Matters of life and death: How estrogen and estrogen receptor binding to the immunoglobulin heavy chain locus may influence outcomes of infection, allergy, and autoimmune disease

• Published in: Cellular immunology Vol. 346; p. 103996
• Main Authors: Jones, Bart G., Penkert, Rhiannon R., Surman, Sherri L., Sealy, Robert E., Pelletier, Stephane, Xu, Beisi, Neale, Geoff, Maul, Robert W., Gearhart, Patricia J., Hurwitz, J.L.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.12.2019
• Subjects: CRISPR; hnRNP; CSR; C; D; SLE or ‘lupus’; J; RNA Pol II; SERM; HS; ChIP; ER; LPS; S; LPS + E; V; IGV; Cas9; AID
• ISSN: 0008-8749; 1090-2163
• DOI: 10.1016/j.cellimm.2019.103996

•Males and females suffer differently from pathogens, allergies and autoimmunity.•ERα binds regulatory elements in the immunoglobulin heavy chain locus.•Estrogen alters ERα binding to sequences near Sµ and Sε.•ERα binds ERE, adenosine-cytidine (AC)-repeats and poly adenosine (poly A) sequences.•Estrogen instructs immunoglobulin expression and disease consequences. Sex hormones are best known for their influences on reproduction, but they also have profound influences on the immune response. Examples of sex-specific differences include: (i) the relatively poor control of influenza virus infections in males compared to females, (ii) allergic asthma, an IgE-associated hypersensitivity reaction that is exacerbated in adolescent females compared to males, and (iii) systemic lupus erythematosus, a life-threatening autoimmune disease with a 9:1 female:male bias. Here we consider how estrogen and estrogen receptor α (ERα) may influence the immune response by modifying class switch recombination (CSR) and immunoglobulin expression patterns. We focus on ERα binding to enhancers (Eμ and the 3′ regulatory region) and switch sites (Sµ and Sε) in the immunoglobulin heavy chain locus. Our preliminary data from ChIP-seq analyses of purified, activated B cells show estrogen-mediated changes in the positioning of ERα binding within and near Sµ and Sε. In the presence of estrogen, ERα is bound not only to estrogen response elements (ERE), but also to adenosine-cytidine (AC)-repeats and poly adenosine (poly A) sequences, in some cases within constant region gene introns. We propose that by binding these sites, estrogen and ERα directly participate in the DNA loop formation required for CSR. We further suggest that estrogen regulates immunoglobulin expression patterns and can thereby influence life-and-death outcomes of infection, hypersensitivity, and autoimmune disease.