Janus kinase 1/2 inhibition for the treatment of autoinflammation associated with heterozygous TNFAIP3 mutation

HA20 commonly manifests as severe orogenital ulceration and uveitis.1 Central nervous system (CNS) inflammation is rare but is reported in patients with HA20, and animal studies have shown that mice with mutant TNFAIP3 are prone to severe neuroinflammation.2,3 Loss of A20 function causes spontaneous...

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Vydáno v:	Journal of allergy and clinical immunology Ročník 144; číslo 3; s. 863 - 866.e5
Hlavní autoři:	Mulhern, Ciara M., Hong, Ying, Omoyinmi, Ebun, Jacques, Thomas S., D'Arco, Felice, Hemingway, Cheryl, Brogan, Paul A., Eleftheriou, Despina
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Elsevier Inc 01.09.2019 Elsevier Limited Mosby
Témata:	A20 protein Age Autoantibodies Biotechnology Calcification Carbon dioxide Central nervous system Cerebrospinal fluid Complement component C3 Complement component C4 Cytokines Fibroblasts Gliosis Hemoglobin Heterozygotes Immunoglobulin A Immunoglobulin D Immunoglobulin G Immunoglobulin M Inflammation Interleukin 6 Kinases Laboratories Monocyte chemoattractant protein 1 Nitroblue tetrazolium test Patients Penicillin Phenotypes Proteins siRNA Skin Software Species Transcription factors Tuberculosis Ulcers
ISSN:	0091-6749, 1097-6825, 1097-6825
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Abstract	HA20 commonly manifests as severe orogenital ulceration and uveitis.1 Central nervous system (CNS) inflammation is rare but is reported in patients with HA20, and animal studies have shown that mice with mutant TNFAIP3 are prone to severe neuroinflammation.2,3 Loss of A20 function causes spontaneous cerebral inflammation, as demonstrated by robust microglial activation, reactive astrogliosis, endothelial activation, increased oxidative/nitrosative stress, and expression of nuclear factor κ (NF-κB)–regulated proinflammatory soluble mediators, such as IL-1β, TNF, IL-6, and monocyte chemoattractant protein 1 (MCP-1) in the brain.3 CNS involvement as the sole clinical manifestation of heterozygous TNFAIP3 variants in human subjects has never been described. Of note, immune cells from subjects II.2 and III.2, as well as heterozygotes for the p.T647P TNFAIP3 variant, exhibited enhanced NF-κB activity and IRF3 activation, but these subjects currently have a much milder phenotype, further emphasizing the previously described clinical heterogeneity of HA20, even within the same kindred.1,2 Additional modifying alleles and genetic and/or environmental risk factors (eg, intercurrent infection or other triggers) might play a role in modifying the phenotype and influence susceptibility to or disease severity of patients with HA20.Methods Patients This study was approved by the Bloomsbury ethics committee (ethics no. 08H071382). Results were analyzed with FlowJo software (version 10.4.2, TreeStar, Ashland, Ore).Dermal fibroblasts and siRNA silencing of TNFAIP3 experiments Dermal fibroblasts were explanted from subject III.1 and from control subjects without any identifiable inflammatory condition and maintained in DMEM/F12 (DMEM/Nutrient Mixture F-12) supplemented with 10% FBS, 100 U/mL penicillin, and 100 μg/mL streptomycin (Life Technologies, Grand Island, NY) at 37°C in 5% CO2 in a humidified incubator. siRNA knockdown was performed in these fibroblasts through transient transfection with 100 nmol/L of siRNA targeting TNFAIP3 (SC-37007; Santa Cruz Biotechnology, Dallas, Tex) or a negative control. siRNAs were transfected through complexation with Lipofectamine RNAiMAX (Thermo Fisher Scientific), according to the manufacturer's instructions. Laboratory investigations Subject III.1 (reference range) Autoantibodies persistent >3 mo Absent∗ Hemoglobin 10 g/L (120-160 g/L) Platelet count 182 × 