IMPAIRED PROLIFERATION OF PERIPHERAL B-CELLS AND INDICATION OF AUTOIMMUNE-DISEASE IN LYN-DEFICIENT MICE

The Src family protein-tyrosine kinase Lyn associates physically with the BCR and has been suggested to play an important role in BCR-mediat ed signaling. Studies with lyn(-/-) mice showed that the number of B c ells decreased by half in their peripheral tissues. In addition, these B cells do not respond normally to a number of stimuli, including BCR cross-linking and CD40 ligand. Induction of tyrosine phosphorylation on a variety of cellular proteins, such as Vav, Cbl, and HS1, upon BCR cross-linking was also abolished in these B cells, Despite the impair ed BCR-mediated signaling, concentrations of IgM and IgA in sera were remarkably elevated, and production of autoantibodies was detected in lyn(-/-) mice. Histological study showed splenomegaly and enlargement of lymph nodes that became evident with age in the mutant mice. The sp leen contained significant number of plasma cells as well as unusual i ymphoblast-like cells carrying Mac1 antigen and cytoplasmic IgM. These cells spontaneously secreted a large amount of IgM in vitro. Finally, significant number of lyn(-/-) mice show glomerulonephritis, an indic ation of autoimmune disease. From these data, we conclude that Lyn pla ys a role in signal transduction for not only clonal expansion and ter minal differentiation of peripheral B cells but also elimination of au toreactive B cells.