Original Article

Monocyte Chemoattractant Protein 1–dependent Leukocytic Infiltrates Are Responsible for Autoimmune Disease in MRL-Fas^lpr Mice

Correspondence to: Vicki Rubin Kelley, Harvard Institutes of Medicine, 77 Ave. Louis Pasteur, Boston, MA 02115. Tel:617-525-5915 Fax:617-525-5830 E-mail:vkelley{at}rics.bwh.harvard.edu.

Infiltrating leukocytes may be responsible for autoimmune disease. We hypothesized that the chemokine monocyte chemoattractant protein (MCP)-1 recruits macrophages and T cells into tissues that, in turn, are required for autoimmune disease. Using the MRL-Fas^lpr strain with spontaneous, fatal autoimmune disease, we constructed MCP-1–deficient MRL-Fas^lpr mice. In MCP-1–intact MRL-Fas^lpr mice, macrophages and T cells accumulate at sites (kidney tubules, glomeruli, pulmonary bronchioli, lymph nodes) in proportion to MCP-1 expression. Deleting MCP-1 dramatically reduces macrophage and T cell recruitment but not proliferation, protects from kidney, lung, skin, and lymph node pathology, reduces proteinuria, and prolongs survival. Notably, serum immunoglobulin (Ig) isotypes and kidney Ig/C3 deposits are not diminished in MCP-1–deficient MRL-Fas^lpr mice, highlighting the requirement for MCP-1–dependent leukocyte recruitment to initiate autoimmune disease. However, MCP-1–deficient mice are not completely protected from leukocytic invasion. T cells surrounding vessels with meager MCP-1 expression remain. In addition, downstream effector cytokines/chemokines are decreased in MCP-1–deficient mice, perhaps reflecting a reduction of cytokine-expressing leukocytes. 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 combat autoimmune diseases.

Key Words: mouse, kidney, lung, chemokine, gene disruption

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