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1.
Nature ; 577(7788): 103-108, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31827281

RESUMO

RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1-7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1-/- mice died postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.


Assuntos
Caspase 8/metabolismo , Doenças Hereditárias Autoinflamatórias/metabolismo , Mutação , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Caspase 3/metabolismo , Feminino , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/patologia , Humanos , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linhagem , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/genética
2.
Proc Natl Acad Sci U S A ; 113(36): 10127-32, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27559085

RESUMO

Systemic autoinflammatory diseases are caused by mutations in genes that function in innate immunity. Here, we report an autoinflammatory disease caused by loss-of-function mutations in OTULIN (FAM105B), encoding a deubiquitinase with linear linkage specificity. We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency. HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with WT OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients' fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. This discovery adds to the emerging spectrum of human diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies.


Assuntos
Alelos , Endopeptidases/genética , Fibroblastos/patologia , Doenças Hereditárias Autoinflamatórias/genética , Leucócitos Mononucleares/patologia , Mutação , Idade de Início , Criança , Pré-Escolar , Consanguinidade , Citocinas/genética , Citocinas/imunologia , Dermatite/fisiopatologia , Endopeptidases/deficiência , Endopeptidases/imunologia , Insuficiência de Crescimento/fisiopatologia , Feminino , Febre/fisiopatologia , Fibroblastos/enzimologia , Fibroblastos/imunologia , Regulação da Expressão Gênica , Células HEK293 , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/enzimologia , Doenças Hereditárias Autoinflamatórias/patologia , Humanos , Leucócitos Mononucleares/enzimologia , Leucócitos Mononucleares/imunologia , Masculino , NF-kappa B/genética , NF-kappa B/imunologia , Paniculite/fisiopatologia , Linhagem , Transdução de Sinais , Ubiquitina/genética , Ubiquitina/imunologia
3.
Can Vet J ; 57(2): 176-82, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26834270

RESUMO

Clinically significant hypersensitivity reactions (HSRs) to the chemotherapy drug L-asparaginase are reported in humans and dogs, but frequency in small animals is not well-defined. This study retrospectively evaluated the frequency of HSR to L-asparaginase given by IM injection to dogs and cats with lymphoid malignancies. The medical records of all dogs and cats treated with at least 1 dose of L-asparaginase chemotherapy over a 5-year period were reviewed. A total of 370 doses of L-asparaginase were administered to the dogs, with 88 of 142 dogs receiving multiple doses, and 6 dogs experiencing an HSR. A total of 197 doses were administered to the cats, with 33 of 68 cats receiving multiple doses, and no cats experiencing an HSR. Hypersensitivity reactions were documented in 4.2% of dogs, and in association with 1.6% of L-asparaginase doses administered. These results show that HSRs occur uncommonly among dogs and cats, even with repeated dosing.


Réactions d'hypersensibilité associées à l'administration de L-asparaginase chez 142 chiens et 68 chats atteints de tumeurs malignes lymphoïdes: 2007­2012. Des réactions d'hypersensibilité cliniquement significatives (HCS) au médicament de chimiothérapie L-asparaginase sont signalées chez les humains et les chiens, mais leur fréquence chez les petits animaux n'est pas bien définie. Cette étude a évalué rétrospectivement la fréquence des HCS au médicament L-asparaginase administré par injection IM aux chiens et aux chats atteints de tumeurs malignes lymphoïdes. On a examiné les dossiers médicaux de tous les chiens et chats traités avec au moins une dose de chimiothérapie au médicament L-asparaginase pendant une période de 5 ans. Un total de 370 doses de L-asparaginase a été administré aux chiens, 88 des 142 chiens ont reçu des doses multiples et 6 chiens ont manifesté des HCS. Un total de 197 doses ont été administrées aux chats, 33 des 68 chats ont reçu des doses multiples et aucun chat n'a manifesté des HCS. Les HCS ont été documentées chez 4,2 % des chiens et en association avec 1,6 % des doses de L-asparaginase administrées. Ces résultats indiquent que les HCS se produisent rarement chez les chiens et les chats, même avec des doses répétées.(Traduit par Isabelle Vallières).


Assuntos
Asparaginase/efeitos adversos , Doenças do Gato/induzido quimicamente , Doenças do Cão/induzido quimicamente , Hipersensibilidade a Drogas/veterinária , Linfoma/veterinária , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças do Gato/tratamento farmacológico , Gatos , Ciclofosfamida/uso terapêutico , Doenças do Cão/tratamento farmacológico , Cães , Doxorrubicina/uso terapêutico , Linfoma/tratamento farmacológico , Prednisona/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Vincristina/uso terapêutico
4.
Clin Pharmacol Ther ; 104(2): 364-373, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29134648

