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1
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0742287033
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Autoimmunity in scleroderma: the origin, pathogenetic role, and clinical significance of autoantibodies
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Harris M.L., and Rosen A. Autoimmunity in scleroderma: the origin, pathogenetic role, and clinical significance of autoantibodies. Curr Opin Rheumatol 15 (2003) 778-784
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Harris, M.L.1
Rosen, A.2
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2
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0142059804
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Systemic and cell type-specific gene expression patterns in scleroderma skin
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This is the first wide-genome analysis of gene expression in biopsies of scleroderma lesions. More than 12 000 human genes were hybridized to RNAs isolated from skin biopsies of individuals with diffuse scleroderma. It was evident a characteristic B cell signature (CD20+ B cells).
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Whitfield M.L., Finlay D.R., Murray J.I., Troyanskaya O.G., Chi J.T., Pergamenschikov A., McCalmont T.H., Brown P.O., Botstein D., and Connolly M.K. Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci U S A 100 (2003) 12319-12324. This is the first wide-genome analysis of gene expression in biopsies of scleroderma lesions. More than 12 000 human genes were hybridized to RNAs isolated from skin biopsies of individuals with diffuse scleroderma. It was evident a characteristic B cell signature (CD20+ B cells).
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Proc Natl Acad Sci U S A
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Whitfield, M.L.1
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Pergamenschikov, A.6
McCalmont, T.H.7
Brown, P.O.8
Botstein, D.9
Connolly, M.K.10
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3
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0036262665
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CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse
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1453, 1462. The tight-skin (TSK/+) mouse, a genetic model of SSc, develops cutaneous fibrosis and autoantibodies against SSc-specific target autoantigens. SSc patients overexpress CD19, an important regulatory molecule in B lymphocytes. The data presented are consistent with the notion that 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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Saito E., Fujimoto M., Hasegawa M., Komura K., Hamaguchi Y., Kaburagi Y., Nagaoka T., Takehara K., Tedder T.F., and Sato S. CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse. J Clin Invest 109 (2002) 1453, 1462. The tight-skin (TSK/+) mouse, a genetic model of SSc, develops cutaneous fibrosis and autoantibodies against SSc-specific target autoantigens. SSc patients overexpress CD19, an important regulatory molecule in B lymphocytes. The data presented are consistent with the notion that 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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J Clin Invest
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Saito, E.1
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Komura, K.4
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Sato, S.10
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4
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2642511623
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Altered blood B lymphocyte homeostasis in systemic sclerosis. Expanded naive B cells and diminished but activated memory B cells
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SSc patients have distinct abnormalities of blood homeostasis and B cell compartments, characterized by expanded naïve B cells and activated but diminished memory B cells. The results suggest that CD19 overexpression in SSc memory B cells is related to their hyper-reactivity.
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Sato S., Fujimoto M., Hasegawa M., and Takehara K. Altered blood B lymphocyte homeostasis in systemic sclerosis. Expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum 50 (2004) 1918-1927. SSc patients have distinct abnormalities of blood homeostasis and B cell compartments, characterized by expanded naïve B cells and activated but diminished memory B cells. The results suggest that CD19 overexpression in SSc memory B cells is related to their hyper-reactivity.
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Arthritis Rheum
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Sato, S.1
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Sato S., Fujimoto M., Tedder T.K., and Takehara K. Quantitative genetic variation in CD19 expression correlates with autoimmunity. J Immunol 165 (2000) 6635-6643
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6
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Elevated serum BAFF levels in patients with systemic sclerosis. Enhanced BAFF signaling in systemic sclerosis B lymphocytes
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Matsushita T., Hasegowa M., Yanoba K., Kodera M., Takehara K., and Sato S. Elevated serum BAFF levels in patients with systemic sclerosis. Enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum 54 (2006) 192-201
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7
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Serum levels of interleukin 6 (IL-6), oncostatin M, soluble IL-6 receptor, and soluble gp130 in patients with systemic sclerosis
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Hasegawa M., Sato S., Fujimoto M., Ihn H., Kikuchi K., and Takehara K. Serum levels of interleukin 6 (IL-6), oncostatin M, soluble IL-6 receptor, and soluble gp130 in patients with systemic sclerosis. J Rheumatol 25 (1998) 308-313
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9
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Ducan M.R., and Berman B. Stimulation of collagen and glycosaminoglycan production in cultured human adult dermal fibroblasts by recombinant human interleukin 6. J Invest Dermatol 97 (1991) 686-692
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Kodera T., McGaha T.L., Phelps R., Paul W.E., and Bona C.A. Disrupting the IL-4 gene rescues mice homozygous for the tight-skin mutation from embryonic death and diminishes TGF-beta production by fibroblasts. Proc Natl Acad Sci U S A 99 (2002) 3800-3805
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11
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Transforming growth factor-beta 1 is required for secretion of IgG of all subclasses by LPS-activated murine B cells in vitro
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The data indicate that low concentrations of TGF-β are essential for stimulating optimal IgG secretion by LPS-activated B cells, in an Ig isotype-nonspecific manner, and may regulate these responses in an autocrine fashion.
