title: Hotspots for Vitamin-Steroid-Thyroid Hormone Response Elements Within Switch Regions of Immunoglobulin Heavy Chain Loci Predict a Direct Influence of Vitamins and Hormones on B Cell Class Switch Recombination.
abstract: Vitamin A deficiencies are common throughout the world and have a significant negative influence on immune protection against viral infections. Mouse models demonstrate that the production of IgA, a first line of defense against viruses at mucosal sites, is inhibited in the context of vitamin A deficiency. In vitro, the addition of vitamin A to activated B cells can enhance IgA expression, but downregulate IgE. Previous reports have demonstrated that vitamin A modifies cytokine patterns, and in so doing may influence antibody isotype expression by an indirect mechanism. However, we have now discovered hundreds of potential response elements among Sμ, Sɛ, and Sα switch sites within immunoglobulin heavy chain loci. These hotspots appear in both mouse and human loci and include targets for vitamin receptors and related proteins (e.g., estrogen receptors) in the nuclear receptor superfamily. Full response elements with direct repeats are relatively infrequent or absent in Sγ regions although half-sites are present. Based on these results, we pose a hypothesis that nuclear receptors have a direct effect on the immunoglobulin heavy chain class switch recombination event. We propose that vitamin A may alter S site accessibility to activation-induced deaminase and nonhomologous end-joining machinery, thereby influencing the isotype switch, antibody production, and protection against viral infections at mucosal sites.
authors.affiliation: 1 Department of Infectious Diseases, St. Jude Children's Research Hospital , Memphis, Tennessee.|2 Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center , Memphis, Tennessee.
authors.forename: Julia L
authors.initials: JL
authors.lastname: Hurwitz
authors.affiliation: 1 Department of Infectious Diseases, St. Jude Children's Research Hospital , Memphis, Tennessee.
authors.forename: Rhiannon R
authors.initials: RR
authors.lastname: Penkert
authors.affiliation: 3 Department of Computational Biology, St. Jude Children's Research Hospital , Memphis, Tennessee.
authors.forename: Beisi
authors.initials: B
authors.lastname: Xu
authors.affiliation: 3 Department of Computational Biology, St. Jude Children's Research Hospital , Memphis, Tennessee.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Fan
authors.affiliation: 4 Department of Pathology, St. Jude Children's Research Hospital , Memphis, Tennessee.
authors.forename: Janet F
authors.initials: JF
authors.lastname: Partridge
authors.affiliation: 5 National Institute on Aging, National Institutes of Health , Baltimore, Maryland.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Maul
authors.affiliation: 5 National Institute on Aging, National Institutes of Health , Baltimore, Maryland.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Gearhart
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D056426:Genetic Loci; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006801:Humans; D017578:Immunoglobulin Class Switching; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D051379:Mice; D020218:Response Elements; D013963:Thyroid Hormones / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism*
chemical_list: D012739:Gonadal Steroid Hormones; D007143:Immunoglobulin Heavy Chains; D013963:Thyroid Hormones; D014801:Vitamin A