title: Bruton's Tyrosine Kinase Deficiency Inhibits Autoimmune Arthritis in Mice but Fails to Block Immune Complex-Mediated Inflammatory Arthritis.
abstract: Bruton's tyrosine kinase (BTK) is a B cell signaling protein that also contributes to innate immunity. BTK inhibitors prevent autoimmune arthritis but have off-target effects, and the mechanisms of protection remain unknown. We undertook these studies using genetic deletion to investigate the role of BTK in adaptive and innate immune responses that drive inflammatory arthritis.
  
  
  
  BTK-deficient K/BxN mice were generated to study the role of BTK in a spontaneous model that requires both adaptive and innate immunity. The K/BxN serum-transfer model was used to bypass the adaptive system and elucidate the role of BTK in innate immune contributions to arthritis.
  
  
  
  BTK deficiency conferred disease protection to K/BxN mice, confirming outcomes of BTK inhibitors. B lymphocytes were profoundly reduced, more than in other models of BTK deficiency. Subset analysis revealed loss of B cells at all developmental stages. Germinal center B cells were also decreased, with downstream effects on numbers of follicular helper T cells and greatly reduced autoantibodies. In contrast, total IgG was only mildly decreased. Strikingly, and in contrast to small molecule inhibitors, BTK deficiency had no effect in the serum-transfer model of arthritis.
  
  
  
  BTK contributes to autoimmune arthritis primarily through its role in B cell signaling and not through innate immune components.
authors.affiliation: Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: Nyhoff
authors.affiliation: Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Bridgette L
authors.initials: BL
authors.lastname: Barron
authors.affiliation: Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Johnson
authors.affiliation: Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Bonami
authors.affiliation: Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Damian
authors.initials: D
authors.lastname: Maseda
authors.affiliation: Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Fensterheim
authors.affiliation: Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.affiliation: Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.affiliation: Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Crofford
authors.affiliation: Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Peggy L
authors.initials: PL
authors.lastname: Kendall
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology*; D001168:Arthritis / Q000201:enzymology* / Q000276:immunology*; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000209:etiology*; D008297:Male; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000172:deficiency*
chemical_list: D000936:Antigen-Antibody Complex; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse