CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse

J Clin Invest. 2002 Jun;109(11):1453-62. doi: 10.1172/JCI15078.


The tight-skin (TSK/+) mouse, a genetic model for human systemic sclerosis (SSc), develops cutaneous fibrosis and autoantibodies against SSc-specific target autoantigens. Although molecular mechanisms explaining the development of fibrosis and autoimmunity in SSc patients or TSK/+ mice remain unknown, we recently demonstrated that SSc patients overexpress CD19, an important regulatory molecule expressed by B lymphocytes. B cells from CD19-deficient mice are hyporesponsive to transmembrane signals, while B cells overexpressing CD19 are hyperresponsive and generate autoantibodies. In this study, TSK/+ B cells also exhibited a hyperresponsive phenotype with decreased surface IgM expression, enhanced serum Ig production, and spontaneous autoantibody production. Moreover, CD19 tyrosine phosphorylation was constitutively augmented in TSK/+ B cells. CD19-mediated [Ca(2+)](i) responses, Vav phosphorylation, and Lyn kinase activity were similarly enhanced. Studies of TSK/+ mice deficient in CD19 expression demonstrated that CD19 deficiency significantly decreased skin fibrosis in TSK/+ mice. Additionally, CD19 loss in TSK/+ mice upregulated surface IgM expression and completely abrogated hyper-gamma-globulinemia and autoantibody production. CD19 deficiency also inhibited IL-6 production by TSK/+ B cells. Thus, chronic B cell activation resulting from augmented CD19 signaling in TSK/+ mice leads to skin sclerosis possibly through IL-6 overproduction as well as autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ADP-ribosyl Cyclase
  • ADP-ribosyl Cyclase 1
  • Animals
  • Antigens, CD*
  • Antigens, CD19 / metabolism
  • Antigens, CD19 / physiology*
  • Antigens, Differentiation / biosynthesis
  • B-Lymphocytes / metabolism*
  • Blotting, Western
  • Calcium / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Enzyme-Linked Immunosorbent Assay
  • Fibrosis / metabolism
  • Flow Cytometry
  • Humans
  • Hydroxyproline / metabolism
  • Immunoglobulin M / metabolism
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / metabolism
  • Membrane Glycoproteins
  • Mice
  • NAD+ Nucleosidase / biosynthesis
  • Phosphorylation
  • Precipitin Tests
  • Scleroderma, Systemic / pathology
  • Signal Transduction
  • Skin / pathology*
  • Time Factors
  • Tyrosine / metabolism
  • Up-Regulation


  • Antigens, CD
  • Antigens, CD19
  • Antigens, Differentiation
  • Immunoglobulin M
  • Interleukin-6
  • Membrane Glycoproteins
  • Tyrosine
  • ADP-ribosyl Cyclase
  • CD38 protein, human
  • Cd38 protein, mouse
  • NAD+ Nucleosidase
  • ADP-ribosyl Cyclase 1
  • Hydroxyproline
  • Calcium