The Experts below are selected from a list of 13581 Experts worldwide ranked by ideXlab platform
Shinichi Sato - One of the best experts on this subject based on the ideXlab platform.
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b Lymphocyte Signaling established by the cd19 cd22 loop regulates autoimmunity in the tight skin mouse
American Journal of Pathology, 2004Co-Authors: Noriko Asano, Thomas F. Tedder, Manabu Fujimoto, Minoru Hasegawa, Norihito Yazawa, Senji Shirasawa, Hitoshi Okochi, Kunihiko Tamaki, Shinichi SatoAbstract:Systemic sclerosis (SSc) is characterized by fibrosis and autoimmmunity. Peripheral blood B cells from SSc patients specifically overexpress CD19, a critical cell-surface signal transduction molecule in B cells. CD19 deficiency in B cells also attenuates skin fibrosis in the tight-skin (TSK/+) mouse, a genetic model for SSc. Herein we analyzed two transgenic mouse lines that overexpress CD19. Remarkably, 20% increase of CD19 expression in mice spontaneously induced SSc-specific anti-DNA topoisomerase I (topo I) antibody (Ab) production, which was further augmented by 200% overexpression. In TSK/+ mice overexpressing CD19, skin thickness did not increase, although anti-topo I Ab levels were significantly augmented, indicating that abnormal CD19 Signaling influences autoimmunity in TSK/+ mice and also that anti-topo I Ab does not have a pathogenic role. The molecular mechanisms for abnormal CD19 Signaling were further assessed. B-cell antigen receptor crosslinking induced exaggerated calcium responses and augmented activation of extracellular signal-regulated kinase in TSK/+ B cells. CD22 function was specifically impaired in TSK/+ B cells. Consistently, CD19, a major target of CD22-negative regulation, was hyperphosphorylated in TSK/+ B cells. These findings indicate that reduced inhibitory signal provided by CD22 results in abnormal activation of Signaling pathways including CD19 in TSK/+ mice and also suggest that this disrupted B cell Signaling contribute to specific autoantibody production.
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B Lymphocyte Signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse.
The American journal of pathology, 2004Co-Authors: Noriko Asano, Thomas F. Tedder, Manabu Fujimoto, Minoru Hasegawa, Norihito Yazawa, Senji Shirasawa, Hitoshi Okochi, Kunihiko Tamaki, Shinichi SatoAbstract:Systemic sclerosis (SSc) is characterized by fibrosis and autoimmmunity. Peripheral blood B cells from SSc patients specifically overexpress CD19, a critical cell-surface signal transduction molecule in B cells. CD19 deficiency in B cells also attenuates skin fibrosis in the tight-skin (TSK/+) mouse, a genetic model for SSc. Herein we analyzed two transgenic mouse lines that overexpress CD19. Remarkably, 20% increase of CD19 expression in mice spontaneously induced SSc-specific anti-DNA topoisomerase I (topo I) antibody (Ab) production, which was further augmented by 200% overexpression. In TSK/+ mice overexpressing CD19, skin thickness did not increase, although anti-topo I Ab levels were significantly augmented, indicating that abnormal CD19 Signaling influences autoimmunity in TSK/+ mice and also that anti-topo I Ab does not have a pathogenic role. The molecular mechanisms for abnormal CD19 Signaling were further assessed. B-cell antigen receptor crosslinking induced exaggerated calcium responses and augmented activation of extracellular signal-regulated kinase in TSK/+ B cells. CD22 function was specifically impaired in TSK/+ B cells. Consistently, CD19, a major target of CD22-negative regulation, was hyperphosphorylated in TSK/+ B cells. These findings indicate that reduced inhibitory signal provided by CD22 results in abnormal activation of Signaling pathways including CD19 in TSK/+ mice and also suggest that this disrupted B cell Signaling contribute to specific autoantibody production.
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CD19-dependent B Lymphocyte Signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse.
The Journal of clinical investigation, 2002Co-Authors: Eriko Saito, Thomas F. Tedder, Manabu Fujimoto, Minoru Hasegawa, Kazuhiro Komura, Yasuhito Hamaguchi, Yuko Kaburagi, Tetsuya Nagaoka, Kazuhiko Takehara, Shinichi SatoAbstract: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.
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CD19 and CD22 regulate a B Lymphocyte signal transduction pathway that contributes to autoimmunity.
The Keio journal of medicine, 2000Co-Authors: Thomas F. Tedder, Shinichi Sato, Jonathan C. Poe, Manabu FujimotoAbstract:The fate of B Lymphocytes is dependent on intrinsic and B cell antigen receptor (BCR)-induced signals. These signals are modified and interpreted by other cell-surface molecules such as CD19 and CD22 that govern mature B cell activation. This review assesses our current understanding of how CD19 and CD22 regulate B Lymphocyte Signaling and how alterations in these response-regulators contribute to autoimmunity in mice and humans. We propose that CD19 functions as a specialized adapter protein that regulates B Lymphocyte Signaling and autoantibody production. Overexpression of CD19 by B cells in systemic sclerosis patients correlates with autoantibody production and transgenic mice that overexpress CD19 produce similar autoantibodies. CD19 establishes a novel Src-family kinase activation loop that regulates basal signal transduction thresholds in resting B cells and amplifies Src-family kinase activation following BCR ligation. Reciprocally, CD22 is a potent regulator of CD19 function. These observations provide insight into how CD19 and CD22 govern the molecular ordering and intensity of signals transduced in B cells that may contribute to autoimmunity.
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CD19 is a central response regulator of B Lymphocyte Signaling thresholds governing autoimmunity
Journal of dermatological science, 1999Co-Authors: Shinichi SatoAbstract:Abstract The CD19/CD21 complex is categorized among the ‘response regulator’ class of receptors which determine the magnitude and outcomes of B cell receptor signals. Small changes in CD19 expression have dramatic effects on Signaling thresholds within B cells, which in turn has considerable impact on the balance between humoral immune responses and tolerance induction. B cell Signaling thresholds lowered by increased CD19 expression may significantly augment host susceptibility to the development of autoimmunity. Signals generated by C3d-antigen complex binding to CD21 may also be involved in the development of autoimmunity by regulating CD19 function. Since CD19 serves as a central regulator of Signaling thresholds in B cells, the CD19/CD21 complex may be an appropriate target for suppressing the development of autoimmunity.
Thomas F. Tedder - One of the best experts on this subject based on the ideXlab platform.
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b Lymphocyte Signaling established by the cd19 cd22 loop regulates autoimmunity in the tight skin mouse
American Journal of Pathology, 2004Co-Authors: Noriko Asano, Thomas F. Tedder, Manabu Fujimoto, Minoru Hasegawa, Norihito Yazawa, Senji Shirasawa, Hitoshi Okochi, Kunihiko Tamaki, Shinichi SatoAbstract:Systemic sclerosis (SSc) is characterized by fibrosis and autoimmmunity. Peripheral blood B cells from SSc patients specifically overexpress CD19, a critical cell-surface signal transduction molecule in B cells. CD19 deficiency in B cells also attenuates skin fibrosis in the tight-skin (TSK/+) mouse, a genetic model for SSc. Herein we analyzed two transgenic mouse lines that overexpress CD19. Remarkably, 20% increase of CD19 expression in mice spontaneously induced SSc-specific anti-DNA topoisomerase I (topo I) antibody (Ab) production, which was further augmented by 200% overexpression. In TSK/+ mice overexpressing CD19, skin thickness did not increase, although anti-topo I Ab levels were significantly augmented, indicating that abnormal CD19 Signaling influences autoimmunity in TSK/+ mice and also that anti-topo I Ab does not have a pathogenic role. The molecular mechanisms for abnormal CD19 Signaling were further assessed. B-cell antigen receptor crosslinking induced exaggerated calcium responses and augmented activation of extracellular signal-regulated kinase in TSK/+ B cells. CD22 function was specifically impaired in TSK/+ B cells. Consistently, CD19, a major target of CD22-negative regulation, was hyperphosphorylated in TSK/+ B cells. These findings indicate that reduced inhibitory signal provided by CD22 results in abnormal activation of Signaling pathways including CD19 in TSK/+ mice and also suggest that this disrupted B cell Signaling contribute to specific autoantibody production.
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B Lymphocyte Signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse.
The American journal of pathology, 2004Co-Authors: Noriko Asano, Thomas F. Tedder, Manabu Fujimoto, Minoru Hasegawa, Norihito Yazawa, Senji Shirasawa, Hitoshi Okochi, Kunihiko Tamaki, Shinichi SatoAbstract:Systemic sclerosis (SSc) is characterized by fibrosis and autoimmmunity. Peripheral blood B cells from SSc patients specifically overexpress CD19, a critical cell-surface signal transduction molecule in B cells. CD19 deficiency in B cells also attenuates skin fibrosis in the tight-skin (TSK/+) mouse, a genetic model for SSc. Herein we analyzed two transgenic mouse lines that overexpress CD19. Remarkably, 20% increase of CD19 expression in mice spontaneously induced SSc-specific anti-DNA topoisomerase I (topo I) antibody (Ab) production, which was further augmented by 200% overexpression. In TSK/+ mice overexpressing CD19, skin thickness did not increase, although anti-topo I Ab levels were significantly augmented, indicating that abnormal CD19 Signaling influences autoimmunity in TSK/+ mice and also that anti-topo I Ab does not have a pathogenic role. The molecular mechanisms for abnormal CD19 Signaling were further assessed. B-cell antigen receptor crosslinking induced exaggerated calcium responses and augmented activation of extracellular signal-regulated kinase in TSK/+ B cells. CD22 function was specifically impaired in TSK/+ B cells. Consistently, CD19, a major target of CD22-negative regulation, was hyperphosphorylated in TSK/+ B cells. These findings indicate that reduced inhibitory signal provided by CD22 results in abnormal activation of Signaling pathways including CD19 in TSK/+ mice and also suggest that this disrupted B cell Signaling contribute to specific autoantibody production.
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CD19-dependent B Lymphocyte Signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse.
The Journal of clinical investigation, 2002Co-Authors: Eriko Saito, Thomas F. Tedder, Manabu Fujimoto, Minoru Hasegawa, Kazuhiro Komura, Yasuhito Hamaguchi, Yuko Kaburagi, Tetsuya Nagaoka, Kazuhiko Takehara, Shinichi SatoAbstract: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.
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CD19 and CD22 regulate a B Lymphocyte signal transduction pathway that contributes to autoimmunity.
The Keio journal of medicine, 2000Co-Authors: Thomas F. Tedder, Shinichi Sato, Jonathan C. Poe, Manabu FujimotoAbstract:The fate of B Lymphocytes is dependent on intrinsic and B cell antigen receptor (BCR)-induced signals. These signals are modified and interpreted by other cell-surface molecules such as CD19 and CD22 that govern mature B cell activation. This review assesses our current understanding of how CD19 and CD22 regulate B Lymphocyte Signaling and how alterations in these response-regulators contribute to autoimmunity in mice and humans. We propose that CD19 functions as a specialized adapter protein that regulates B Lymphocyte Signaling and autoantibody production. Overexpression of CD19 by B cells in systemic sclerosis patients correlates with autoantibody production and transgenic mice that overexpress CD19 produce similar autoantibodies. CD19 establishes a novel Src-family kinase activation loop that regulates basal signal transduction thresholds in resting B cells and amplifies Src-family kinase activation following BCR ligation. Reciprocally, CD22 is a potent regulator of CD19 function. These observations provide insight into how CD19 and CD22 govern the molecular ordering and intensity of signals transduced in B cells that may contribute to autoimmunity.
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CD19 regulates intrinsic B Lymphocyte signal transduction and activation through a novel mechanism of processive amplification.
Immunologic research, 2000Co-Authors: Manabu Fujimoto, Jonathan C. Poe, M Hasegawa, Thomas F. TedderAbstract:The fate of B Lymphocytes is dependent on intrinsic and B cell antigen receptor (BCR)-induced signals. These signals are interpreted and modified by response regulators such as CD19 that govern mature B cell activation. The current understanding of how CD19 governs B Lymphocyte Signaling is outlined in this review. Primarily, CD19 establishes a novel Src-family kinase amplification loop that regulates basal signal transduction thresholds in resting B cells. Moreover, CD19 amplifies Src-family kinase activation following BCR ligation. CD19 amplification of Lyn activity leads to processive phosphorylation of CD19 and downstream substrates including CD22. Phosphorylated CD19 recruits other effector molecules including Vav, Grb2, phosphoinositide 3-kinase, phospholipase Cgamma2, and c-Abl, which may contribute to CD19 regulation of B cell function. CD19/Lyn complex formation also regulates phosphorylation of CD22 and FcgammaRIIB, which inhibit B cell signal transduction through the recruitment of the SHPI and SHIP phosphatases. These observations provide insight into how CD19 governs the molecular ordering and intensity of signals transduced in B cells, and how perturbations in CD19 expression or Signaling function may contribute to autoimmunity.
Pamela L Schwartzberg - One of the best experts on this subject based on the ideXlab platform.
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t and b cell Signaling in activated pi3k delta syndrome from immunodeficiency to autoimmunity
Immunological Reviews, 2019Co-Authors: Silvia Preite, Jennifer L. Cannons, Julio Gomezrodriguez, Pamela L SchwartzbergAbstract:Phosphatidylinositol 3 kinases (PI3K) are a family of lipid kinases that are activated by a variety of cell-surface receptors, and regulate a wide range of downstream readouts affecting cellular metabolism, growth, survival, differentiation, adhesion, and migration. The importance of these lipid kinases in Lymphocyte Signaling has recently been highlighted by genetic analyses, including the recognition that both activating and inactivating mutations of the catalytic subunit of PI3Kδ, p110δ, lead to human primary immunodeficiencies. In this article, we discuss how studies on the human genetic disorder "Activated PI3K-delta syndrome" and mouse models of this disease (Pik3cdE1020K/+ mice) have provided fundamental insight into pathways regulated by PI3Kδ in T and B cells and their contribution to Lymphocyte function and disease, including responses to commensal bacteria and the development of autoimmunity and tumors. We highlight critical roles of PI3Kδ in T follicular helper cells and the orchestration of the germinal center reaction, as well as in CD8+ T-cell function. We further present data demonstrating the ability of the AKT-resistant FOXO1AAA mutant to rescue IgG1 class switching defects in Pik3cdE1020K/+ B cells, as well as data supporting a role for PI3Kδ in promoting multiple T-helper effector cell lineages.
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Fine-tuning Lymphocyte regulation: what’s new with tyrosine kinases and phosphatases?
Current opinion in immunology, 2004Co-Authors: Jennifer L. Cannons, Pamela L SchwartzbergAbstract:Although the basic mechanisms of Lymphocyte Signaling have been established, recent studies have provided new insights into how fine-tuning the regulation of tyrosine kinases and phosphatases contributes to the delicate balance required for appropriate Lymphocyte activation. Recent studies include new work on the roles of the immune synapse in regulating T-cell receptor Signaling, the discovery of new functions for the Src-family kinase Fyn and the Tec kinase Itk, particularly in regulation of the actin cytoskeleton, and new insights into positive and negative feedback mechanisms in antigen receptor Signaling.
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tec kinases modulators of Lymphocyte Signaling and development
Current Opinion in Immunology, 2001Co-Authors: Carol Lewis, Christine Broussard, Michael J Czar, Pamela L SchwartzbergAbstract:Abstract The Tec kinases are implicated as important components of the antigen receptor Signaling required for proper Lymphocyte activation and development. Recent data suggest that these kinases contribute to multiprotein complexes containing LAT and SLP-76 in T cells, and BLNK/SLP-65 in B cells, which are required for activation of PLC-γ and downstream pathways.
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Tec family kinases in Lymphocyte Signaling and function.
Current opinion in immunology, 2000Co-Authors: Edward M. Schaeffer, Pamela L SchwartzbergAbstract:Abstract The Tec kinases are required for full Ca2+ mobilization in Lymphocytes. Recent data suggest that this process occurs via a multiprotein complex that includes LAT and SLP-76 in T cells and BLNK/SLP-65 in B cells. Mutational analyses have revealed critical roles for Tec kinases in Lymphocyte development and function.
George C. Tsokos - One of the best experts on this subject based on the ideXlab platform.
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Targeting Lymphocyte Signaling pathways as a therapeutic approach to systemic lupus erythematosus.
Current opinion in rheumatology, 2011Co-Authors: Vasileios C. Kyttaris, George C. TsokosAbstract:Purpose of review Over the past year several key pathways in systemic lupus erythematosus (SLE) Lymphocyte Signaling have been identified. Pathways that can be exploited for therapy are discussed in this review.
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T-cell Signaling abnormalities in human systemic lupus erythematosus.
Autoimmunity, 1Co-Authors: Madhusoodana P. Nambiar, Sandeep Krishnan, George C. TsokosAbstract:Abnormal expression of key Signaling molecules and defective functions of T Lymphocytes play a significant role in the pathogenesis of systemic lupus erythematosus (SLE). T-cell receptor (TCR)/CD3-mediated stimulation of SLE T cells shows increased protein tyrosine phosphorylation of cellular proteins, with faster kinetics, heightened calcium response, and decreased interleukin (IL)-2 production. The molecular mechanism of T-cell Signaling abnormalities in SLE T cells is complex and cannot be explained fully by the current theories of T-cell Signaling. Current research on Lymphocyte Signaling abnormalities in SLE has been directed toward investigating various factors that contribute to abnormal tyrosine phosphorylation, intracellular calcium response, and cytokine production. Latest developments suggest multiple components, including altered receptor structure, supramolecular assembly, modulation of membrane clustering, aberrant cellular distribution, and precompartmentalization with lipid rafts invariably contributing to abnormal T-cell Signaling in SLE T cells. The methods and protocols described here pertaining to T-cell Signaling abnormalities in SLE T cells are very much optimized in many ways, and they were derived by the combined tasks and continuous efforts of many researchers in the laboratory over a long period. These simplified protocols can be readily applied to study T-cell Signaling abnormalities in SLE to identify the genetic, molecular, and biochemical factors contributing to aberrant immune cell function and unravel the pathophysiology of SLE.
Manabu Fujimoto - One of the best experts on this subject based on the ideXlab platform.
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b Lymphocyte Signaling established by the cd19 cd22 loop regulates autoimmunity in the tight skin mouse
American Journal of Pathology, 2004Co-Authors: Noriko Asano, Thomas F. Tedder, Manabu Fujimoto, Minoru Hasegawa, Norihito Yazawa, Senji Shirasawa, Hitoshi Okochi, Kunihiko Tamaki, Shinichi SatoAbstract:Systemic sclerosis (SSc) is characterized by fibrosis and autoimmmunity. Peripheral blood B cells from SSc patients specifically overexpress CD19, a critical cell-surface signal transduction molecule in B cells. CD19 deficiency in B cells also attenuates skin fibrosis in the tight-skin (TSK/+) mouse, a genetic model for SSc. Herein we analyzed two transgenic mouse lines that overexpress CD19. Remarkably, 20% increase of CD19 expression in mice spontaneously induced SSc-specific anti-DNA topoisomerase I (topo I) antibody (Ab) production, which was further augmented by 200% overexpression. In TSK/+ mice overexpressing CD19, skin thickness did not increase, although anti-topo I Ab levels were significantly augmented, indicating that abnormal CD19 Signaling influences autoimmunity in TSK/+ mice and also that anti-topo I Ab does not have a pathogenic role. The molecular mechanisms for abnormal CD19 Signaling were further assessed. B-cell antigen receptor crosslinking induced exaggerated calcium responses and augmented activation of extracellular signal-regulated kinase in TSK/+ B cells. CD22 function was specifically impaired in TSK/+ B cells. Consistently, CD19, a major target of CD22-negative regulation, was hyperphosphorylated in TSK/+ B cells. These findings indicate that reduced inhibitory signal provided by CD22 results in abnormal activation of Signaling pathways including CD19 in TSK/+ mice and also suggest that this disrupted B cell Signaling contribute to specific autoantibody production.
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B Lymphocyte Signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse.
