title: 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 (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, Ca(2+) 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.
authors.affiliation: Harold Simmons Arthritis Research Center, Department of Internal Medicine and Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lindsey R
authors.initials: LR
authors.lastname: Whyburn
authors.forename: Kristina E
authors.initials: KE
authors.lastname: Halcomb
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Contreras
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Owen N
authors.initials: ON
authors.lastname: Witte
authors.forename: Anne B
authors.initials: AB
authors.lastname: Satterthwaite
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D016175:B-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D003432:Cross-Linking Reagents / Q000378:metabolism; D018628:Gene Dosage; D008213:Lymphocyte Activation / Q000235:genetics*; D008231:Lymphopenia / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology; D019076:Transgenes / Q000276:immunology; D019061:src-Family Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D001323:Autoantibodies; D003432:Cross-Linking Reagents; D009856:Oncogene Proteins, Viral; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases