Reduced Dosage of Bruton’s Tyrosine Kinase Uncouples B Cell Hyperresponsiveness from Autoimmunity in lyn −/− Mice

Abstract

The development of autoimmunity is correlated with heightened sensitivity of B cells to B cell Ag receptor (BCR) cross-linking. BCR signals are down-regulated by Lyn, which phosphorylates inhibitory receptors. lyn−/− mice have reduced BCR signaling thresholds and develop autoantibodies, glomerulonephritis, splenomegaly due to myeloid hyperplasia, and increased B-1 cell numbers. Bruton’s tyrosine kinase (Btk), a critical component of BCR signaling pathways, is required for autoantibody production in lyn−/− mice. It is unclear whether Btk mediates autoimmunity at the level of BCR signal transduction or B cell development, given that lyn−/−Btk−/− mice have a severe reduction in conventional B and B-1 cell numbers. To address this issue, we crossed a transgene expressing a low dosage of Btk (Btklow) in B cells to lyn−/−Btk−/− mice. Conventional B cell populations were restored to levels similar to those in lyn−/− mice. These cells were as hypersensitive to BCR cross-linking as lyn−/− B cells as measured by proliferation, Ca2+ flux, and activation of extracellular signal-regulated kinase and Akt. However, lyn−/−Btklow mice did not produce anti-ssDNA, anti-dsDNA, anti-histone, or anti-histone/DNA IgM or IgG. They also lacked B-1 cells and did not exhibit splenomegaly. Thus, B cell hyperresponsiveness is insufficient for autoimmunity in lyn−/− mice. These studies implicate B-1 and/or myeloid cells as key contributors to the lyn−/− autoimmune phenotype.