Systemic lupus erythematosus (SLE) is a multifaceted and multigenetic autoimmune disease, and lupus nephritis remains the most common manifestation of SLE with increased risk of death and end-stage renal disease.

Tim-1 has been identified to be expressed on various immune cells in the immune system and regulate their responses and many types of immune disorders. We generated a loss of function Tim-1 mutant mouse (Tim-1deltamucin) and demonstrated that this mouse had a profound defect in B cell IL-10 production. Associated with the loss of IL-10 production in B cells, older Tim-1deltamucin mice developed spontaneous systemic autoimmunity associated with hyperactive T cells, with increased production of IFN-gamma and elevated serum levels of Ig and autoantibodies. However, Tim-1deltamucin mice did not develop frank systemic autoimmune disease unless they were crossed onto the Fas-mutant lpr mice. Tim-1deltamucinlpr mice developed accelerated and fulminant systemic autoimmunity with accumulation of abnormal double-negative T cells and autoantibodies to a number of lupus-associated autoantigens. Our data suggest that Tim-1 plays a critical role in maintaining suppressive Breg function and self-tolerance.

Interestingly, TIM-1 was also identified as kidney injury molecule-1 (KIM-1), which is highly induced on kidney epithelial cells upon kidney injury. A recent study demonstrated that Tim-1/KIM-1 confers phagocytic functions on kidney epithelial cells for the clearance of apoptotic cells, suggesting that Tim-1/KIM-1 induced in injured kidneys may play an important role for successful tissue repair and resolution by averting an autoimmune inflammatory attack. Since we found that kidney epithelial cells from Tim-1deltamucin mice lost their ability to uptake apoptotic cells, we expected that at least Tim-1deltamucinlpr mice would develop more severe kidney pathology due to frank systemic autoimmunity. Surprisingly, Tim-1deltamucinlpr mice had overall normal kidney function and showed little immune complex deposit in glomeruli, while lpr mice showed impaired kidney function and extensive immune complex deposits in glomeruli. Kidneys from lpr but not Tim-1deltamucin or Tim-1deltamucinlpr mice showed expression of Tim-1. Furthermore, we generated a mouse that overexpresses Tim-1 specifically in kidney cells, and we found that this mouse developed spontaneous kidney pathology with massive infiltration of immune cells. Therefore, we hypothesize that Tim-1 expression in kidneys during lupus promotes kidney pathology.

We have recently successfully generated a Tim-1 conditional knockout mouse. With all these available tools, we can now clearly determine the role of Tim-1 in kidnays during lupus. Specially, we will study Tim-1 expression in kidneys during lupus and how loss of Tim-1 expression in kidneys affects kidney pathology during lupus. The accomplishment of the study may provide novel therapeutic strategies for treating lupus kidney pathology.