title: AID dysregulation in lupus-prone MRL/Fas(lpr/lpr) mice increases class switch DNA recombination and promotes interchromosomal c-Myc/IgH loci translocations: modulation by HoxC4.
abstract: Immunoglobulin gene somatic hypermutation (SHM) and class switch DNA recombination (CSR) play important roles in the generation of autoantibodies in systemic lupus erythematosus. Systemic lupus is characterized by the production of an array of pathogenic high-affinity mutated and class-switched, mainly IgG, antibodies to a variety of self-antigens, including nuclear components, such as dsDNA, histones, and chromatin. We previously found that MRL/Fas(lpr/lpr) mice, which develop a systemic autoimmune syndrome sharing many features with human lupus, display greatly upregulated CSR, particularly to IgG2a, in B cells of the spleen, lymph nodes, and Peyer's patches. In MRL/Fas(lpr/lpr) mice, the significant upregulation of CSR is associated with increased expression of activation-induced cytidine deaminase (AID), which is critical for CSR and SHM. We also found that HoxC4 directly activates the promoter of the AID gene to induce AID expression, CSR and SHM. Here, we show that in both lupus patients and lupus-prone MRL/Fas(lpr/lpr) mice, the expression of HoxC4 and AID is significantly upregulated. To further analyze the role of HoxC4 in lupus, we generated HoxC4(-/-) MRL/Fas(lpr/lpr) mice. In these mice, HoxC4-deficiency resulted in reduced AID expression, impaired CSR, and decreased serum anti-dsDNA IgG, particularly IgG2a, autoantibodies, which were associated with a reduction in IgG deposition in kidney glomeruli. In addition, consistent with our previous findings in MRL/Fas(lpr/lpr) mice that upregulated AID expression is associated with extensive DNA lesions, comprising deletions and insertions in the IgH locus, we found that c-Myc to IgH (c-Myc/IgH) translocations occur frequently in B cells of MRL/Fas(lpr/lpr) mice. The frequency of such translocations was significantly reduced in HoxC4(-/-) MRL/Fas(lpr/lpr) mice. These findings suggest that in lupus B cells, upregulation of HoxC4 plays a major role in dysregulation of AID expression, thereby increasing CSR and autoantibody production and promoting c-Myc/IgH translocations.
authors.affiliation: School of Medicine and School of Biological Sciences, Institute for Immunology, University of California, 3028 Hewitt Hall, Irvine, CA 92697-4120, USA.
authors.forename: Clayton A
authors.initials: CA
authors.lastname: White
authors.forename: J
authors.initials: J
authors.lastname: Seth Hawkins
authors.forename: Egest J
authors.initials: EJ
authors.lastname: Pone
authors.forename: Elliot S
authors.initials: ES
authors.lastname: Yu
authors.forename: Ahmed
authors.initials: A
authors.lastname: Al-Qahtani
authors.forename: Thach
authors.initials: T
authors.lastname: Mai
authors.forename: Hong
authors.initials: H
authors.lastname: Zan
authors.forename: Paolo
authors.initials: P
authors.lastname: Casali
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D016259:Genes, myc; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D015854:Up-Regulation / Q000235:genetics; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D001323:Autoantibodies; D018398:Homeodomain Proteins; C490904:Hoxc4 protein, mouse; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase