PubMed:28139313 JSONTXT

{"project":"kaiyin_test","denotations":[{"id":"T1","span":{"begin":200,"end":216},"obj":"PosReg"},{"id":"T2","span":{"begin":223,"end":232},"obj":"Var"},{"id":"T3","span":{"begin":240,"end":296},"obj":"Gene"},{"id":"T4","span":{"begin":356,"end":364},"obj":"NegReg"},{"id":"T5","span":{"begin":365,"end":390},"obj":"CPA"},{"id":"T6","span":{"begin":395,"end":406},"obj":"PosReg"},{"id":"T7","span":{"begin":407,"end":450},"obj":"Interaction"},{"id":"T8","span":{"begin":954,"end":983},"obj":"Var"},{"id":"T9","span":{"begin":987,"end":992},"obj":"Gene"},{"id":"T10","span":{"begin":1133,"end":1142},"obj":"PosReg"},{"id":"T11","span":{"begin":1143,"end":1175},"obj":"CPA"},{"id":"T12","span":{"begin":1180,"end":1190},"obj":"NegReg"},{"id":"T13","span":{"begin":1191,"end":1210},"obj":"CPA"},{"id":"T14","span":{"begin":1216,"end":1224},"obj":"Var"},{"id":"T15","span":{"begin":1225,"end":1234},"obj":"PosReg"},{"id":"T16","span":{"begin":1235,"end":1273},"obj":"MPA"},{"id":"T17","span":{"begin":1661,"end":1666},"obj":"Gene"},{"id":"T18","span":{"begin":1667,"end":1670},"obj":"PosReg"},{"id":"T19","span":{"begin":1671,"end":1680},"obj":"Var"},{"id":"T20","span":{"begin":1712,"end":1735},"obj":"CPA"}],"relations":[{"id":"R1","pred":"CauseOf","subj":"T2","obj":"T4"},{"id":"R10","pred":"ThemeOf","subj":"T13","obj":"T12"},{"id":"R11","pred":"CauseOf","subj":"T14","obj":"T15"},{"id":"R12","pred":"ThemeOf","subj":"T16","obj":"T15"},{"id":"R13","pred":"ThemeOf","subj":"T9","obj":"T8"},{"id":"R14","pred":"CauseOf","subj":"T19","obj":"T18"},{"id":"R15","pred":"ThemeOf","subj":"T20","obj":"T18"},{"id":"R16","pred":"ThemeOf","subj":"T17","obj":"T19"},{"id":"R2","pred":"CauseOf","subj":"T2","obj":"T1"},{"id":"R3","pred":"ThemeOf","subj":"T3","obj":"T2"},{"id":"R4","pred":"ThemeOf","subj":"T5","obj":"T4"},{"id":"R5","pred":"CauseOf","subj":"T2","obj":"T6"},{"id":"R6","pred":"ThemeOf","subj":"T7","obj":"T6"},{"id":"R7","pred":"CauseOf","subj":"T8","obj":"T10"},{"id":"R8","pred":"ThemeOf","subj":"T11","obj":"T10"},{"id":"R9","pred":"CauseOf","subj":"T8","obj":"T12"}],"text":"Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation.\nBACKGROUND: Gain-of-function (GOF) mutations in the human signal transducer and activator of transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity with impaired TH17 cell differentiation and exaggerated responsiveness to type I and II interferons. Allogeneic bone marrow transplantation has been attempted in severely affected patients, but outcomes have been poor.\nOBJECTIVE: We sought to define the effect of increased STAT1 activity on T helper cell polarization and to investigate the therapeutic potential of ruxolitinib in treating autoimmunity secondary to STAT1 GOF mutations.\nMETHODS: We used in vitro polarization assays, as well as phenotypic and functional analysis of STAT1-mutated patient cells.\nRESULTS: We report a child with a novel mutation in the linker domain of STAT1 who had life-threatening autoimmune cytopenias and chronic mucocutaneous candidiasis. Naive lymphocytes from the affected patient displayed increased TH1 and follicular T helper cell and suppressed TH17 cell responses. The mutation augmented cytokine-induced STAT1 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reduced hyperresponsiveness to type I and II interferons, normalized TH1 and follicular T helper cell responses, improved TH17 differentiation, cured mucocutaneous candidiasis, and maintained remission of immune-mediated cytopenias.\nCONCLUSIONS: Autoimmunity and infection caused by STAT1 GOF mutations are the result of dysregulated T helper cell responses. Janus kinase inhibitor therapy could represent an effective targeted treatment for long-term disease control in severely affected patients for whom hematopoietic stem cell transplantation is not available."}

{"project":"name_no","denotations":[{"id":"T1","span":{"begin":200,"end":216},"obj":"PosReg"},{"id":"T2","span":{"begin":223,"end":232},"obj":"Var"},{"id":"T3","span":{"begin":240,"end":296},"obj":"Gene"},{"id":"T4","span":{"begin":356,"end":364},"obj":"NegReg"},{"id":"T5","span":{"begin":365,"end":390},"obj":"CPA"},{"id":"T6","span":{"begin":395,"end":406},"obj":"PosReg"},{"id":"T7","span":{"begin":407,"end":450},"obj":"Interaction"},{"id":"T8","span":{"begin":954,"end":983},"obj":"Var"},{"id":"T9","span":{"begin":987,"end":992},"obj":"Gene"},{"id":"T10","span":{"begin":1133,"end":1142},"obj":"PosReg"},{"id":"T11","span":{"begin":1143,"end":1175},"obj":"CPA"},{"id":"T12","span":{"begin":1180,"end":1190},"obj":"NegReg"},{"id":"T13","span":{"begin":1191,"end":1210},"obj":"CPA"},{"id":"T14","span":{"begin":1216,"end":1224},"obj":"Var"},{"id":"T15","span":{"begin":1225,"end":1234},"obj":"PosReg"},{"id":"T16","span":{"begin":1235,"end":1273},"obj":"MPA"},{"id":"T17","span":{"begin":1661,"end":1666},"obj":"Gene"},{"id":"T18","span":{"begin":1667,"end":1670},"obj":"PosReg"},{"id":"T19","span":{"begin":1671,"end":1680},"obj":"Var"},{"id":"T20","span":{"begin":1712,"end":1735},"obj":"CPA"}],"relations":[{"id":"R1","pred":"CauseOf","subj":"T2","obj":"T4"},{"id":"R10","pred":"ThemeOf","subj":"T13","obj":"T12"},{"id":"R11","pred":"CauseOf","subj":"T14","obj":"T15"},{"id":"R12","pred":"ThemeOf","subj":"T16","obj":"T15"},{"id":"R13","pred":"ThemeOf","subj":"T9","obj":"T8"},{"id":"R14","pred":"CauseOf","subj":"T19","obj":"T18"},{"id":"R15","pred":"ThemeOf","subj":"T20","obj":"T18"},{"id":"R16","pred":"ThemeOf","subj":"T17","obj":"T19"},{"id":"R2","pred":"CauseOf","subj":"T2","obj":"T1"},{"id":"R3","pred":"ThemeOf","subj":"T3","obj":"T2"},{"id":"R4","pred":"ThemeOf","subj":"T5","obj":"T4"},{"id":"R5","pred":"CauseOf","subj":"T2","obj":"T6"},{"id":"R6","pred":"ThemeOf","subj":"T7","obj":"T6"},{"id":"R7","pred":"CauseOf","subj":"T8","obj":"T10"},{"id":"R8","pred":"ThemeOf","subj":"T11","obj":"T10"},{"id":"R9","pred":"CauseOf","subj":"T8","obj":"T12"}],"text":"Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation.\nBACKGROUND: Gain-of-function (GOF) mutations in the human signal transducer and activator of transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity with impaired TH17 cell differentiation and exaggerated responsiveness to type I and II interferons. Allogeneic bone marrow transplantation has been attempted in severely affected patients, but outcomes have been poor.\nOBJECTIVE: We sought to define the effect of increased STAT1 activity on T helper cell polarization and to investigate the therapeutic potential of ruxolitinib in treating autoimmunity secondary to STAT1 GOF mutations.\nMETHODS: We used in vitro polarization assays, as well as phenotypic and functional analysis of STAT1-mutated patient cells.\nRESULTS: We report a child with a novel mutation in the linker domain of STAT1 who had life-threatening autoimmune cytopenias and chronic mucocutaneous candidiasis. Naive lymphocytes from the affected patient displayed increased TH1 and follicular T helper cell and suppressed TH17 cell responses. The mutation augmented cytokine-induced STAT1 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reduced hyperresponsiveness to type I and II interferons, normalized TH1 and follicular T helper cell responses, improved TH17 differentiation, cured mucocutaneous candidiasis, and maintained remission of immune-mediated cytopenias.\nCONCLUSIONS: Autoimmunity and infection caused by STAT1 GOF mutations are the result of dysregulated T helper cell responses. Janus kinase inhibitor therapy could represent an effective targeted treatment for long-term disease control in severely affected patients for whom hematopoietic stem cell transplantation is not available."}