Abrogation of lupus nephritis in Activation-Induced Deaminase-deficient MRL/lpr Mice1

We generated MRL/lpr mice deficient in the Activation Induced Deaminase (AID). Because AID is required for immunoglobulin hypermutation and class switch recombination, these mice lack hypermutated IgG antibodies. Unlike their AID wild-type littermates, AID-deficient MRL/lpr mice not only lacked autoreactive IgG antibodies, but also experienced a dramatic increase in the levels of autoreactive IgM. This phenotype in AID-deficient mice translated into a dramatic reduction in glomerulonephritis, minimal mononuclear cell infiltration in the kidney, and a dramatic increase in survival to levels comparable to previously reported for MRL/lpr mice completely lacking B cells and levels well below those of mice lacking secreted antibodies. Therefore, this study, wherein littermates with either high levels of autoreactive IgM or autorective IgG are directly examined, proves that J Immunol. Author manuscript; available in PMC 2008 June 1. Published in final edited form as: J Immunol. 2007 June 1; 178(11): 7422–7431. PMCID: PMC2131724 NIHMSID: NIHMS33549 Page 1 of 24 Abrogation of lupus nephritis in Activation-Induced Deaminase-deficient MRL/lpr Mice 3/17/2010 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2131724/?tool=pmcentrez autoreactive IgM antibodies alone are not sufficient to promote kidney disease in MRL/lpr mice. In addition, the substantial decrease in mortality combined with a dramatic increase in autoreactive IgM antibodies in AIDdeficient MRL/lpr mice, suggest that autoreactive IgM antibodies might not only fail to promote nephritis, but may also provide a protective role in MRL/lpr mice. This novel mouse model containing high levels of autoreactive, unmutated IgM antibodies will help delineate the contribution of autoreactive IgM to autoimmunity.