Systemic lupus erythematosus (SLE) is a chronic autoimmune disease and genetic predisposition is firmly established as a key element in susceptibility. T cells from patients and mice with systemic lupus erythematosus produce decreased amounts of IL2 upon activation. But the reason and roles of the IL-2 deficiency in lupus pathogenesis have so far remained unclear. On the other hand, accumulating evidences emphasize that dominant function of IL-2 in vivo is maintenance of immune system homeostasis and tolerance to self through dominating T regulatory cell development and activity. Recently we made an unexpected discovery that lupus Sle2c1 sublocus leads to markedly decreased IL-2 production by CD4+ T cells upon activation in vitro. Aften/vards, we further mapped this IL-2 deficiency to the shorter Sle2c1-Rec1 sublocus and proved that other cytokines were not significantly affected. Therefore, basing on these facts, we hypothesize that a defective gene responsible for the IL-2 deficiency locates in the Sle2c1-Rec1 sublocus and directs the synthesis of a dysfunctional molecule that specifically disturbs IL-2 expression. The IL-2 deficiency may take effects on T regulatory cells and play roles in autoimmune lupus development. To address these issues, we propose three aims basing on our B6.Sle2c1-Rec1 congenic mouse as a powerful tool: (1) to identify the gene responsible for IL-2 deficiency through cycles of generating congenic sub-strains and screening the IL-2 deficiency, (2) to dissect the molecular mechanisms of the IL-2 deficiency through exploring the signaling pathways of regulation IL-2 production, and (3) to investigate the impact of the IL-2 deficiency on number and function of T regulatory cells and autoimmune pathogenesis in systemic lupus erythematosus model. The log-term objective of this research is to find out an effective therapeutic target for lupus disease treatment. The study in this purposed project on the interrelation of the IL-2 deficiency and lupus opens a new research field for me. This grant will provide me with additional training that certainly enhances my skill ability towards independent investigation of autoimmune diseases.
IL-2 is essential for maintaining immune tolerance and homeostasis. However, the T cells of lupus patients and mouse models have a phenotypic hallmark of IL-2 deficiency. Our design of this project aims at identifying the gene responsible for the IL-2 deficiency and elucidating its roles in lupus pathogenesis, which will contribute to discovering a new therapeutic target for lupus treatment.
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|Xu, Zhiwei; Potula, Hari-Hara S K; Vallurupalli, Anusha et al. (2011) Cyclin-dependent kinase inhibitor Cdkn2c regulates B cell homeostasis and function in the NZM2410-derived murine lupus susceptibility locus Sle2c1. J Immunol 186:6673-82|
|Xu, Zhiwei; Vallurupalli, Anusha; Fuhrman, Christopher et al. (2011) A New Zealand Black-derived locus suppresses chronic graft-versus-host disease and autoantibody production through nonlymphoid bone marrow-derived cells. J Immunol 186:4130-9|
|Xu, Zhiwei; Cuda, Carla M; Croker, Byron P et al. (2011) The NZM2410-derived lupus susceptibility locus Sle2c1 increases Th17 polarization and induces nephritis in fas-deficient mice. Arthritis Rheum 63:764-74|