CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse
Eriko Saito, … , Thomas F. Tedder, Shinichi Sato
Eriko Saito, … , Thomas F. Tedder, Shinichi Sato
Published June 1, 2002
Citation Information: J Clin Invest. 2002;109(11):1453-1462. https://doi.org/10.1172/JCI15078.
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Article Genetics

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

Abstract

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 [Ca2+]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-γ-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.

Authors

Eriko Saito, Manabu Fujimoto, Minoru Hasegawa, Kazuhiro Komura, Yasuhito Hamaguchi, Yuko Kaburagi, Tetsuya Nagaoka, Kazuhiko Takehara, Thomas F. Tedder, Shinichi Sato

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Figure 1

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CD19 signal transduction in B cells from TSK/+ and wild-type littermates...
CD19 signal transduction in B cells from TSK/+ and wild-type littermates. (a and b) Constitutive tyrosine phosphorylation of CD19 (a) and Vav (b) in B cells. Splenic B cells were obtained from three mice of each group. Proteins were immunoprecipitated from lysates of unstimulated B cells with either anti-CD19 or anti-Vav Ab’s. Immunoprecipitated proteins were subjected to SDS-PAGE and transferred onto membranes for subsequent anti-phosphotyrosine (anti-pTyr) immunoblotting. All blots were subsequently stripped of anti-pTyr Ab’s and reprobed with the precipitating Ab’s to verify equivalent amounts of proteins in each lane. Each lane represents results from individual mice but represents results obtained with at least six sets of mice. (c) Constitutive Lyn kinase activity in B cells. Splenic B cells were solubilized and immunoprecipitated with anti-Lyn Ab. Immunoprecipitates were then incubated with cdc2(6–20)NH2 peptide and [γ-32P] ATP. The radioactivity incorporated into cdc2 peptide was quantified by scintillation counting. Relative mean (± SEM) kinase activities are obtained from three experiments. Kinase activity was shown as percentage of wild-type B cells that were defined as 100%. *P < 0.05.