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* Laboratory of Molecular Genetics,
Laboratory of Experimental Pathology, and
Biostatistics Branch, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC, 27709; and
Pathology Associates, Charles River Laboratories, Cary, NC 27513
We generated MRL/lpr mice deficient in activation-induced deaminase (AID). Because AID is required for Ig hypermutation and class switch recombination, these mice lack hypermutated IgG Abs. Unlike their AID wild-type littermates, AID-deficient MRL/lpr mice not only lacked autoreactive IgG Abs but also experienced a dramatic increase in the levels of autoreactive IgM. This phenotype in AID-deficient mice translated into a significant reduction in glomerulonephritis, minimal mononuclear cell infiltration in the kidney, and a dramatic increase in survival to levels comparable to those previously reported for MRL/lpr mice completely lacking B cells and well below those of mice lacking secreted Abs. Therefore, this study wherein littermates with either high levels of autoreactive IgM or autoreactive IgG were directly examined proves that autoreactive IgM Abs 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 Abs in AID-deficient MRL/lpr mice suggest that autoreactive IgM Abs 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 Abs will help delineate the contribution of autoreactive IgM to autoimmunity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences.
2 Address correspondence and reprint requests to Dr. Marilyn Diaz, Laboratory of Molecular Genetics, D3-01, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T. W. Alexander Drive, Research Triangle Park, NC 27709. E-mail address: diaz{at}niehs.nih.gov
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; AID, activation-induced deaminase; ANA, antinuclear Ab; CSR, class switch recombination; GC, germinal center; SHM, somatic hypermutation; PNA, peanut agglutinin.
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