title: Abrogation of lupus nephritis in activation-induced deaminase-deficient MRL/lpr mice.
abstract: 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.
authors.affiliation: Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Chuancang
authors.initials: C
authors.lastname: Jiang
authors.forename: Julie
authors.initials: J
authors.lastname: Foley
authors.forename: Natasha
authors.initials: N
authors.lastname: Clayton
authors.forename: Grace
authors.initials: G
authors.lastname: Kissling
authors.forename: Micheal
authors.initials: M
authors.lastname: Jokinen
authors.forename: Ronald
authors.initials: R
authors.lastname: Herbert
authors.forename: Marilyn
authors.initials: M
authors.lastname: Diaz
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000378:metabolism; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000378:metabolism; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000473:pathology; D008181:Lupus Nephritis / Q000201:enzymology* / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D013045:Species Specificity; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase