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1.
Cell ; 186(23): 5114-5134.e27, 2023 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-37875108

RESUMO

Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ.


Assuntos
Interferon gama , Janus Quinase 2 , Infecções por Mycobacterium , Humanos , Masculino , Proteínas de Ciclo Celular/metabolismo , Interferon gama/imunologia , Interleucina-12 , Interleucina-23 , Janus Quinase 2/metabolismo , Mycobacterium/fisiologia , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/metabolismo , Proteínas Oncogênicas/metabolismo
2.
Sci Immunol ; 8(80): eabq5204, 2023 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-36763636

RESUMO

Patients with autosomal recessive (AR) IL-12p40 or IL-12Rß1 deficiency display Mendelian susceptibility to mycobacterial disease (MSMD) due to impaired IFN-γ production and, less commonly, chronic mucocutaneous candidiasis (CMC) due to impaired IL-17A/F production. We report six patients from four kindreds with AR IL-23R deficiency. These patients are homozygous for one of four different loss-of-function IL23R variants. All six patients have a history of MSMD, but only two suffered from CMC. We show that IL-23 induces IL-17A only in MAIT cells, possibly contributing to the incomplete penetrance of CMC in patients unresponsive to IL-23. By contrast, IL-23 is required for both baseline and Mycobacterium-inducible IFN-γ immunity in both Vδ2+ γδ T and MAIT cells, probably contributing to the higher penetrance of MSMD in these patients. Human IL-23 appears to contribute to IL-17A/F-dependent immunity to Candida in a single lymphocyte subset but is required for IFN-γ-dependent immunity to Mycobacterium in at least two lymphocyte subsets.


Assuntos
Interferon gama , Interleucina-23 , Infecções por Mycobacterium , Mycobacterium , Humanos , Predisposição Genética para Doença , Interleucina-17/genética , Interleucina-23/genética , Infecções por Mycobacterium/imunologia
3.
Science ; 376(6599): eabm6380, 2022 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-35587511

RESUMO

The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor κB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells.


Assuntos
Toxinas Bacterianas , Síndrome de Cri-du-Chat , Endopeptidases , Haploinsuficiência , Proteínas Hemolisinas , Infecções Estafilocócicas , Staphylococcus aureus , Toxinas Bacterianas/imunologia , Síndrome de Cri-du-Chat/genética , Síndrome de Cri-du-Chat/imunologia , Endopeptidases/genética , Haploinsuficiência/genética , Haploinsuficiência/imunologia , Proteínas Hemolisinas/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Celular/genética , Necrose , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/patologia
4.
J Exp Med ; 216(9): 2038-2056, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31217193

RESUMO

Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-ß and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients' iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I and/or III IFN-mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature.


Assuntos
Influenza Humana/genética , Padrões de Herança/genética , Pneumonia/genética , Receptor 3 Toll-Like/deficiência , Alelos , Criança , Pré-Escolar , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Evolução Fatal , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Heterozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Lactente , Recém-Nascido , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/fisiologia , Interferons/metabolismo , Mutação com Perda de Função/genética , Pulmão/patologia , Masculino , Mutação de Sentido Incorreto/genética , Poli I-C/farmacologia , Transporte Proteico
5.
J Med Chem ; 50(23): 5853-7, 2007 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-17956080

RESUMO

Tyrosine kinases often play pivotal roles in the pathogenesis of cancer and are good candidates for therapeutic intervention and targeted molecular imaging. The precursor synthesis, radiosynthesis, and biological characterization of a fluorine-18 analog of dasatinib, a multitargeted kinase inhibitor, are reported. Compound 5 potently inhibits Abl, Src, and Kit kinases and inhibits K562 and M07e/p210bcr-abl human leukemic cell growth. Using positron emission tomography, we visualized K562 tumor xenografts in mice with [18F]-5.


Assuntos
Radioisótopos de Flúor , Pirimidinas/síntese química , Compostos Radiofarmacêuticos/síntese química , Tiazóis/síntese química , Animais , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dasatinibe , Proteínas de Fusão bcr-abl , Humanos , Camundongos , Camundongos Nus , Tomografia por Emissão de Pósitrons , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/farmacologia , Tiazóis/farmacocinética , Tiazóis/farmacologia , Transplante Heterólogo , Quinases da Família src/antagonistas & inibidores
6.
J Clin Invest ; 123(11): 4781-5, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24216514

RESUMO

Approximately 90% of patients with isolated agammaglobulinemia and failure of B cell development have mutations in genes required for signaling through the pre­B cell and B cell receptors. The nature of the gene defect in the majority of remaining patients is unknown. We recently identified 4 patients with agammaglobulinemia and markedly decreased numbers of peripheral B cells. The B cells that could be detected had an unusual phenotype characterized by the increased expression of CD19 but the absence of a B cell receptor. Genetic studies demonstrated that all 4 patients had the exact same de novo mutation in the broadly expressed transcription factor E47. The mutant protein (E555K) was stable in patient-derived EBV-transformed cell lines and cell lines transfected with expression vectors. E555K in the transfected cells localized normally to the nucleus and resulted in a dominant negative effect when bound to DNA as a homodimer with wild-type E47. Mutant E47 did permit DNA binding by a tissue-specific heterodimeric DNA-binding partner, myogenic differentiation 1 (MYOD). These findings document a mutational hot-spot in E47 and represent an autosomal dominant form of agammaglobulinemia. Further, they indicate that E47 plays a critical role in enforcing the block in development of B cell precursors that lack functional antigen receptors.


Assuntos
Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Linfócitos B/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Mutação de Sentido Incorreto , Receptores de Antígenos de Linfócitos B/deficiência , Agamaglobulinemia/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos , Linfócitos B/metabolismo , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular Transformada , DNA/genética , DNA/metabolismo , Feminino , Genes Dominantes , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Estabilidade Proteica , Homologia de Sequência de Aminoácidos
7.
Clin Cancer Res ; 17(10): 3282-92, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21385926

RESUMO

UNLABELLED: PURPOSE/EXPERIMENTAL DESIGN: Treatment of cerebral tumors and peritumoral brain edema remains a clinical challenge and is associated with high morbidity and mortality. Dexamethasone is an effective drug for treating brain edema, but it is associated with well-documented side effects. Corticorelin acetate (Xerecept) or human corticotrophin-releasing factor (hCRF) is a comparatively new drug and has been evaluated in two orthotopic glioma models (U87 and C6), by a direct comparison with dexamethasone and temozolomide. RESULTS: In vitro combination therapy and monotherapy showed a variable response in 6 different glioma cell lines. In vivo studies showed a dose-dependent effect of hCRF (0.03 and 0.1 mg/kg q12h) on survival of U87 intracranial xenograft-bearing animals [median survival: control--41 days (95% CI 25-61); "low-hCRF" 74.5 days (95% CI 41-88); "high-hCRF" >130 days (95% CI not reached)]. Dexamethasone treatment had no effect on survival, but significant toxicity was observed. A survival benefit was observed with temozolomide and temozolomide + hCRF-treated animals but with significant temozolomide toxicity. C6-bearing animals showed no survival benefit, but there were similar treatment toxicities. The difference in hCRF treatment response between U87 and C6 intracranial gliomas can be explained by a difference in receptor expression. RT-PCR identified CRF2r mRNA in U87 xenografts; no CRF receptors were identified in C6 xenografts. CONCLUSIONS: hCRF was more effective than either dexamethasone or temozolomide in the treatment of U87 xenografts, and results included improved prognosis with long-term survivors and only mild toxicity. The therapeutic efficacy of hCRF seems to be dependent on tumor hCRF receptor (CRFr) expression. These results support further clinical assessment of the therapeutic efficacy of hCRF and levels of CRFr expression in different human gliomas.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Hormônio Liberador da Corticotropina/uso terapêutico , Dacarbazina/análogos & derivados , Dexametasona/uso terapêutico , Glioma/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Dacarbazina/uso terapêutico , Glioma/patologia , Humanos , Masculino , Camundongos , Camundongos Nus , Ratos , Temozolomida , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Clin Cancer Res ; 17(5): 1099-110, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21245090

RESUMO

PURPOSE: To determine whether treatment response to the Aurora B kinase inhibitor, AZD1152, could be monitored early in the course of therapy by noninvasive [(18)F]-labeled fluoro-2-deoxyglucose, [(18)F]FDG, and/or 3'-deoxy-3'-[(18)F]fluorothymidine, [(18)F]FLT, PET imaging. EXPERIMENTAL DESIGN: AZD1152-treated and control HCT116 and SW620 xenograft-bearing animals were monitored for tumor size and by [(18)F]FDG, and [(18)F]FLT PET imaging. Additional studies assessed the endogenous and exogenous contributions of thymidine synthesis in the two cell lines. RESULTS: Both xenografts showed a significant volume-reduction to AZD1152. In contrast, [(18)F]FDG uptake did not demonstrate a treatment response. [(18)F]FLT uptake decreased to less than 20% of control values in AZD1152-treated HCT116 xenografts, whereas [(18)F]FLT uptake was near background levels in both treated and untreated SW620 xenografts. The EC(50) for AZD1152-HQPA was approximately 10 nmol/L in both SW620 and HCT116 cells; in contrast, SW620 cells were much more sensitive to methotrexate (MTX) and 5-Fluorouracil (5FU) than HCT116 cells. Immunoblot analysis demonstrated marginally lower expression of thymidine kinase in SW620 compared with HCT116 cells. The aforementioned results suggest that SW620 xenografts have a higher dependency on the de novo pathway of thymidine utilization than HCT116 xenografts. CONCLUSIONS: AZD1152 treatment showed antitumor efficacy in both colon cancer xenografts. Although [(18)F]FDG PET was inadequate in monitoring treatment response, [(18)F]FLT PET was very effective in monitoring response in HCT116 xenografts, but not in SW620 xenografts. These observations suggest that de novo thymidine synthesis could be a limitation and confounding factor for [(18)F]FLT PET imaging and quantification of tumor proliferation, and this may apply to some clinical studies as well.


Assuntos
Neoplasias do Colo/diagnóstico por imagem , Didesoxinucleosídeos , Fluordesoxiglucose F18 , Organofosfatos/uso terapêutico , Tomografia por Emissão de Pósitrons/métodos , Quinazolinas/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Radioisótopos de Flúor , Fluoruracila/uso terapêutico , Células HCT116 , Humanos , Immunoblotting , Antígeno Ki-67/análise , Metotrexato/uso terapêutico , Camundongos , Camundongos Nus , Compostos Radiofarmacêuticos , Timidina/biossíntese , Timidina Quinase/genética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Exp Med ; 208(8): 1635-48, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21727188

RESUMO

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/ß, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/ß, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.


Assuntos
Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Interleucina-17/imunologia , Modelos Moleculares , Fator de Transcrição STAT1/genética , Linfócitos T/imunologia , Sequência de Bases , Ensaio de Desvio de Mobilidade Eletroforética , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunofluorescência , Mutação em Linhagem Germinativa/genética , Humanos , Immunoblotting , Interferon gama/sangue , Interferon gama/metabolismo , Interferons , Interleucinas/metabolismo , Masculino , Dados de Sequência Molecular , Linhagem , Fosforilação , Receptor de Interferon alfa e beta/imunologia , Fator de Transcrição STAT1/química , Fator de Transcrição STAT1/metabolismo , Alinhamento de Sequência , Análise de Sequência de DNA
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