Our laboratory has focused its efforts on "Genetic Dissection of SLE Pathogenesis". SLE (systemic lupus erythematosus) is a systemic autoimmune disease with a wide spectrum of phenotypes and pathological changes. Equally varied and intriguing are the diverse immunological mechanisms that underlie this disease. Much of what we have learned about this disease has come from studying mouse models of this disease. Importantly, several genetic loci that confer lupus susceptibility in mice have recently been identified. Sle1, Sle2 and Sle3 are three such important loci.
We also know that these three loci impact the immune system in very different ways. Sle1 triggers the formation of high titers of anti-nuclear autoantibodies, which do not appear to be intrinsically pathogenic. Sle2 triggers generalized (i.e., not antigen-specific) B-cell hyperactivity, but this is not sufficient to cause any disease. Sle3, in contrast, leads to T-cell activation, increased CD4:CD8 ratios, reduced activation-induced T-cell death, and low titers of antinuclear autoantibodies. As one would predict, when these individual susceptibility loci are bred together, full-blown lupus ensues.
Ongoing projects in our laboratory are aimed at elucidating the immunopathological mechanisms through which these loci lead to autoimmunity. Specifically, we are dissecting out the respective contributions of these loci to (a) breaching B-cell and/or T-cell tolerance (using antigen receptor transgenic models), (b) shaping the B-cell and T-cell repertoire at different stages of lymphocyte development and differentiation, and (c) effecting glomerular pathology, via autoantibody-dependent and independent pathways. Additional studies in our laboratory are aimed at defining the molecular pathways that are triggered at each of the above steps leading to disease. Collectively, these studies will help chart out the molecular blueprints for lupus development.
RESEARCH INTERESTS
Dissection of pathogenic steps leading to systemic autoimmunity and lupus, using genetic, immunologic and molecular tools.
RECENT PUBLICATIONS
Mehrad B, Park SJ, Akangire G, Standiford TJ, Wu T, Zhu J, Mohan C, "The lupus-susceptibility locus, Sle3, mediates enhanced resistance to bacterial infections" J Immunol., 176(5):3233-9., March 2006
Fu, C Xie, J Zhu, J Thomas, XJ Zhou, and C Mohan., "Innate immune nephritis - A novel experimentally induced murine nephritis model contingent upon FcR and Toll receptor stimulation and IL-1/TNF-a production." J Immunol, 176(1):632-9, January 2006
Li J, Liu Y, Xie C, Zhu J, Zhou XJ, Morel L, C Mohan., "Deficiency of Type I interferon contributes to Sle2-associated component lupus phenotypes." Arthritis Rheum, 52:3063-3072, 2005
Xie S., Sharma R., Kaliyaperumal A., Datta SK., and C. Mohan., "Genetics of lupus susceptibility in NZB/SWR hybrids - lessons from an intercross study." Arthritis Rheum, 52(2):659-667., 2005
Fu Y, Xie C, Yan M, Li Q, Lu C, and C Mohan., "LPS-induced mesangial transcriptomics ? evaluating the role of interferon regulatory factor-1." Kidney Int, 67:1350-1361, 2005
SIGNIFICANT PUBLICATIONS
Kumar KR, Li L, Yan M, Bhaskarabhatla M, Mobley AB, Nguyen C, Mooney JM, Schatzle JD, Wakeland EK, Mohan C, "Regulation of B cell tolerance by the lupus susceptibility gene ly108" Science, 312(5780):166, June 2006
Q Li Zhen, C Xie, T Wu, M Mackay, C Aranow, C Putterman, C Mohan., "Glomerular proteome arrays - a novel approach to study glomerular-reactive autoantibodies in lupus" J Clin Invest, 115:3428-3439, 2005
Zhu J, Liu X, Xie C, Yan M, Yu Y, Sobel ES, Wakeland EK, and Mohan C., "Genetic dissection of lupus: T-cell hyperactivity as a consequence of hyperstimulatory antigen presenting cells." J Clin Invest, 115:1869-1878., 2005
Liang Z, Xie C, Chen C, Kreska D, Hsu K, Li L, Zhou X-J, and Mohan C, "Pathogenic profiles and molecular signatures of ANAs derived from NZM2410 lupus mice" Journal of Experimental Medicine, 199:381-398, 2003
Shi X, Xie C, Kreska D, Richardson J, Mohan C, "Genetic Dissection of SLE: Sle1 and Fas impact distinct pathways leading to lymphoproliferative autoimmunity" Journal of Experimental Medicine, 196:281-292, 2002
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