The immune system must decide whether to mount an immune response to a particular entity or whether to ignore it. The latter outcome is referred to as immunological tolerance. A great deal has been learned about tolerance over the past decade, but our understanding is still fragmentary, despite its importance for understanding autoimmune disease, managing acceptance of organ transplants, and promoting cancer immunotherapy. We have unexpectedly found that mice deficient in the Lyn tyrosine kinase have B lymphocytes that exhibit elevated responsiveness to antigenic stimulation. In vivo, these mice make high levels of autoantibodies directed at nuclear components such as double-stranded DNA and some of them develop kidney disease. Double mutant mice defective in Lyn and another Src-family kinase, Fyn were found to develop a much more severe autoimmune lupus-like kidney disease, with 50% of the animals dying by 7 months of age. We hypothesize that the defect in Lyn makes B cells hyperresponsive and also defective in tolerance induction, resulting in production of antibodies directed at nuclear components released by apoptotic cells. We further hypothesize that the defect in fyn contributes to more rapid disease incidence, possibly by making the kidneys more susceptible to damage resulting from immune complex deposition. In addition, Fyn-deficiency may lead to defects in T cell tolerance. These hypotheses will be tested by three Specific Aims: 1) We shall determine the effects of Lyn and Fyn deficiencies on tolerance to double-stranded (ds) DNA using Ig- transgenic mice developed by Martin Weigert and coworkers. 2) We shall determine the role of helper T cells in IgG anti-dsDNA production by Lyn-/- mice and examine the effects of lyn and fyn defects on T cell tolerance, and 3) We shall define the cellular basis of defects leading to autoimmune disease in lyn-/-fyn-/- mice. This will be done by bone marrow transplantation and by adoptive transfer of mature lymphocytes. The proposed studies may lead to significant insights into the nature of the severe autoimmune disease in lyn-/-fyn-/- mice, which in turn may aid in understanding the causes of human autoimmune diseases such as systemic lupus erythematosus.
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