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Snapper C.M., Waegell W., Beernink H., and Dasch J.R. Transforming growth factor-beta 1 is required for secretion of IgG of all subclasses by LPS-activated murine B cells in vitro. J Immunol 151 (1993) 4625-4636. The data indicate that low concentrations of TGF-β are essential for stimulating optimal IgG secretion by LPS-activated B cells, in an Ig isotype-nonspecific manner, and may regulate these responses in an autocrine fashion.
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Salojin K.V., Le Tonqueze M.L., Saraux A., Nassonov E.L., Dueymes M., Piette J.C., and Youinou P.Y. Antiendothelial cell antibodies: a useful markers of systemic sclerosis. Am J Med 102 (1997) 178-185
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Sgonc R., Gruschwitz M.S., Boeck G., Sepp N., Gruber J., and Wick G. Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95. Arthritis Rheum 43 (2000) 2550-2562
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15
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Bordron A., Dueymes M., Levy Y., Jamin C., Leroy J.P., Piette J.C., Shoenfeld Y., and Youinou P.Y. The binding of some human anti-endothelial cell antibodies induces endothelial cell apoptosis. J Clin Invest 101 (1998) 2029-2035
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16
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Worda M., Sgonc R., Dietrich H., Niederegger H., Sundick R.S., Gershwin M.E., and Wick G. In vivo analysis of the apoptosis-inducing effect of anti-endothelial cell antibodies in systemic sclerosis by the chorionallantoic membrane assay. Arthritis Rheum 48 (2003) 2605-2614
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17
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Systemic sclerosis immunoglobulin G autoantibodies bind the human cytomegalovirus late protein UL94 and induce apoptosis
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Lunardi C., Bason C., Navone R., Millo E., Damonte G., Corrocher R., and Puccetti A. Systemic sclerosis immunoglobulin G autoantibodies bind the human cytomegalovirus late protein UL94 and induce apoptosis. Nat Med 10 (2000) 1183-1186
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18
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Lunardi C., Dolcino M., Peterlana D., Bason C., Navone R., Tamassia N., Beri R., Corrocher R., and Puccetti A. Antibodies against human cytomegalovirus in the pathogenesis of systemic sclerosis: a gene array approach. PLoS Med 3 (2006) e2
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19
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Anti-endothelial cell antibodies from patients with limited cutaneous systemic sclerosis bind to centromeric protein B (CENP-B)
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Servettaz A., Tamby M.C., Guilpain P., Reinbolt J., Garcia dela Pena-Lefebvre P., Allanore Y., Kahan A., Meyer O., Guillevin L., and Mouthon L. Anti-endothelial cell antibodies from patients with limited cutaneous systemic sclerosis bind to centromeric protein B (CENP-B). Clin Immunol 120 (2006) 212-219
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Servettaz, A.1
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20
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Novel fibrogenic pathways are activated in response to endothelial apoptosis: implications in the pathophysiology of systemic sclerosis
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The data show that human fibroblasts derived from sclerodermal skin lesions are more sensitive to the antiapoptotic activity of a synthetic peptide containing an EGF motif present on a perlecan fragment compared to fibroblasts derived from normal controls. Hence, the authors propose that an increase in endothelial apoptosis and/or increased sensitivity of fibroblasts to mediators produced by apoptotic EC may explain the fibrotic response of patients' fibroblasts.
