B Lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse

Am J Pathol. 2004 Aug;165(2):641-50. doi: 10.1016/S0002-9440(10)63328-7.


Systemic sclerosis (SSc) is characterized by fibrosis and autoimmmunity. Peripheral blood B cells from SSc patients specifically overexpress CD19, a critical cell-surface signal transduction molecule in B cells. CD19 deficiency in B cells also attenuates skin fibrosis in the tight-skin (TSK/+) mouse, a genetic model for SSc. Herein we analyzed two transgenic mouse lines that overexpress CD19. Remarkably, 20% increase of CD19 expression in mice spontaneously induced SSc-specific anti-DNA topoisomerase I (topo I) antibody (Ab) production, which was further augmented by 200% overexpression. In TSK/+ mice overexpressing CD19, skin thickness did not increase, although anti-topo I Ab levels were significantly augmented, indicating that abnormal CD19 signaling influences autoimmunity in TSK/+ mice and also that anti-topo I Ab does not have a pathogenic role. The molecular mechanisms for abnormal CD19 signaling were further assessed. B-cell antigen receptor crosslinking induced exaggerated calcium responses and augmented activation of extracellular signal-regulated kinase in TSK/+ B cells. CD22 function was specifically impaired in TSK/+ B cells. Consistently, CD19, a major target of CD22-negative regulation, was hyperphosphorylated in TSK/+ B cells. These findings indicate that reduced inhibitory signal provided by CD22 results in abnormal activation of signaling pathways including CD19 in TSK/+ mice and also suggest that this disrupted B cell signaling contribute to specific autoantibody production.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • Antigens, CD19 / genetics
  • Antigens, CD19 / physiology*
  • Antigens, Differentiation, B-Lymphocyte / metabolism*
  • Autoantibodies / metabolism*
  • Autoimmunity*
  • B-Lymphocytes / immunology*
  • Calcium / metabolism
  • Cell Adhesion Molecules*
  • Cross-Linking Reagents
  • DNA Topoisomerases, Type I / immunology
  • Female
  • Fibrosis / metabolism
  • Fibrosis / pathology*
  • Humans
  • Lectins / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation
  • Receptors, Antigen, B-Cell / metabolism
  • Scleroderma, Systemic / immunology
  • Scleroderma, Systemic / metabolism
  • Scleroderma, Systemic / pathology
  • Sialic Acid Binding Ig-like Lectin 2
  • Signal Transduction
  • Skin / pathology*


  • Antigens, CD
  • Antigens, CD19
  • Antigens, Differentiation, B-Lymphocyte
  • Autoantibodies
  • CD22 protein, human
  • Cd22 protein, mouse
  • Cell Adhesion Molecules
  • Cross-Linking Reagents
  • Lectins
  • Receptors, Antigen, B-Cell
  • Sialic Acid Binding Ig-like Lectin 2
  • Mitogen-Activated Protein Kinases
  • DNA Topoisomerases, Type I
  • Calcium