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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Saito, E; Fujimoto, M; Hasegawa, M; Komura, K; Hamaguchi, Y; Kaburagi, Y; Nagaoka, T; Takehara, K; Tedder, TF; Sato, S

Published Date

  • June 2002

Published In

Volume / Issue

  • 109 / 11

Start / End Page

  • 1453 - 1462

PubMed ID

  • 12045259

Pubmed Central ID

  • 12045259

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/JCI15078

Language

  • eng