Nuclear Receptors, Ligands and the Mammalian B Cell

Abstract

Questions concerning the influences of nuclear receptors and their ligands on mammalian B cells are vast in number. Here, we briefly review the effects of nuclear receptor ligands, including estrogen and vitamins, on immunoglobulin production and protection from infectious diseases. We describe nuclear receptor interactions with the B cell genome and the potential mechanisms of gene regulation. Attention to the nuclear receptor/ligand regulation of B cell function may help optimize B cell responses, improve pathogen clearance, and prevent damaging responses toward inert- and self-antigens.

Keywords: estrogen; immunoglobulin; regulatory elements; vitamins.

Figure 1

Vitamin A deficient (VAD) male mice exhibit higher bacteria burdens than control males and VAD females. To produce VAD mice, pregnant C57BL/6 (H2-b) mice were purchased from Jackson Laboratories (Bar harbor, ME). Mice were placed on either a control or a VAD diet upon their arrival in the animal facility at St. Jude (days 4–5 gestation). VAD (cat. no. 5WA2, Test Diets) and control (cat. no. 5W9M) diets differed only in vitamin A content, containing either 0 or 15 international units (IU)/g vitamin A palmitate, respectively. Upon reaching adulthood, C57BL/6 control (CON) and VAD mice were lightly anesthetized with isoflurane and intranasally infected with 0.5–1 × 10⁵ CFU of Streptococcus pneumoniae, strain A66.1 (as described previously [86,98,99]). Lung bacterial titers were determined 24 h post-infection, assigned the value ‘1′ if below detection. Each dot represents an individual mouse. Results from two experiments are shown, respectively, indicated by circles and diamonds. Significant differences between the paired groups were determined by Mann–Whitney U tests.

Figure 2

Purified murine B cells were stimulated for 1 day with lipopolysaccharide (LPS) or LPS + supplemental estrogen, followed by chromatin immunoprecipitation studies with antibodies toward ERα (termed ER in this figure) or RNA Pol II, as described previously [48,107,108,109,117]. Briefly, splenic B cells were isolated from adult, C57BL/6 female mouse spleens, by negative selection with anti-CD43 and anti-CD11b antibodies. The cells were then stimulated overnight with LPS with or without supplemental estrogen (100 nM). Immunoprecipitations were with anti-ERα or anti-RNA Pol II antibodies. Integrative Genomics Viewer (IGV) software was used to generate the figures and to identify motifs in forward and reverse (REV) orientations. (A) The switch site (Sμ), Cμ and a portion of the Cδ gene fragment are shown from right to left. Potential ER binding sites are shown using the motif RRYYRNNNTGANC (IGV ‘Find motif’ function). The positions of adenosine–cytidine (AC)-repeats (CACACA) and poly A (AAAAA) are shown. (B) The Ig kappa V9-129 gene fragment is shown with motifs listed. (C) The IL-6 gene is shown, with the same motifs listed as in (B). The detailed methods and results from chromatin immunoprecipitation studies have been described previously [48,106,107,108,109,117].