109/L (150-450 × 109/L) WBC count 6.25 × 109/L (4.0-11 × 109/L) Lymphocyte subsets Normal IgG 19.9 g/L (3.1-13.8 g/L) IgA 1.94 g/L (0.4-0.7 g/L) IgM 2.29 g/L (0.5-2.2 g/L) IgD 7 kU/L (2-100 kU/L) Adenovirus, CMV, EBV, HSV, VZV, parechovirus PCR Negative Toxoplasma species PCR Negative Mycoplasma species antibodies Negative QuantiFERON Negative Nitroblue tetrazolium test Normal Brucella species serology Negative Toxocara species serology Normal 16s PCR and 18s PCR CSF Negative JC and BK virus Negative Complement C3 1.77 g/L (0.75-1.65 g/L) Complement C4 0.24 g/L (0.14-0.54 g/L) Liver enzymes ALT: 15 U/L (10-25 U/L) ALP: 96 U/L (150-380 U/L) CSF white cell count <1 × 106 CSF cytospin Negative CSF oligoclonal bands Negative Table E1 Subject III.1's routine clinical laboratory investigations
AbstractList	HA20 commonly manifests as severe orogenital ulceration and uveitis.1 Central nervous system (CNS) inflammation is rare but is reported in patients with HA20, and animal studies have shown that mice with mutant TNFAIP3 are prone to severe neuroinflammation.2,3 Loss of A20 function causes spontaneous cerebral inflammation, as demonstrated by robust microglial activation, reactive astrogliosis, endothelial activation, increased oxidative/nitrosative stress, and expression of nuclear factor κ (NF-κB)–regulated proinflammatory soluble mediators, such as IL-1β, TNF, IL-6, and monocyte chemoattractant protein 1 (MCP-1) in the brain.3 CNS involvement as the sole clinical manifestation of heterozygous TNFAIP3 variants in human subjects has never been described. Of note, immune cells from subjects II.2 and III.2, as well as heterozygotes for the p.T647P TNFAIP3 variant, exhibited enhanced NF-κB activity and IRF3 activation, but these subjects currently have a much milder phenotype, further emphasizing the previously described clinical heterogeneity of HA20, even within the same kindred.1,2 Additional modifying alleles and genetic and/or environmental risk factors (eg, intercurrent infection or other triggers) might play a role in modifying the phenotype and influence susceptibility to or disease severity of patients with HA20.Methods Patients This study was approved by the Bloomsbury ethics committee (ethics no. 08H071382). Results were analyzed with FlowJo software (version 10.4.2, TreeStar, Ashland, Ore).Dermal fibroblasts and siRNA silencing of TNFAIP3 experiments Dermal fibroblasts were explanted from subject III.1 and from control subjects without any identifiable inflammatory condition and maintained in DMEM/F12 (DMEM/Nutrient Mixture F-12) supplemented with 10% FBS, 100 U/mL penicillin, and 100 μg/mL streptomycin (Life Technologies, Grand Island, NY) at 37°C in 5% CO2 in a humidified incubator. siRNA knockdown was performed in these fibroblasts through transient transfection with 100 nmol/L of siRNA targeting TNFAIP3 (SC-37007; Santa Cruz Biotechnology, Dallas, Tex) or a negative control. siRNAs were transfected through complexation with Lipofectamine RNAiMAX (Thermo Fisher Scientific), according to the manufacturer's instructions. Laboratory investigations Subject III.1 (reference range) Autoantibodies persistent >3 mo Absent∗ Hemoglobin 10 g/L (120-160 g/L) Platelet count 182 × 109/L (150-450 × 109/L) WBC count 6.25 × 109/L (4.0-11 × 109/L) Lymphocyte subsets Normal IgG 19.9 g/L (3.1-13.8 g/L) IgA 1.94 g/L (0.4-0.7 g/L) IgM 2.29 g/L (0.5-2.2 g/L) IgD 7 kU/L (2-100 kU/L) Adenovirus, CMV, EBV, HSV, VZV, parechovirus PCR Negative Toxoplasma species PCR Negative Mycoplasma species antibodies Negative QuantiFERON Negative Nitroblue tetrazolium test Normal Brucella species serology Negative Toxocara species serology Normal 16s PCR and 18s PCR CSF Negative JC and BK virus Negative Complement C3 1.77 g/L (0.75-1.65 g/L) Complement C4 0.24 g/L (0.14-0.54 g/L) Liver enzymes ALT: 15 U/L (10-25 U/L) ALP: 96 U/L (150-380 U/L) CSF white cell count <1 × 106 CSF cytospin Negative CSF oligoclonal bands Negative Table E1 Subject III.1's routine clinical laboratory investigations
Author	Hong, Ying Brogan, Paul A. Jacques, Thomas S. D'Arco, Felice Hemingway, Cheryl Mulhern, Ciara M. Omoyinmi, Ebun Eleftheriou, Despina
AuthorAffiliation	e ARUK Centre for Adolescent Rheumatology, UCL Great Ormond Street Institute of Child Health, London, United Kingdom b Histopathology Department, UCL Great Ormond Street Hospital Institute of Child Health, London, United Kingdom a UCL Great Ormond Street Institute of Child Health, London, United Kingdom c Neuroradiology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom d Paediatric Neurology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
AuthorAffiliation_xml	– name: a UCL Great Ormond Street Institute of Child Health, London, United Kingdom – name: b Histopathology Department, UCL Great Ormond Street Hospital Institute of Child Health, London, United Kingdom – name: c Neuroradiology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom – name: e ARUK Centre for Adolescent Rheumatology, UCL Great Ormond Street Institute of Child Health, London, United Kingdom – name: d Paediatric Neurology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
Author_xml	– sequence: 1 givenname: Ciara M. surname: Mulhern fullname: Mulhern, Ciara M. organization: UCL Great Ormond Street Institute of Child Health, London, United Kingdom – sequence: 2 givenname: Ying surname: Hong fullname: Hong, Ying organization: UCL Great Ormond Street Institute of Child Health, London, United Kingdom – sequence: 3 givenname: Ebun surname: Omoyinmi fullname: Omoyinmi, Ebun organization: UCL Great Ormond Street Institute of Child Health, London, United Kingdom – sequence: 4 givenname: Thomas S. surname: Jacques fullname: Jacques, Thomas S. organization: Histopathology Department, UCL Great Ormond Street Hospital Institute of Child Health, London, United Kingdom – sequence: 5 givenname: Felice surname: D'Arco fullname: D'Arco, Felice organization: Neuroradiology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom – sequence: 6 givenname: Cheryl surname: Hemingway fullname: Hemingway, Cheryl organization: Paediatric Neurology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom – sequence: 7 givenname: Paul A. surname: Brogan fullname: Brogan, Paul A. organization: UCL Great Ormond Street Institute of Child Health, London, United Kingdom – sequence: 8 givenname: Despina surname: Eleftheriou fullname: Eleftheriou, Despina email: d.eleftheriou@ucl.ac.uk organization: UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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Cites_doi	10.1038/ng.3459 10.1371/journal.pone.0181874 10.4049/jimmunol.174.3.1507 10.1136/annrheumdis-2017-212403 10.1186/1742-2094-11-122 10.1074/jbc.M111.283762
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Snippet	HA20 commonly manifests as severe orogenital ulceration and uveitis.1 Central nervous system (CNS) inflammation is rare but is reported in patients with HA20,...
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SubjectTerms	A20 protein Age Autoantibodies Biotechnology Calcification Carbon dioxide Central nervous system Cerebrospinal fluid Complement component C3 Complement component C4 Cytokines Fibroblasts Gliosis Hemoglobin Heterozygotes Immunoglobulin A Immunoglobulin D Immunoglobulin G Immunoglobulin M Inflammation Interleukin 6 Kinases Laboratories Monocyte chemoattractant protein 1 Nitroblue tetrazolium test Patients Penicillin Phenotypes Proteins siRNA Skin Software Species Transcription factors Tuberculosis Ulcers
Title	Janus kinase 1/2 inhibition for the treatment of autoinflammation associated with heterozygous TNFAIP3 mutation
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