期刊
AUTOIMMUNITY
卷 42, 期 2, 页码 89-103出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/08916930802629554
关键词
Activation-induced cytidine deaminase (AID); antibody; autoantibody; B cell; class switch DNA recombination (CSR); DNA deletion; DNA insertion; lupus; somatic hypermutation (SHM)
类别
资金
- NIH [AI 045011, AI 060573, AI 079705]
- Korea Research Foundation [KRF-2005-214-C00131]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [T32AI060573, R56AI045011, R01AI045011, R01AI079705, R56AI079705] Funding Source: NIH RePORTER
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of an array of pathogenic autoantibodies, including high-affinity anti-dsDNA IgG antibodies. These autoantibodies are mutated and class-switched, mainly to IgG, indicating that immunoglobulin (Ig) gene somatic hypermutation (SHM) and class switch DNA recombination (CSR) are important in their generation. Lupus-prone MRL/faslpr/lpr mice develop a systemic autoimmune syndrome that shares many features with human SLE. We found that Ig genes were heavily mutated in MRL/faslpr/lpr mice and contained long stretches of DNA deletions and insertions. The spectrum of mutations in MRL/faslpr/lpr B cells was significantly altered, including increased dG/dC transitions, increased targeting of the RGYW/WRCY mutational hotspot and the WGCW AID-targeting hotspot. We also showed that MRL/faslpr/lpr greatly upregulated CSR, particularly to IgG2a and IgA in B cells of the spleen, lymph nodes and Peyer's patches. In MRL/faslpr/lpr mice, the significant upregulation of SHM and CSR was associated with increased expression of activation-induced cytidine deaminase (AID), which mediates DNA lesion, the first step in SHM and CSR, and translesion DNA synthesis (TLS) polymerase (pol) , pol and pol , which are involved in DNA synthesis/repair process associated with SHM and, possibly, CSR. Thus, in lupus-prone MRL/faslpr/lpr mice, SHM and CSR are upregulated, as a result of enhanced AID expression and, therefore, DNA lesions, and dysregulated DNA repair factors, including TLS polymerases, which are involved in the repair process of AID-mediated DNA lesions.
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