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

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

doi:10.1172/jci200215078

Cited by 66 publications

(81 citation statements)

References 32 publications

(60 reference statements)

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“…The overexpression of CD19 appears to be partly based on genetic polymorphism of CD19 gene itself (9), suggesting that CD19 may be causally involved in a proportion of patients. Such a possibility is supported by the TSK mouse model, in which introduction of the CD19 deficiency resulted not only in the reduction of autoantibody production and hyper-gammaglobulinemia but also in skin fibrosis (8). Our present study suggested that CD22 polymorphism may also be causally involved in a small proportion of patients.…”

Section: Discussionsupporting

confidence: 62%

Association of CD22 gene polymorphism with susceptibility to limited cutaneous systemic sclerosis

et al. 2007

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Activating and inhibitory signal transducers, CD19 and CD22, have been substantially implicated both in human systemic sclerosis (SSc) and tight-skin mouse, a model for SSc. We previously showed that a single nucleotide polymorphism (SNP) in CD19 promoter region was significantly associated with increased CD19 expression level and with susceptibility to SSc. In the present study, we examined whether CD22 polymorphisms were associated with susceptibility to SSc. CD22 variations were genotyped in 126 Japanese patients with SSc [47 diffuse cutaneous SSc and 79 limited cutaneous SSc (lcSSc)] and 93 unrelated healthy controls. At the c.2304C > A SNP coding for a synonymous substitution in exon 13, A/A genotype was observed in six patients with SSc (4.8 %) but none in the controls (P=0.040). All six patients with A/A genotype belonged to the lcSSc subgroup (7.6%, P=0.008 vs controls). Surface expression level of CD22 tended to be lower in B cells from the patients with A/A genotype (n=5) as compared with C/A (n=7) or C/C (n=14) genotype (17% decrease, P=0.0032). Taken together with our previous observation on CD19 polymorphism, intrinsic difference in the expression level of CD19 and CD22 was suggested to play a causative role in a proportion of patients with lcSSc.

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Section: Discussionsupporting

confidence: 62%

Association of CD22 gene polymorphism with susceptibility to limited cutaneous systemic sclerosis

et al. 2007

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“…Comparison with the scleroderma gene expression pattern demonstrated a strong contribution of the B lymphocyte signature, suggesting a potential role for B cells in the pathogenesis of scleroderma (Whitfield et al, 2003). Consistent with this result, B cells also appear to have a pathogenic role in the tight-skin mouse model of scleroderma (Saito et al, 2002). These studies support the idea that rituximab, an anti-CD20 monoclonal antibody which targets B cells, may be useful in the treatment of scleroderma.…”

Section: Three Examples Of Gene Module Analysissupporting

confidence: 69%

Learning More from Microarrays: Insights from Modules and Networks

Wong

Chang

2005

Journal of Investigative Dermatology

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Global gene expression patterns can provide comprehensive molecular portraits of biologic diversity and complex disease states, but understanding the physiologic meaning and genetic basis of the myriad gene expression changes have been a challenge. Several new analytic strategies have now been developed to improve the interpretation of microarray data. Because genes work together in groups to carry out specific functions, defining the unit of analysis by coherent changes in biologically meaningful sets of genes, termed modules, improves our understanding of the biological processes underlying the gene expression changes. The gene module approach has been used in exploratory discovery of defective oxidative phosphorylation in diabetes mellitus and also has allowed definitive hypothesis testing on a genomic scale for the relationship between wound healing and cancer and for the oncogenic mechanism of cyclin D. To understand the genetic basis of global gene expression patterns, computational modeling of regulatory networks can highlight key regulators of the gene expression changes, and many of these predictions can now be experimentally validated using global chromatin-immunoprecipitation analysis.

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“…While B cells and BCR signaling have been demonstrated to be integral to the pathogenesis in some forms of autoimmunity, such as systemic sclerosis, Bregs and efficient BCR signaling have also been shown to be protective. 11,12 In the EAE model, CD19-deficient mice develop a severe, nonremitting form of autoimmunity, suggesting that fully functional BCR signaling is required for adequate B cellmediated control of autoimmunity. 13,14 Furthermore, CD22 −/− mice lack the CD22-mediated counter-regulation of the BCR, and these animals show an increased number of immature B cells, which may have regulatory functions.…”

Section: Role Of Antigen-specificity and Bcr Signaling In Breg Funcmentioning

confidence: 99%

Regulatory B cells require antigen recognition for effective allograft tolerance induction

Kimura

Rickert

Kojima

et al. 2020

American Journal of Transplantation

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Through multiple mechanisms, regulatory B cells (Breg) have been shown to play an important role in the development of allograft tolerance. However, a careful understanding of the role of antigen‐specificity in Breg‐mediated allograft tolerance has remained elusive. In experimental models of islet and cardiac transplantation, it has been established that Bregs can be induced in vivo by anti‐CD45RB ± anti‐TIM1antibody treatment, resulting in prolonged, Breg‐dependent allograft tolerance. The importance of Breg antigen recognition has been suggested but not confirmed through adoptive transfer experiments, using tolerant WT C57BL/6 animals challenged with either BALB/c or C3H grafts. However, the importance of receptor‐specificity has not been formally tested. Here, we utilize the novel ovalbumin‐specific B cell receptor transnuclear (OBI) mice in multiple primary tolerance and adoptive transfer experiments to establish that Breg‐dependent allograft tolerance relies on antigen recognition by B cells. Additionally, we identify that this Breg‐dependent tolerance relies on the function of transforming growth factor‐β. Together, these experiments mark important progress toward understanding how best to improve Breg‐mediated allograft tolerance.

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

Cited by 66 publications

References 32 publications

Association of CD22 gene polymorphism with susceptibility to limited cutaneous systemic sclerosis

Association of CD22 gene polymorphism with susceptibility to limited cutaneous systemic sclerosis

Learning More from Microarrays: Insights from Modules and Networks

Regulatory B cells require antigen recognition for effective allograft tolerance induction

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