Monocyte chemoattractant protein 1-dependent leukocytic infiltrates are responsible for autoimmune disease in MRL-Fas(lpr) mice

Infiltrating leukocytes may be responsible far autoimmune disease. We hypot hesized that the chemokine monocyte chemoattractant protein (MCP)-1 recruit s macrophages and T cells into tissues that, in turn, are required for auto immune disease. Using the MRL-Fas(lpr) strain with spontaneous, fatal autoi mmune disease, we constructed MCP-1-deficient MRL-Fas(lpr) mice. In MCP-1-i ntact MRL-Fas(lpr) mice, macrophages and T cells accumulate at sites (kidne y tubules, glomeruli, pulmonary bronchioli, lymph nodes) in proportion to M CP-1 expression. Deleting MCP-1 dramatically reduces macrophage and T cell recruitment but not proliferation, protects from kidney, lung, skin, and ly mph node pathology, reduces proteinuria, and prolongs survival. Notably, se rum immunoglobulin (Ig) isotypes and kidney Ig/C3 deposits are not diminish ed in MCP-1-deficient MRL-Fas(lpr) mice, highlighting the requirement for M CP-1-dependent leukocyte recruitment to initiate autoimmune disease. Howeve r, MCP-1-deficient mice are not completely protected from leukocytic invasi on. T cells surrounding vessels with meager MCP-1 expression remain. In add ition, downstream effector cytokines/chemokines are decreased in MCP-1-defi cient mice, perhaps reflecting a reduction of cytokine-expressing leukocyte s. Thus, MCP-1 promotes MRL-Fas(lpr) autoimmune disease through macrophage and T cell recruitment, amplified by increasing local cytokines/chemokines. We suggest that MCP-1 is a principal therapeutic target with which to comb at autoimmune diseases.