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

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

doi:10.1172/jci15078

Cited by 85 publications

(69 citation statements)

References 34 publications

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“…Although the function of the CD22/Lyn signaling-inhibitor complex was not addressed (41,42), it is likely that the decreased expression of Lyn in SLE B cells may contribute to the B cell overactivity. Consistent with studies in rodents showing that a 20% overexpression of CD19 induced autoantibody production in normal mice, expression of CD19 and CD21 levels were shown to be 20% higher on B cells from patients with systemic sclerosis compared with healthy individuals (17). In Japanese patients with SLE, a CD19 single-nucleotide polymorphism (SNP), which was rare in Caucasians, was increased (44).…”

Section: Bcr Signaling Alterations In Humanssupporting

confidence: 68%

“…By regulating Src kinases and PI 3-kinase activity, CD19 lowers the threshold of BCR-mediated signaling. Strikingly, study of CD19 Ϫ/Ϫ mice revealed an apparent tight regulation of CD19 cell surface density during B cell development (17). In contrast to mice that overexpress CD19, CD19 Ϫ/Ϫ mice have a markedly elevated BCR signaling threshold as compared with wild-type mice.…”

Section: Protein Kinase C␦ (Pkc␦)mentioning

confidence: 99%

“…In TSK mice, CD19 deficiency results in quiescent B cells, with significantly reduced autoantibody production and presence of skin fibrosis (17). Thus, even subtle increases in CD19 density are sufficient to predispose mice to produce autoimmune manifestations, suggesting that modest alterations in CD19 expression could contribute to the development of autoantibodies in humans.…”

Section: Protein Kinase C␦ (Pkc␦)mentioning

confidence: 99%

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B lymphocyte signaling pathways in systemic autoimmunity: Implications for pathogenesis and treatment

Zouali¹,

Sármay

2004

Arthritis & Rheumatism

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Section: Bcr Signaling Alterations In Humanssupporting

confidence: 68%

Section: Protein Kinase C␦ (Pkc␦)mentioning

confidence: 99%

Section: Protein Kinase C␦ (Pkc␦)mentioning

confidence: 99%

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B lymphocyte signaling pathways in systemic autoimmunity: Implications for pathogenesis and treatment

Zouali¹,

Sármay

2004

Arthritis & Rheumatism

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“…Accordingly, completely depleting or modulating the numbers or activity of B cells by targeting cell surface antigens or other pathway components has emerged as an important therapeutic opportunity for multiple diseases (3)(4)(5)(6)(7)(8).…”

mentioning

confidence: 99%

The Plasma Cell Signature in Autoimmune Disease

Streicher¹,

Morehouse²,

Groves³

et al. 2013

Arthritis & Rheumatology

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Objective. Production of pathogenic autoantibodies by self-reactive plasma cells (PCs) is a hallmark of autoimmune diseases. We undertook this study to investigate the prevalence of PCs and their relationship to known pathogenic pathways to increase our understanding of the role of PCs in disease progression and treatment response.Methods. We developed a sensitive gene expression-based method to overcome the challenges of measuring PCs using flow cytometry. Whole-genome microarray analysis of sorted cellular fractions identified a panel of genes, IGHA1, IGJ, IGKC, IGKV4-1, and TNFRSF17, expressed predominantly in PCs. The sensitivity of the PC signature score created from the combined expression levels of these genes was assessed through ex vivo experiments with sorted cells. This PC gene expression signature was used for monitoring changes in PC levels following anti-CD19 therapy, for evaluating the relationship between PCs and other autoimmune disease-related genes, and for estimating PC levels in affected blood and tissue from patients with multiple autoimmune diseases.Results. The PC signature was highly sensitive and capable of detecting a change in as few as 360 PCs. The PC signature was reduced more than 90% in scleroderma patients following anti-CD19 treatment, and this reduction was highly correlated (r ‫؍‬ 0.80) with inhibition of collagen gene expression. Evaluation of multiple autoimmune diseases revealed that 30-35% of lupus and rheumatoid arthritis patients had increased levels of PCs.Conclusion. This newly developed PC signature provides a robust and accurate method of measuring PC levels in the clinic. Our results highlight subsets of patients across multiple autoimmune diseases who may benefit from PC-depleting therapy.

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“…Although the pathogenic role of autoantibodies in SSc remains unknown, a relationship between autoantibodies and ongoing tissue damage has been suggested: antitopoisomerase I antibody levels correlate closely with disease activity and severity in SSc [12]. Furthermore, the elimination of autoantibody production results in diminished skin fibrosis in a tight-skin mouse, a genetic model for human SSc [13]. We have reported that anti-MMP-1 autoantibody that is able to inhibit the enzymatic activity of MMP-1 is detected in patients with SSc [10].…”

Section: Introductionmentioning

confidence: 99%

Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis

Nishijima

Hayakawa

Matsushita

et al. 2004

Clinical and Experimental Immunology

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SUMMARY Systemic sclerosis (SSc) is characterized by multi-organ fibrosis with an autoimmune background. Although autoantibodies are detected frequently in SSc patients, the role of autoantibody in the development of fibrosis remains unknown. Connective tissue homeostasis is a balance between the synthesis and degradation of the extracellular matrix (ECM); ECM degradation is regulated mainly by matrix metalloproteinases (MMPs). Anti-MMP-1 antibody is suggested to inhibit MMP-1 and be involved in the development of the fibrosis in SSc. However, the accumulation of various ECM components in the tissue of SSc cannot be explained by the anti-MMP-1 antibody alone. In this study, we examined the presence or levels of antibody to MMP-3, a protein which degrades various ECM components relevant to SSc fibrosis. Enzyme-linked immunosorbent assay (ELISA) using human recombinant MMP-3 revealed that IgG anti-MMP-3 autoantibody levels were elevated significantly in the sera from SSc patients, but not in patients with active systemic lupus erythematosus or dermatomyositis. IgG and IgM anti-MMP-3 antibody levels were significantly higher in diffuse cutaneous SSc, a severe form, than those in limited cutaneous SSc. Consistently, IgG anti-MMP-3 antibody levels correlated significantly with fibrosis of the skin, lung and renal blood vessels. The presence of IgG anti-MMP-3 autoantibody in sera from SSc patients was confirmed by immunoblotting analysis. Remarkably, MMP-3 activity was inhibited by IgG anti-MMP-3 antibody. These results suggest that anti-MMP-3 antibody is a serological marker that reflects the severity of SSc and also suggest that it may contribute to the development of fibrosis by inhibiting MMP-3 activity and reducing the ECM turnover.

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

Cited by 85 publications

References 34 publications

B lymphocyte signaling pathways in systemic autoimmunity: Implications for pathogenesis and treatment

B lymphocyte signaling pathways in systemic autoimmunity: Implications for pathogenesis and treatment

The Plasma Cell Signature in Autoimmune Disease

Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis

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