title: Expression of natural autoantibodies in MRL-lpr mice protects from lupus nephritis and improves survival.
abstract: Natural autoantibodies (NAA) and their associated B cells constitute a substantial proportion of the normal Ab and B cell repertoire. They often have weak reactivity toward a variety of self-Ags such as DNA, nucleoproteins, and phospholipids. It remains controversial whether NAA contribute to or protect from autoimmune diseases. Using site-directed transgenic (sd-tg) mice expressing a prototypic NAA, we investigated the effect of NAA and NAA-producing B cells in disease development in the autoimmune-prone MRL/MpJ-Fas(lpr) (MRL-lpr) mice. We found that the expression of NAA in MRL-lpr mice prevented proteinuria and reduced kidney immune complex formation. The mice had significantly improved survival. Administration of the IgM NAA to MRL-lpr mice also delayed the onset of nephritis. The sd-tg MRL-lpr mice had decreased levels of anti-dsDNA Abs, anti-Hep2 nuclear Abs, and anti-Sm/ribonucleoprotein Abs. There is a shift in the IgG subclass profile from IgG2a and IgG3 to IgG1 in the sd-tg MRL-lpr mice. The CD4(+) T cells from the sd-tg MRL-lpr mice had increased expression of the negative costimulatory molecule CTLA-4 and increased production of IL-10 as compared with those from the wild-type mice. Furthermore, the NAA B cells produced large amounts of IL-10 upon TLR stimulation. These results indicate that NAA and NAA-producing B cells play an important role in protection from lupus nephritis and suggest that the NAA B cells may have an immune regulatory function via the provision of IL-10.
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Kaiissar
authors.initials: K
authors.lastname: Mannoor
authors.forename: Agata
authors.initials: A
authors.lastname: Matejuk
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Michael
authors.initials: M
authors.lastname: Beardall
authors.forename: Ching
authors.initials: C
authors.lastname: Chen
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology*; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000096:biosynthesis / Q000276:immunology; D004247:DNA / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000276:immunology; D007075:Immunoglobulin M / Q000008:administration & dosage; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D007668:Kidney / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008181:Lupus Nephritis / Q000276:immunology* / Q000378:metabolism / Q000401:mortality; D051379:Mice; D019463:Mice, Inbred MRL lpr; D011507:Proteinuria / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556062:IL10 protein, mouse; D007075:Immunoglobulin M; D016753:Interleukin-10; D004247:DNA