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Disrupting Mer receptor tyrosine kinase expression prevents autoimmune chronic graft-versus-host disease

The Mer receptor tyrosine kinase mediates apoptotic cell phagocytosis and modulates macrophage cytokine production. Mer knockout mice (Mer-KO) have defective clearance of apoptotic debris and develop systemic lupus erythematosus-like autoimmune disease. Because of their spontaneous autoimmune propensity, we wondered whether Mer-KO mice (backcrossed 10 generations onto C57BL/6) might be particularly susceptible to the systemic lupus erythematosus-like autoimmunity induced by chronic graft-versus-host disease (GVHD). Using the well-established cGVH model (bm12 → B6 mice), we were surprised to observe that the Mer-KO mice were protected from the development of GVHD. Mer-KO recipients of bm12 spleen cells failed to develop detectable anti-dsDNA and antichromatin autoantibodies, while the B6 hosts produced significant amounts of these antibodies that peaked at week 2. Slightly increased levels of rheumatoid factor were found in Mer-KO mice, although much lower than B6 control hosts. Mer-KO mice did not develop splenomegaly. The lack of autoantibody formation was not due to an absence of alloreactivity, because spleen cells from bm12 mice proliferated equally in response to irradiated wild-type and Mer-KO irradiated spleen cells. GVHD developed normally in F1 (Mer-KO × B6) hosts given bm12 donor cells, thus indicating that the failure to develop GVHD was not due to mer-KO-derived minor MHC genes. These findings indicate a hitherto unrecognized requirement for Mer in the genesis of alloreactivity-induced autoimmunity. Future experiments will determine whether this reflects the role of this kinase in recognition and phagocytosis of apoptotic cells, its function in regulating cytokine production, or perhaps a new function in the immune response.

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Shao, WH., Eisenberg, R.A. & Cohen, P.L. Disrupting Mer receptor tyrosine kinase expression prevents autoimmune chronic graft-versus-host disease. Arthritis Res Ther 9 (Suppl 3), P7 (2007).

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