TY - JOUR
T1 - AID dysregulation in lupus-prone MRL/Fas lpr/lpr mice increases class switch DNA recombination and promotes interchromosomal c-Myc/IgH loci translocations
T2 - Modulation by HoxC4
AU - White, Clayton A.
AU - Seth Hawkins, J.
AU - Pone, Egest J.
AU - Yu, Elliot S.
AU - Al-Qahtani, Ahmed
AU - Mai, Thach
AU - Zan, Hong
AU - Casali, Paolo
N1 - Funding Information:
Declaration of Interest: This work was supported by U.S. National Institutes of Health grants AI 079705, AI 045011, and AI 060573 to P.C. The Reproductive Scientist Development Program through U.S. National Institutes of Health grant K12 HD 000849 and the March of Dimes Birth Defects Foundation provided support to J. S. H. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
KW - Activation-induced cytidine deaminase (AID)
KW - B-cell lymphoma
KW - C-Myc/IgH translocation
KW - Class switch DNA recombination (CSR)
KW - HoxC4
KW - Systemic lupus erythematosus (SLE)
UR - http://www.scopus.com/inward/record.url?scp=80155198846&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80155198846&partnerID=8YFLogxK
U2 - 10.3109/08916934.2011.577128
DO - 10.3109/08916934.2011.577128
M3 - Article
C2 - 21585311
AN - SCOPUS:80155198846
SN - 0891-6934
VL - 44
SP - 585
EP - 598
JO - Autoimmunity
JF - Autoimmunity
IS - 8
ER -