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CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2002 Jun; Vol. 109 (11), pp. 1453-62. - Publication Year :
- 2002
-
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 [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.
- Subjects :
- ADP-ribosyl Cyclase
ADP-ribosyl Cyclase 1
Animals
Antigens, CD19 metabolism
Antigens, Differentiation biosynthesis
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
Time Factors
Tyrosine metabolism
Up-Regulation
Antigens, CD
Antigens, CD19 physiology
B-Lymphocytes metabolism
Skin pathology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9738
- Volume :
- 109
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 12045259
- Full Text :
- https://doi.org/10.1172/JCI15078