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Laplante P., Raymond M.A., Gagnon G., Vigneault N., Sasseville A.M.J., Langelier Y., Bernard M., Raymond Y., and Hebert M.J. Novel fibrogenic pathways are activated in response to endothelial apoptosis: implications in the pathophysiology of systemic sclerosis. J Immunol 174 (2005) 5740-5749. The data show that human fibroblasts derived from sclerodermal skin lesions are more sensitive to the antiapoptotic activity of a synthetic peptide containing an EGF motif present on a perlecan fragment compared to fibroblasts derived from normal controls. Hence, the authors propose that an increase in endothelial apoptosis and/or increased sensitivity of fibroblasts to mediators produced by apoptotic EC may explain the fibrotic response of patients' fibroblasts.
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Laplante, P.1
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21
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Recognition of granzyme B-generated autoantigen fragments in scleroderma patients with ischemic digits loss
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Schachna L., Wigley F.M., Morris S., Gelber A.C., Rosen A., and Casciola-Rosen L. Recognition of granzyme B-generated autoantigen fragments in scleroderma patients with ischemic digits loss. Arthritis Rheum 46 (2002) 1873-1884
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22
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Henault J., Tremblay M., Clement I., Raymond Y., and Senecal J.L. Direct binding of anti-DNA topoisomerase I autoantibodies to the cell surface of fibroblasts in patients with systemic sclerosis. Arthritis Rheum 50 (2004) 3265-3274
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23
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33644915273
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DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti-topoisomerase I autoantibodies from systemis sclerosis patients
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Henault J., Robitaille G., Senecal J.L., and Raymond Y. DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti-topoisomerase I autoantibodies from systemis sclerosis patients. Arthritis Rheum 54 (2006) 963-973
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24
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Hu P.Q., Fertig N., Medsger Jr. T.A., and Wright T.M. Correlation of serum anti-DANN topoisomerase I antibody levels with disease severity and activity in systemic sclerosis. Arthritis Rheum 48 (2003) 1363-1373
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25
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Autoantibodies to fibroblasts induce a proadhesive and proinflammatory fibroblast phenotype in patients with systemic sclerosis
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This study investigated whether IgGs from SSc sera reacting with human fibroblasts modulate fibroblasts' function. Sera from 69 patients with SSc and 41 with diffuse cutaneous SSc (dcSSc), 30 patients with sarcoidosis, and 50 matched healthy controls were examined. The prevalence of binding was significantly higher in dcSSc than in lcSSc (P < 0.05). Only IgGs from SSc sera that were positive for anti-fibroblast antibody (AFA) induced a dose-dependent upregulation of ICAM-1 expression and IL-6 production, enhancement of U937 cell adhesion, and increased levels of IL-1alpha, IL-1beta, and IL-6 mRNA in fibroblasts. These data confirmed the presence of AFA in SSc sera and demonstrated, for the first time, that autoantibodies reacting with fibroblast surface molecules act as an extrinsic stimulus inducing fibroblast activation in vitro.
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Chizzolini C., Raschi E., Rezzonico R., Testoni C., Mallone R., Gabrielli A., Facchini A., Del Papa N., Borghi M.O., Dayer J.M., et al. Autoantibodies to fibroblasts induce a proadhesive and proinflammatory fibroblast phenotype in patients with systemic sclerosis. Arthritis Rheum 46 (2002) 1602-1613. This study investigated whether IgGs from SSc sera reacting with human fibroblasts modulate fibroblasts' function. Sera from 69 patients with SSc and 41 with diffuse cutaneous SSc (dcSSc), 30 patients with sarcoidosis, and 50 matched healthy controls were examined. The prevalence of binding was significantly higher in dcSSc than in lcSSc (P < 0.05). Only IgGs from SSc sera that were positive for anti-fibroblast antibody (AFA) induced a dose-dependent upregulation of ICAM-1 expression and IL-6 production, enhancement of U937 cell adhesion, and increased levels of IL-1alpha, IL-1beta, and IL-6 mRNA in fibroblasts. These data confirmed the presence of AFA in SSc sera and demonstrated, for the first time, that autoantibodies reacting with fibroblast surface molecules act as an extrinsic stimulus inducing fibroblast activation in vitro.
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Chizzolini, C.1
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26
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0036272386
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Antifibroblast antibodies from systemic sclerosis patients are internalized by fibroblasts via a caveolin-linked pathway
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Ronda N., Gatti R., Giacosa R., Raschi E., Testoni C., Meroni P.L., Buzio C., and Orlandini G. Antifibroblast antibodies from systemic sclerosis patients are internalized by fibroblasts via a caveolin-linked pathway. Arthritis Rheum 46 (2002) 1595-1601
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Ronda, N.1
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27
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33845510782
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Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension
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This study investigated the presence of anti-fibroblast antibodies in patients with idiopathic or scleroderma-associated pulmonary arterial hypertension (PAH) and healthy controls. The data show that IgG AFA are present in the serum of patients with PAH. IgGs from patients with idiopathic or scleroderma-associated PAH express distinct reactivity profiles with fibroblasts antigens, suggesting distinct target antigens.
