TY - JOUR
T1 - Reduced dosage of Bruton's tyrosine kinase uncouples B cell hyperresponsiveness from autoimmunity in lyn-/- mice
AU - Whyburn, Lindsey R.
AU - Halcomb, Kristina E.
AU - Contreras, Cristina M.
AU - Lowell, Clifford A.
AU - Witte, Owen N.
AU - Satterthwaite, Anne B.
PY - 2003/8/15
Y1 - 2003/8/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.171.4.1850
DO - 10.4049/jimmunol.171.4.1850
M3 - Article
C2 - 12902486
AN - SCOPUS:0043092190
SN - 0022-1767
VL - 171
SP - 1850
EP - 1858
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -