangement of the second H-chains, and induce cell proliferation. IgM-expressing immature B cells alter the gene expression pattern and prepare for egress into the circulation. Immature B cells enter the spleen as transitional B cells, receive survival signals through B-cell activating factor receptor (BAFF-R), and complete the first stage of development, depending on the specificity of their BCR. Upon contact with antigens and support by B helper neutrophils, MZB cells develop into short-lived PC. FOB cells are activated by antigen binding for development in the germinal centers with the aid of helper T cells. T cell-independent activation promotes the differentiation of FOB or MZB cells to PCs, whereas T cell-dependent activation leads them to memory B cells.

Figure 2

The mechanism underlying B cell recruitment and differentiation in the endometrium with CE. CXCL13 (a CXCR5 antagonist) and CD62E (a ligand for endoglycan) are abnormally expressed in endometrial endothelial cells with CE and display a selective chemotactic activity for B cells. IL-6 (a B cell differentiation factor) concentration is also elevated in the endometrium and induces the differentiation from extravasated B cells to ESPC to produce Ig.

Figure 3

Proliferative phenotype and progesterone resistance in the endometrium with CE and endometriosis. TNF-α level is elevated in the uterine cavity in both pathological conditions. High concentration of TNF-α promotes local estrogen biosynthesis in endometrial glandular epithelial cells via estrogen receptor-α signaling, which in turn potentially alters the epithelial cells to the proliferative phenotype and provokes their survival. For example, the endometrium with CE is characterized by the delayed endometrial differentiation in the secretory phase (after ovulation) when this mucosal tissue has to prepare for the implantation of blastocysts. In addition, approximately one-third of the endometrium with CE displays an “out-of-phase” morphological appearance in glandular and surface epithelial cells, i.e., pseudostratification and/or mitotic nuclei, the findings seen in the proliferative phase (before ovulation). While the endometrial expression levels of messenger RNAs involved in cellular proliferation (ki-67), anti-apoptosis (bcl2 and bax), and ovarian steroid receptors (esr1, esr2, and pgr) are abnormally raised in the secretory phase, the expression of messenger RNAs potentially associated with embryo receptivity (il11, ccl4, igf1, and casp8) and decidualization (prl and igfbp1) are reduced, supporting the idea that the endometrium is unable to respond enough to ovarian steroid stimulation and to transform its component cells to acquire the receptivity for implanting blastocysts.