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1.  Altered Thymic Selection by Over-Expressing Cellular FLICE Inhibitory Protein in T Cells Causes Lupus-like Syndrome in BALB/c but not C57BL/6 Strain 
Cell death and differentiation  2009;17(3):522-533.
Cellular FLICE inhibitory protein (c-FLIP) is an endogenous inhibitor of the caspase-8 pro-apoptotic signaling pathway downstream of death receptors. Recent evidence indicates that the long form of c-FLIP (c-FLIPL) is required for proliferation and effector T cell development. However, the role of c-FLIPL in triggering autoimmunity has not been carefully investigated. We now report that c-FLIPL transgenic (Tg) mice develop splenomegaly, lymphadenopathy, multi-organ infiltration, high titers of autoantibodies, and proliferative glomerulonephritis with immune complex deposition in a strain-dependent fashion. The development of autoimmunity requires CD4+ T cells and may result from impaired thymic selection. At the molecular level, c-FLIPL over-expression inhibits the ZAP-70 activation, thus impairing the signaling pathway derived from ZAP-70 required for thymic selection. Therefore, we have identified c-FLIPL as a susceptibility factor under the influence of epistatic modifiers for the development of autoimmunity.
PMCID: PMC2822025  PMID: 19816511
2.  Focal and segmental glomerulosclerosis induced in mice lacking decay-accelerating factor in T cells 
The Journal of Clinical Investigation  2009;119(5):1264-1274.
Heritable and acquired diseases of podocytes can result in focal and segmental glomerulosclerosis (FSGS). We modeled FSGS by passively transferring mouse podocyte–specific sheep Abs into BALB/c mice. BALB/c mice deficient in the key complement regulator, decay-accelerating factor (DAF), but not WT or CD59-deficient BALB/c mice developed histological and ultrastructural features of FSGS, marked albuminuria, periglomerular monocytic and T cell inflammation, and enhanced T cell reactivity to sheep IgG. All of these findings, which are characteristic of FSGS, were substantially reduced by depleting CD4+ T cells from Daf–/– mice. Furthermore, WT kidneys transplanted into Daf–/– recipients and kidneys of DAF-sufficient but T cell–deficient Balb/cnu/nu mice reconstituted with Daf–/– T cells developed FSGS. In contrast, DAF-deficient kidneys in WT hosts and Balb/cnu/nu mice reconstituted with DAF-sufficient T cells did not develop FSGS. Thus, we have described what we believe to be a novel mouse model of FSGS attributable to DAF-deficient T cell immune responses. These findings add to growing evidence that complement-derived signals shape T cell responses, since T cells that recognize sheep Abs bound to podocytes can lead to cellular injury and development of FSGS.
PMCID: PMC2673859  PMID: 19349693
3.  RANTES and Monocyte Chemoattractant Protein–1 (MCP-1) Play an Important Role in the Inflammatory Phase of Crescentic Nephritis, but Only MCP-1 Is Involved in Crescent Formation and Interstitial Fibrosis 
The Journal of Experimental Medicine  1997;185(7):1371-1380.
The involvement of chemokines in inflammation is well established, but their functional role in disease progression, and particularly in the development of fibrosis, is not yet understood. To investigate the functional role that the chemokines monocyte chemoattractant protein–1 (MCP-1) and RANTES play in inflammation and the progression to fibrosis during crescentic nephritis we have developed and characterized a murine model for this syndrome. Significant increases in T-lymphocytes and macrophages were observed within glomeruli and interstitium, paralleled by an induction of mRNA expression of MCP-1 and RANTES, early after disease initiation. Blocking the function of MCP-1 or RANTES resulted in significant decreases in proteinuria as well as in numbers of infiltrating leukocytes, indicating that both MCP-1 and RANTES (regulated upon activation in normal T cells expressed and secreted) play an important role in the inflammatory phase of crescentic nephritis. In addition, neutralization of MCP-1 resulted in a dramatic decrease in both glomerular crescent formation and deposition of type I collagen. These results highlight a novel role for MCP-1 in crescent formation and development of interstitial fibrosis, and indicate that in addition to recruiting inflammatory cells this chemokine is critically involved in irreversible tissue damage.
PMCID: PMC2196251  PMID: 9104823

Results 1-3 (3)