The American journal of pathology, 2004Co-Authors: Noriko Asano, Thomas F. Tedder, Manabu Fujimoto, Minoru Hasegawa, Norihito Yazawa, Senji Shirasawa, Hitoshi Okochi, Kunihiko Tamaki, Shinichi SatoAbstract:Systemic sclerosis (SSc) is characterized by fibrosis and autoimmmunity. Peripheral blood B cells from SSc patients specifically overexpress CD19, a critical cell-surface signal transduction molecule in B cells. CD19 deficiency in B cells also attenuates skin fibrosis in the tight-skin (TSK/+) mouse, a genetic model for SSc. Herein we analyzed two transgenic mouse lines that overexpress CD19. Remarkably, 20% increase of CD19 expression in mice spontaneously induced SSc-specific anti-DNA topoisomerase I (topo I) antibody (Ab) production, which was further augmented by 200% overexpression. In TSK/+ mice overexpressing CD19, skin thickness did not increase, although anti-topo I Ab levels were significantly augmented, indicating that abnormal CD19 Signaling influences autoimmunity in TSK/+ mice and also that anti-topo I Ab does not have a pathogenic role. The molecular mechanisms for abnormal CD19 Signaling were further assessed. B-cell antigen receptor crosslinking induced exaggerated calcium responses and augmented activation of extracellular signal-regulated kinase in TSK/+ B cells. CD22 function was specifically impaired in TSK/+ B cells. Consistently, CD19, a major target of CD22-negative regulation, was hyperphosphorylated in TSK/+ B cells. These findings indicate that reduced inhibitory signal provided by CD22 results in abnormal activation of Signaling pathways including CD19 in TSK/+ mice and also suggest that this disrupted B cell Signaling contribute to specific autoantibody production.
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CD19-dependent B Lymphocyte Signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse.
The Journal of clinical investigation, 2002Co-Authors: Eriko Saito, Thomas F. Tedder, Manabu Fujimoto, Minoru Hasegawa, Kazuhiro Komura, Yasuhito Hamaguchi, Yuko Kaburagi, Tetsuya Nagaoka, Kazuhiko Takehara, Shinichi SatoAbstract: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.
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CD19 and CD22 regulate a B Lymphocyte signal transduction pathway that contributes to autoimmunity.
The Keio journal of medicine, 2000Co-Authors: Thomas F. Tedder, Shinichi Sato, Jonathan C. Poe, Manabu FujimotoAbstract:The fate of B Lymphocytes is dependent on intrinsic and B cell antigen receptor (BCR)-induced signals. These signals are modified and interpreted by other cell-surface molecules such as CD19 and CD22 that govern mature B cell activation. This review assesses our current understanding of how CD19 and CD22 regulate B Lymphocyte Signaling and how alterations in these response-regulators contribute to autoimmunity in mice and humans. We propose that CD19 functions as a specialized adapter protein that regulates B Lymphocyte Signaling and autoantibody production. Overexpression of CD19 by B cells in systemic sclerosis patients correlates with autoantibody production and transgenic mice that overexpress CD19 produce similar autoantibodies. CD19 establishes a novel Src-family kinase activation loop that regulates basal signal transduction thresholds in resting B cells and amplifies Src-family kinase activation following BCR ligation. Reciprocally, CD22 is a potent regulator of CD19 function. These observations provide insight into how CD19 and CD22 govern the molecular ordering and intensity of signals transduced in B cells that may contribute to autoimmunity.
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CD19 regulates intrinsic B Lymphocyte signal transduction and activation through a novel mechanism of processive amplification.
Immunologic research, 2000Co-Authors: Manabu Fujimoto, Jonathan C. Poe, M Hasegawa, Thomas F. TedderAbstract:The fate of B Lymphocytes is dependent on intrinsic and B cell antigen receptor (BCR)-induced signals. These signals are interpreted and modified by response regulators such as CD19 that govern mature B cell activation. The current understanding of how CD19 governs B Lymphocyte Signaling is outlined in this review. Primarily, CD19 establishes a novel Src-family kinase amplification loop that regulates basal signal transduction thresholds in resting B cells. Moreover, CD19 amplifies Src-family kinase activation following BCR ligation. CD19 amplification of Lyn activity leads to processive phosphorylation of CD19 and downstream substrates including CD22. Phosphorylated CD19 recruits other effector molecules including Vav, Grb2, phosphoinositide 3-kinase, phospholipase Cgamma2, and c-Abl, which may contribute to CD19 regulation of B cell function. CD19/Lyn complex formation also regulates phosphorylation of CD22 and FcgammaRIIB, which inhibit B cell signal transduction through the recruitment of the SHPI and SHIP phosphatases. These observations provide insight into how CD19 governs the molecular ordering and intensity of signals transduced in B cells, and how perturbations in CD19 expression or Signaling function may contribute to autoimmunity.
