AID dysregulation in lupus-prone MRL/Faslpr/lpr mice promotes interchromosomal c-Myc/IgH loci translocations, increased class switch DNA recombination and production of anti-dsDNA IgG autoantibodies: modulation by HoxC4 (148.25)

Abstract

Abstract Activation-induced cytidine deaminase (AID) initiates immunoglobulin (Ig) gene somatic hypermutation (SHM) and class switch DNA recombination (CSR), which are critical in the generation of pathogenic autoantibodies. In these studies, we addressed the regulation of AID by HoxC4 in lupus. We found that SLE patients and lupus-prone MRL/Faslpr/lpr mice displayed increased expression of HoxC4, which directly activates the promoter of the AID gene, and increased expression of AID. Dysregulation of these proteins was associated with increased CSR in B cells of MRL/Faslpr/lpr mice. In the HoxC4-/- MRL/Faslpr/lpr mice we generated, HoxC4-deficiency resulted in reduced AID expression, impaired CSR and decreased serum anti-dsDNA IgG, particularly IgG2a production, in association with a reduction in IgG deposition in kidney glomeruli. Consistent with our previous findings that upregulated AID expression is associated with extensive DNA lesions, we found a high frequency of c-Myc to IgH translocations in MRL/Faslpr/lpr mice. The frequency of c-Myc to IgH translocations was significantly reduced in autoimmune MRL/Faslpr/lpr mice deficient in HoxC4. Our findings showed that HoxC4 is upregulated in lupus B cells, and this plays a major role in dysregulating AID expression, increasing CSR and autoantibody production, and promoting c-Myc to IgH translocations.