3694 Background: Current treatments for Thrombotic Thrombocytopenic Purpura (TTP) fail to success... more 3694 Background: Current treatments for Thrombotic Thrombocytopenic Purpura (TTP) fail to successfully control this life-threatening syndrome in up to 20% of patients, and of those patients who survive the first episode, a substantial fraction experience at least one relapse. Genetic mutation or autoantibody inhibition of the ultra-large von-Willebrand factor protease, A Disintegrin And Metalloproteinase with a Thrombospondin Type 1 Motif (ADAMTS13), reduces its enzymatic activity and is an important factor that promotes TTP development. Case reports of acute TTP episodes following infections or Type I interferon (IFN) treatment, a phenomenon also observed in systemic lupus erythematosus (SLE), suggest that inflammatory dysregulation could be important in this disease. SLE patients have elevated serum Type I IFN activity and a peripheral blood Type I IFN gene signature, which are associated with the presence of autoantibodies specific for RNA-binding nuclear antigens. Purpose: This ...
Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunct... more Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio...
Approximately 40% of patients who survive acute episodes of thrombotic thrombocytopenic purpura (... more Approximately 40% of patients who survive acute episodes of thrombotic thrombocytopenic purpura (TTP) associated with severe acquired ADAMTS13 deficiency experience one or more relapses. Risk factors for relapse other than severe ADAMTS13 deficiency and ADAMTS13 autoantibodies are unknown. ADAMTS13 autoantibodies, TTP episodes following infection or type I interferon treatment and reported ensuing systemic lupus erythematosus in some patients suggest immune dysregulation. This cross-sectional study asked whether autoantibodies against RNA-binding proteins or peripheral blood gene expression profiles measured during remission are associated with history of prior relapse in acquired ADAMTS13-deficient TTP. Peripheral blood from 38 well-characterized patients with autoimmune ADAMTS13-deficient TTP in remission was examined for autoantibodies and global gene expression. A subset of TTP patients (9 patients, 24%) exhibited a peripheral blood gene signature composed of elevated ribosomal ...
SDF-1alpha (CXCL12) signaling via its receptor, CXCR4, stimulates T cell chemotaxis and gene expr... more SDF-1alpha (CXCL12) signaling via its receptor, CXCR4, stimulates T cell chemotaxis and gene expression. The ZAP-70 tyrosine kinase critically mediates SDF-1alpha-dependent migration and prolonged ERK mitogen-activated protein (MAP) kinase activation in T cells. However, the molecular mechanism by which CXCR4 or other G protein-coupled receptors activate ZAP-70 has not been characterized. Here we show that SDF-1alpha stimulates the physical association of CXCR4 and the T cell receptor (TCR) and utilizes the ZAP-70 binding ITAM domains of the TCR for signal transduction. This pathway is responsible for several of the effects of SDF-1alpha on T cells, including prolonged ERK MAP kinase activity, increased intracellular calcium ion concentrations, robust AP-1 transcriptional activity, and SDF-1alpha costimulation of cytokine secretion. These results suggest new paradigms for understanding the effects of SDF-1alpha and other chemokines on immunity.
Approximately 40% of patients who survive acute episodes of thrombotic thrombocytopenic purpura (... more Approximately 40% of patients who survive acute episodes of thrombotic thrombocytopenic purpura (TTP) associated with severe acquired ADAMTS13 deficiency experience one or more relapses. Risk factors for relapse other than severe ADAMTS13 deficiency and ADAMTS13 autoantibodies are unknown. ADAMTS13 autoantibodies, TTP episodes following infection or type I interferon treatment and reported ensuing systemic lupus erythematosus in some patients suggest immune dysregulation. This cross-sectional study asked whether autoantibodies against RNA-binding proteins or peripheral blood gene expression profiles measured during remission are associated with history of prior relapse in acquired ADAMTS13-deficient TTP. Peripheral blood from 38 well-characterized patients with autoimmune ADAMTS13-deficient TTP in remission was examined for autoantibodies and global gene expression. A subset of TTP patients (9 patients, 24%) exhibited a peripheral blood gene signature composed of elevated ribosomal ...
