title: 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 [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.
authors.affiliation: Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Saito
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Minoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Komura
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Hamaguchi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kaburagi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nagaoka
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takehara
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Tedder
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sato
mesh_terms: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD; D018941:Antigens, CD19 / Q000378:metabolism / Q000502:physiology*; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000378:metabolism*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005355:Fibrosis / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D008562:Membrane Glycoproteins; D051379:Mice; D009244:NAD+ Nucleosidase / Q000096:biosynthesis; D010766:Phosphorylation; D011233:Precipitin Tests; D012595:Scleroderma, Systemic / Q000473:pathology; D015398:Signal Transduction; D012867:Skin / Q000473:pathology*; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D018941:Antigens, CD19; D000943:Antigens, Differentiation; D007075:Immunoglobulin M; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D014443:Tyrosine; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498155:Cd38 protein, mouse; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D006909:Hydroxyproline; D002118:Calcium