RESUMO

Population pharmacokinetic (popPK) modeling was used to characterize the PK profile of the oral Janus kinase (JAK)1/JAK2 inhibitor, baricitinib, in 18 patients with Mendelian interferonopathies who are enrolled in a compassionate use program. Patients received doses between 0.1 to 17 mg per day. Covariates of weight and renal function significantly influenced volume-of-distribution and clearance, respectively. The half-life of baricitinib in patients less than 40 kg was substantially shorter than in adult populations, requiring the need for dosing up to 4 times daily. On therapeutic doses, the mean area-under-the-concentration-vs.-time curve was 2,388 nM*hr, which is 1.83-fold higher than mean baricitinib exposures in adult patients with rheumatoid arthritis receiving doses of 4 mg once-daily. Dose-dependent decreases in interferon (IFN) biomarkers confirmed an in vivo effect of baricitinib on type-1 IFN signaling. PopPK and pharmacodynamic data support a proposal for a weight- and estimated glomerular filtration rate-based dosing regimen in guiding baricitinib dosing in patients with rare interferonopathies.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Azetidinas/administração & dosagem , Azetidinas/farmacocinética , Cálculos da Dosagem de Medicamento , Inflamação/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/farmacocinética , Modelos Biológicos , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Administração Oral , Adolescente , Fatores Etários , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/enzimologia , Doenças Autoimunes/genética , Azetidinas/efeitos adversos , Peso Corporal , Criança , Pré-Escolar , Ensaios de Uso Compassivo , Feminino , Predisposição Genética para Doença , Taxa de Filtração Glomerular , Humanos , Lactente , Inflamação/diagnóstico , Inflamação/enzimologia , Inflamação/genética , Janus Quinase 1/metabolismo , Janus Quinase 2/metabolismo , Inibidores de Janus Quinases/efeitos adversos , Masculino , Purinas , Pirazóis , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Adulto Jovem
5.
Nat Genet ; 49(3): 438-443, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28166214

RESUMO

We analyzed 1,900 Turkish Behçet's disease cases and 1,779 controls genotyped with the Immunochip. The most significantly associated SNP was rs1050502, a tag SNP for HLA-B*51. In the Turkish discovery set, we identified three new risk loci, IL1A-IL1B, IRF8, and CEBPB-PTPN1, with genome-wide significance (P < 5 × 10-8) by direct genotyping and ADO-EGR2 by imputation. We replicated the ADO-EGR2, IRF8, and CEBPB-PTPN1 loci by genotyping 969 Iranian cases and 826 controls. Imputed data in 608 Japanese cases and 737 controls further replicated ADO-EGR2 and IRF8, and meta-analysis additionally identified RIPK2 and LACC1. The disease-associated allele of rs4402765, the lead marker at IL1A-IL1B, was associated with both decreased IL-1α and increased IL-1ß production. ABO non-secretor genotypes for two ancestry-specific FUT2 SNPs showed strong disease association (P = 5.89 × 10-15). Our findings extend the list of susceptibility genes shared with Crohn's disease and leprosy and implicate mucosal factors and the innate immune response to microbial exposure in Behçet's disease susceptibility.


Assuntos
Síndrome de Behçet/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Irã (Geográfico) , Masculino , Turquia
6.
mBio ; 7(5)2016 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-27677792

RESUMO

The chlamydial protease-like activity factor (CPAF) is hypothesized to be an important secreted virulence factor; however, challenges in denaturing its proteolytic activity have hampered attempts to identify its legitimate targets. Here, we use a genetic and proteomic approach to identify authentic CPAF targets. Human epithelial cells infected with CPAF-sufficient and CPAF-deficient chlamydiae were lysed using known CPAF-denaturing conditions. Their protein profiles were analyzed using isobaric mass tags and liquid chromatography-tandem mass spectrometry. Comparative analysis of CPAF-sufficient and CPAF-deficient infections identified a limited number of CPAF host and chlamydial protein targets. Host targets were primarily interferon-stimulated gene products, whereas chlamydial targets were type III secreted proteins. We provide evidence supporting a cooperative role for CPAF and type III secreted effectors in blocking NF-κB p65 nuclear translocation, resulting in decreased beta interferon and proinflammatory cytokine synthesis. Genetic complementation of null organisms with CPAF restored p65 nuclear translocation inhibition and proteolysis of chlamydial type III secreted effector proteins (T3SEs). We propose that CPAF and T3SEs cooperate in the inhibition of host innate immunity. IMPORTANCE: Chlamydia trachomatis is an important human pathogen responsible for over 100 million infections each year worldwide. Its success as an intracellular pathogen revolves around its ability to evade host immunity. The chlamydial protease-like activity factor (CPAF) is a conserved serine protease secreted into the host cytosol of infected cells that is thought to play an important role in immune evasion. Currently, CPAF's authentic in situ target(s) and mechanism of action in immune evasion are poorly characterized. Using a CPAF-deficient strain and high-throughput proteomics, we report novel CPAF host and chlamydial targets. Host targets were primarily interferon-stimulated genes, whereas chlamydial targets were exclusively type III secreted proteins. We propose a novel mechanism for CPAF and type III secreted proteins in the evasion of host innate immune responses. These findings provide new insights into CPAF's function as a virulence factor and a better understanding of how chlamydiae evade host immunity.

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