title: Modulating proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and end-organ disease in murine lupus.
abstract: BACKGROUND
  Systemic lupus erythematosus is a chronic autoimmune disease characterized by an abundance of autoantibodies against nuclear antigens. Bruton's tyrosine kinase (Btk) is a proximal transducer of the BCR signal that allows for B-cell activation and differentiation. Recently, selective inhibition of Btk by PCI-32765 has shown promise in limiting activity of multiple cells types in various models of cancer and autoimmunity. The aim of this study was to determine the effect of Btk inhibition by PCI-32765 on the development of lupus in lupus-prone B6.Sle1 and B6.Sle1.Sle3 mice.
  
  
  METHODS
  B6.Sle1 or B6.Sle1.Sle3 mice received drinking water containing either the Btk inhibitor PCI-32765 or vehicle for 56 days. Following treatment, mice were examined for clinical and pathological characteristics of lupus. The effect of PCI-32765 on specific cell types was also investigated.
  
  
  RESULTS
  In this study, we report that Btk inhibition dampens humoral autoimmunity in B6.Sle1 monocongenic mice. Moreover, in B6.Sle1.Sle3 bicongenic mice that are prone to severe lupus, Btk inhibition also dampens humoral and cellular autoimmunity, as well as lupus nephritis.
  
  
  CONCLUSIONS
  These findings suggest that partial crippling of cell signaling in B cells and antigen presenting cells (APCs) may be a viable alternative to total depletion of these cells as a therapeutic modality for lupus.
authors.forename: Jack
authors.initials: J
authors.lastname: Hutcheson
authors.forename: Kamala
authors.initials: K
authors.lastname: Vanarsa
authors.forename: Anna
authors.initials: A
authors.lastname: Bashmakov
authors.forename: Simer
authors.initials: S
authors.lastname: Grewal
authors.forename: Deena
authors.initials: D
authors.lastname: Sajitharan
authors.forename: Betty Y
authors.initials: BY
authors.lastname: Chang
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Buggy
authors.forename: Xin J
authors.initials: XJ
authors.lastname: Zhou
authors.forename: Yong
authors.initials: Y
authors.lastname: Du
authors.forename: Anne B
authors.initials: AB
authors.lastname: Satterthwaite
authors.forename: Chandra
authors.initials: C
authors.lastname: Mohan
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D013163:Splenomegaly / Q000276:immunology / Q000517:prevention & control; D016896:Treatment Outcome
chemical_list: D001323:Autoantibodies; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D000225:Adenine