3694 Background: Current treatments for Thrombotic Thrombocytopenic Purpura (TTP) fail to success... more 3694 Background: Current treatments for Thrombotic Thrombocytopenic Purpura (TTP) fail to successfully control this life-threatening syndrome in up to 20% of patients, and of those patients who survive the first episode, a substantial fraction experience at least one relapse. Genetic mutation or autoantibody inhibition of the ultra-large von-Willebrand factor protease, A Disintegrin And Metalloproteinase with a Thrombospondin Type 1 Motif (ADAMTS13), reduces its enzymatic activity and is an important factor that promotes TTP development. Case reports of acute TTP episodes following infections or Type I interferon (IFN) treatment, a phenomenon also observed in systemic lupus erythematosus (SLE), suggest that inflammatory dysregulation could be important in this disease. SLE patients have elevated serum Type I IFN activity and a peripheral blood Type I IFN gene signature, which are associated with the presence of autoantibodies specific for RNA-binding nuclear antigens. Purpose: This ...
Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunct... more Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio...
Approximately 40% of patients who survive acute episodes of thrombotic thrombocytopenic purpura (... more Approximately 40% of patients who survive acute episodes of thrombotic thrombocytopenic purpura (TTP) associated with severe acquired ADAMTS13 deficiency experience one or more relapses. Risk factors for relapse other than severe ADAMTS13 deficiency and ADAMTS13 autoantibodies are unknown. ADAMTS13 autoantibodies, TTP episodes following infection or type I interferon treatment and reported ensuing systemic lupus erythematosus in some patients suggest immune dysregulation. This cross-sectional study asked whether autoantibodies against RNA-binding proteins or peripheral blood gene expression profiles measured during remission are associated with history of prior relapse in acquired ADAMTS13-deficient TTP. Peripheral blood from 38 well-characterized patients with autoimmune ADAMTS13-deficient TTP in remission was examined for autoantibodies and global gene expression. A subset of TTP patients (9 patients, 24%) exhibited a peripheral blood gene signature composed of elevated ribosomal ...
SDF-1alpha (CXCL12) signaling via its receptor, CXCR4, stimulates T cell chemotaxis and gene expr... more SDF-1alpha (CXCL12) signaling via its receptor, CXCR4, stimulates T cell chemotaxis and gene expression. The ZAP-70 tyrosine kinase critically mediates SDF-1alpha-dependent migration and prolonged ERK mitogen-activated protein (MAP) kinase activation in T cells. However, the molecular mechanism by which CXCR4 or other G protein-coupled receptors activate ZAP-70 has not been characterized. Here we show that SDF-1alpha stimulates the physical association of CXCR4 and the T cell receptor (TCR) and utilizes the ZAP-70 binding ITAM domains of the TCR for signal transduction. This pathway is responsible for several of the effects of SDF-1alpha on T cells, including prolonged ERK MAP kinase activity, increased intracellular calcium ion concentrations, robust AP-1 transcriptional activity, and SDF-1alpha costimulation of cytokine secretion. These results suggest new paradigms for understanding the effects of SDF-1alpha and other chemokines on immunity.
Approximately 40% of patients who survive acute episodes of thrombotic thrombocytopenic purpura (... more Approximately 40% of patients who survive acute episodes of thrombotic thrombocytopenic purpura (TTP) associated with severe acquired ADAMTS13 deficiency experience one or more relapses. Risk factors for relapse other than severe ADAMTS13 deficiency and ADAMTS13 autoantibodies are unknown. ADAMTS13 autoantibodies, TTP episodes following infection or type I interferon treatment and reported ensuing systemic lupus erythematosus in some patients suggest immune dysregulation. This cross-sectional study asked whether autoantibodies against RNA-binding proteins or peripheral blood gene expression profiles measured during remission are associated with history of prior relapse in acquired ADAMTS13-deficient TTP. Peripheral blood from 38 well-characterized patients with autoimmune ADAMTS13-deficient TTP in remission was examined for autoantibodies and global gene expression. A subset of TTP patients (9 patients, 24%) exhibited a peripheral blood gene signature composed of elevated ribosomal ...
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