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Reduced Dosage of Bruton’s Tyrosine Kinase Uncouples B Cell Hyperresponsiveness from Autoimmunity in lyn^-/- Mice¹

Lindsey R. Whyburn^2,*, Kristina E. Halcomb^2,*, Cristina M. Contreras^*, Clifford A. Lowell, Owen N. Witte and Anne B. Satterthwaite^3,*,

Harold Simmons Arthritis Research Center, ^* Department of Internal Medicine and Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Laboratory Medicine, University of California, San Francisco, CA 94143; and Howard Hughes Medical Institute and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095

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 (Btk^low) 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^-/-Btk^low 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.

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