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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901207v1 183/5/3505    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Sim, D. L. Articles by Deshmukh, U. S. PubMed PubMed Citation Articles by Sim, D. L. Articles by Deshmukh, U. S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

Genetic Complementation Results in Augmented Autoantibody Responses to Lupus-Associated Antigens¹

Davis L. Sim^*,,, Harini Bagavant, Yogesh M. Scindia, Yan Ge^*,, Felicia Gaskin, Shu Man Fu^2,3,*,, and Umesh S. Deshmukh^2,3,

^* Department of Microbiology, Division of Nephrology, Center for Immunity, Inflammation, and Regenerative Medicine, Division of Rheumatology and Immunology, Department of Medicine, and Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, School of Medicine, Charlottesville, VA 22908

Lupus-prone female New Zealand Mixed (NZM)2328 mice develop high titers of anti-nuclear and anti-dsDNA autoantibodies. Despite high expression of type I IFNs, these mice do not develop autoantibodies to the small nuclear ribonucleoprotein (snRNP) complex. Thus, additional genetic factors must regulate the generation of anti-snRNP autoantibodies. In contrast, despite much lower expression of type 1 IFNs, the diabetes-prone NOD mice spontaneously make anti-snRNP autoantibodies, albeit at a low incidence. To determine whether combination of high type I IFN response of NZM mice with appropriate susceptibility genes of NOD mice would result in anti-snRNP Ab response, cohorts of (NZM2328 x NOD)F₁ mice were generated and characterized for development of autoimmunity. In comparison with parental strains, the PBMCs from F₁ mice showed intermediate expression of type I IFN-responsive genes and augmented expression of IL-6 transcripts. TLR7 expression was similar in all strains. The F₁ mice had very high incidence and titer of anti-snRNP autoantibodies, anti-nuclear Abs, and anti-dsDNA autoantibodies. The levels of anti-snRNP autoantibody correlated with the expression levels of type I IFN-responsive genes. None of the F₁ mice developed diabetes, and only female mice developed severe renal disease. Our data demonstrate that only in presence of appropriate susceptibility genes, anti-snRNP autoantibodies are induced and type I IFNs amplify this response. A synergy between IL-6 and type I IFNs might be critical for amplifying overall autoantibody responses in systemic lupus erythematosus. In NZM/NOD F₁ mouse, genetic complementation between NZM and NOD genes leads to expression of phenotypes similar to those seen in certain lupus patients.

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 work was supported by National Institutes of Health Grants P01-AR-45222, R01-AR-47988, and R01-AR-49449 (to S.M.F.), and R01-DK069769 (to H.B.); K01AR051391 (to U.S.D.); grants from Lupus Research Institute (to U.S.D.); and Alliance for Lupus Research Award 68164 (to S.M.F.).

² S.M.F. and U.S.D. are cosenior authors and contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Umesh S. Deshmukh, University of Virginia, Health Sciences Center, Box 800133, Charlottesville, VA 22908; E-mail address: usd7w{at}virginia.edu or Dr. Shu Man Fu, University of Virginia, HSC, Box 800133, Charlottesville, VA 22908; E-mail address: sf2e{at}virginia.edu

⁴ Abbreviations used in this paper: snRNP, small nuclear ribonucleoprotein; ANA, anti-nuclear Ab; GN, glomerulonephritis; NZM, New Zealand Mixed; RNP, ribonucleoprotein; Sm, Smith.