Abstract
Estrogen enhances antibody and autoantibody responses through yet to be defined mechanisms. It has been suggested that estrogen up-regulates the expression of activation-induced cytosine deaminase (AID), which is critical for antibody class switch DNA recombination (CSR) and somatic hypermutation (SHM), through direct activation of this gene. AID, as we have shown, is induced by the HoxC4 homeodomain transcription factor, which binds to a conserved HoxC4/Oct site in the AICDA/Aicda promoter. Here we show that estrogen-estrogen receptor (ER) complexes do not directly activate the AID gene promoter in B cells undergoing CSR. Rather, they bind to three evolutionarily conserved and cooperative estrogen response elements (EREs) we identified in the HOXC4/HoxC4 promoter. By binding to these EREs, ERs synergized with CD154 or LPS and IL-4 signaling to up-regulate HoxC4 expression, thereby inducing AID and CSR without affecting B cell proliferation or plasmacytoid differentiation. Estrogen administration in vivo significantly potentiated CSR and SHM in the specific antibody response to the 4-hydroxy-3-nitrophenylacetyl hapten conjugated with chicken γ-globulin. Ablation of HoxC4 (HoxC4(-/-)) abrogated the estrogen-mediated enhancement of AID gene expression and decreased CSR and SHM. Thus, estrogen enhances AID expression by activating the HOXC4/HoxC4 promoter and inducing the critical AID gene activator, HoxC4.
Highlights
class switch DNA recombination (CSR) and somatic hypermutation (SHM) are critical for the maturation of antibody response to foreign antigens and self-antigens
As we have shown, in both human and mouse B cells, HOXC4/HoxC4 expression is induced by germinal centers (GCs) differentiation-inducing stimuli, such as CD154 or LPS and IL-4, that are required for induction of AICDA/Aicda expression (38 – 40)
B, E2 enhanced in a dose-dependent manner HOXC4 and AICDA expression in 2E2 B cells stimulated by anti-CD40 mAb and rhIL-4
Summary
CSR and SHM are critical for the maturation of antibody response to foreign antigens and self-antigens. Estrogen Enhances SHM in the NP-CGG Antibody Response in a HoxC4-dependent Fashion—To determine the effect of estrogen on SHM, we sequenced Ig V186.2-DJH transcripts expressed by B cells from the HoxC4ϩ/ϩ and HoxC4Ϫ/Ϫ littermate female mice used in the experiments of Fig. 3
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