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Tamby M.C., Humbert M., Guilpain P., Servettaz A., Dupin N., Christner J.J., Simonneau G., Fermanian J., Weill B., Guillevin L., et al. Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension. Eur Respir J 28 (2006) 799-880. This study investigated the presence of anti-fibroblast antibodies in patients with idiopathic or scleroderma-associated pulmonary arterial hypertension (PAH) and healthy controls. The data show that IgG AFA are present in the serum of patients with PAH. IgGs from patients with idiopathic or scleroderma-associated PAH express distinct reactivity profiles with fibroblasts antigens, suggesting distinct target antigens.
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Autoantibodies to fibrillin-1 activate normal human fibroblasts in culture through the TGF beta pathway and recapitulate the scleroderma phenotype
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Zhou X., Tan F.K., Wallis D., Milewicz D.M., Guo X., Bona C.A., and Arnett F.C. Autoantibodies to fibrillin-1 activate normal human fibroblasts in culture through the TGF beta pathway and recapitulate the scleroderma phenotype. J Immunol 175 (2005) 4555-4560
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Brinckmann J., Hunzelmann N., El-Hallous E., Krieg T., Sakai L.Y., Krengel S., and Reinhardt D.P. Absence of autoantibodies against correctly folded recombinant fibrillin-1 in systemic sclerosis patients. Arthritis Res Ther 7 (2005) R1221-R1226
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Stimulatory autoantibodies against PDGFR appear to be a specific hallmark of scleroderma. Their biologic activity on fibroblasts strongly suggests that they may have a causal role in the pathogenesis of the disease.
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Baroni S.S., Santillo M., Bevilacqua F., Luchetti M., Spadoni T., Mancini M., Fraticelli P., Sambo P., Funaro A., Kazlauskas A., et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 354 (2006) 2667-2676. Stimulatory autoantibodies against PDGFR appear to be a specific hallmark of scleroderma. Their biologic activity on fibroblasts strongly suggests that they may have a causal role in the pathogenesis of the disease.
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(2006)
N Engl J Med
, vol.354
, pp. 2667-2676
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Baroni, S.S.1
Santillo, M.2
Bevilacqua, F.3
Luchetti, M.4
Spadoni, T.5
Mancini, M.6
Fraticelli, P.7
Sambo, P.8
Funaro, A.9
Kazlauskas, A.10
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PDGF and reactive oxygen species (ROS) regulate Ras protein levels in primary human fibroblasts via ERK1/2. Amplification of ROS-ERK-Ras signalling in systemic sclerosis fibroblasts
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This study highlights the links between Ras protein levels and ROS. In vivo this circuitry is amplified in fibroblasts derived from scleroderma lesions that produce vast excess of ROS and undergo rapid senescence. The authors propose that stabilization of Ras protein by ROS and ERK1/2 amplifies the response of primary fibroblasts to growth factors and represents a crucial factor in the onset and progression of systemic sclerosis.
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Svegliati S., Cancello R., Sambo P., Luchetti M., Paroncini P., Orlandini G., Discepoli G., Paterno R., Santillo M., Cuozzo C., et al. PDGF and reactive oxygen species (ROS) regulate Ras protein levels in primary human fibroblasts via ERK1/2. Amplification of ROS-ERK-Ras signalling in systemic sclerosis fibroblasts. J Biol Chem 280 (2005) 36474-36482. This study highlights the links between Ras protein levels and ROS. In vivo this circuitry is amplified in fibroblasts derived from scleroderma lesions that produce vast excess of ROS and undergo rapid senescence. The authors propose that stabilization of Ras protein by ROS and ERK1/2 amplifies the response of primary fibroblasts to growth factors and represents a crucial factor in the onset and progression of systemic sclerosis.
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(2005)
J Biol Chem
, vol.280
, pp. 36474-36482
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Svegliati, S.1
Cancello, R.2
Sambo, P.3
Luchetti, M.4
Paroncini, P.5
Orlandini, G.6
Discepoli, G.7
Paterno, R.8
Santillo, M.9
Cuozzo, C.10
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