The female sex hormone 17β-estradiol (E2) increases the risk of developing certain autoimmune diseases, such as systemic lupus erythematosus (SLE) and Sjogren syndrome (SS), in genetically susceptible women and certain mouse strains. E2 signals through two nuclear receptors, namely estrogen receptor ERα and ERβ. These receptors are expressed in most immune cell types, including B cells. Both ERα and ERβ receptors differentially regulate the maturation and selection of B cells. Accordingly, studies have noted that steady-state levels of the ERα mRNA and protein are significantly higher in PBMCs from SLE patients when compared with gender- and age-matched normal individuals. Further, studies on lupus in mouse models indicated a prominent role of ERα, but not ERβ, in the development of disease. ERs are ligand-activated nuclear receptors that can either directly bind to estrogen responsive elements (EREs) that are present in gene promoters or serve as cofactors with other transcription factors (such as AP-1 and NF-κB) to activate the transcription of the target genes. The E2 target genes that influence B cell development and functions include: BCL2 (survival of autoreactive cells), BAFF (survival and differentiation of autoreactive cells), AID (production of pathogenic autoantibodies), and IRF5 (B cell differentiation). E2-mediated increased expression of these (and other) genes results in an increased production of pathogenic autoantibodies. Several clinical manifestations of autoimmune diseases are thought to be the result of autoantibody and immune complex deposition in tissues and organs; thus, leading to secondary inflammatory responses and organ damage. Evidence indicates that activation of toll-like receptors (TLR)-dependent and independent innate immune responses, which result in increased production of type I interferon-α/β (IFN-α/β) and an increased expression of the IFN-inducible genes (“IFN-signature”), contribute to the development of disease phenotype in certain autoimmune diseases (e.g., SLE and SS). We have identified a feedforward loop between IFN-α/β and ERα in B cells. Further, our studies revealed that the expression of certain E2-responsive genes such as BAFF, IRF5, and UNC93b (encodes for a transporter of certain TLRs) is also induced by type I IFNs in immune cells, including B cells. Notably, activation of IFN-signaling in murine B cells (CD19+) induced inflammasome activity, thus increasing the production of proinflammatory cytokines (e.g., IL-1β and IL-18). Although recent advancement in the field have provided new insights into the role of E2/ERα-signaling in B cells and implicated its role in sex bias in the development of certain autoimmune diseases, further work is needed to fully understand the molecular mechanisms. These studies are integral to identifying new approaches to effectively treat autoimmune diseases.
Disclosure of Interest None declared