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1.
Yonsei Med J ; 59(8): 1004-1007, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30187709

RESUMO

Bronchiectasis is a chronic disease characterized by airway infection and inflammation, leading to permanent dilation of the bronchi. Evaluation of underlying etiology is important in managing young bronchiectasis patients with recurrent infections caused by unusual pathogens. The signal transducer and activator of transcription 1 (STAT1) protein plays a key role in STAT signaling and immune system regulation. Heterozygotes for gain-of-function (GOF) alleles of the STAT1 gene usually display autosomal dominant chronic mucocutaneous candidiasis (CMC) and a wide range of clinical features, such as bronchiectasis. Here, we report on a patient with CMC and bronchiectasis with various types of infections who carried a pathogenic variant of the STAT1 gene. The 24-year-old female presented with recurrent respiratory bacterial and nontuberculous mycobacterial infections complicated by severe bronchiectasis and CMC. Whole-exome sequencing revealed a c.800C>T (p.Ala267Val) heterozygous mutation in the STAT1 gene. Further analysis by Sanger sequencing of STAT1 from the patient and her parents revealed the patient had a de novo occurrence of the variant. This is the first report of a Korean patient with a GOF pathogenic variant in STAT1. Physicians should be aware of the existence of this variant as a genetic factor associated with CMC and bronchiectasis complicated by recurrent infection.


Assuntos
Bronquiectasia/complicações , Bronquiectasia/genética , Candidíase Mucocutânea Crônica/genética , Mutação com Ganho de Função , Infecções Respiratórias/microbiologia , Fator de Transcrição STAT1/genética , Sequenciamento Completo do Exoma/métodos , Bronquiectasia/imunologia , Candidíase Mucocutânea Crônica/imunologia , Candidíase Mucocutânea Crônica/microbiologia , Feminino , Humanos , Mutação , Polimorfismo de Nucleotídeo Único , República da Coreia , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Adulto Jovem
2.
Front Immunol ; 9: 3047, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30671054

RESUMO

The induction and action of type I interferon (IFN) is of fundamental importance in human immune defenses toward microbial pathogens, particularly viruses. Basic discoveries within the molecular and cellular signaling pathways regulating type I IFN induction and downstream actions have shown the essential role of the IFN regulatory factor (IRF) and the signal transducer and activator of transcription (STAT) families, respectively. However, the exact biological and immunological functions of these factors have been most clearly revealed through the study of inborn errors of immunity and the resultant infectious phenotypes in humans. The spectrum of human inborn errors of immunity caused by mutations in IRFs and STATs has proven very diverse. These diseases encompass herpes simplex encephalitis (HSE) and severe influenza in IRF3- and IRF7/IRF9 deficiency, respectively. They also include Mendelian susceptibility to mycobacterial infection (MSMD) in STAT1 deficiency, through disseminated measles infection associated with STAT2 deficiency, and finally staphylococcal abscesses and chronic mucocutaneous candidiasis (CMC) classically described with Hyper-IgE syndrome (HIES) in the case of STAT3 deficiency. More recently, increasing focus has been on aspects of autoimmunity and autoinflammation playing an important part in many primary immunodeficiency diseases (PID)s, as exemplified by STAT1 gain-of-function causing CMC and autoimmune thyroiditis, as well as a recently described autoinflammatory syndrome with hypogammaglobulinemia and lymphoproliferation as a result of STAT3 gain-of-function. Here I review the infectious, inflammatory, and autoimmune disorders arising from mutations in IRF and STAT transcription factors in humans, highlightning the underlying molecular mechanisms and immunopathogenesis as well as the clinical/therapeutic perspectives of these new insights.


Assuntos
Candidíase Mucocutânea Crônica/metabolismo , Encefalite por Herpes Simples/metabolismo , Influenza Humana/metabolismo , Fatores Reguladores de Interferon/metabolismo , Síndrome de Job/metabolismo , Infecções por Mycobacterium/metabolismo , Fatores de Transcrição STAT/metabolismo , Autoimunidade , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Encefalite por Herpes Simples/genética , Encefalite por Herpes Simples/imunologia , Humanos , Imunidade Inata , Influenza Humana/genética , Influenza Humana/imunologia , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Janus Quinases/metabolismo , Síndrome de Job/genética , Síndrome de Job/imunologia , Mutação , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/imunologia , Receptor de Interferon alfa e beta/metabolismo , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/imunologia
3.
Front Immunol ; 9: 2956, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30627128

RESUMO

Candida albicans is a commensal fungus that can cause disease ranging in severity from moderate to severe mucosal infections to more serious life-threating disseminated infections in severely immunocompromised hosts. Chronic mucocutaneous candidiasis (CMC) occurs in patients with mutations in genes affecting IL-17-mediated immunity, such as STAT3, AIRE, RORC, CARD9, IL12B, and IL12RB1, or gain of function (GOF) mutations in STAT1. New strategies for the treatment of candidiasis are needed because of the increased burden of infections and the emergence of drug-resistant strains. In this study, we investigated an aspect of the role of antibodies in the control of C. albicans infection. We tested in vitro the effects of C. albicans opsonization with commercial human polyvalent intravenous IgG (IV IgG) on NADPH oxidase activity and killing of the fungi by blood leukocytes from 11 healthy donors and found a significant enhancement in both phenomena that was improved by IV IgG opsonization. Then, we hypothesized that the opsonization of Candida in vivo could help its elimination by mucosal phagocytes in human patients with mucocutaneous candidiasis. We tested a novel adjunctive treatment for oral candidiasis in humans based on topical treatment with IV IgG. For this purpose, we choose two pediatric patients with well-characterized primary immunodeficiencies who are susceptible to CMC. Two 8-year-old female patients with an autosomal recessive mutation in the IL12RB1 gene (P1, with oral candidiasis) and a GOF mutation in STAT1 (P2, with severe CMC persistent since the age of 8 months and resistant to pharmacological treatments) were treated with IV IgG administered daily three times a day as a mouthwash over the course of 2 weeks. The treatment with the IV IgG mouthwash reduced C. albicans mouth infection by 98 and 70% in P1 and P2, respectively, after 13 days, and complete fungal clearance was observed after complementary nystatin and caspofungin treatments, respectively. Therefore, treatment of oral candidiasis with human polyvalent IgG administered as a mouthwash helps eliminate mucosal infection in humans, circumventing drug resistance, and opening its potential use in patients with primary or transient immunodeficiency.


Assuntos
Antifúngicos/administração & dosagem , Candidíase Mucocutânea Crônica/tratamento farmacológico , Candidíase Bucal/tratamento farmacológico , Imunoglobulinas Intravenosas/administração & dosagem , Antissépticos Bucais/administração & dosagem , Administração Oral , Candida albicans/efeitos dos fármacos , Candida albicans/imunologia , Candida albicans/isolamento & purificação , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Candidíase Mucocutânea Crônica/microbiologia , Candidíase Bucal/genética , Candidíase Bucal/imunologia , Candidíase Bucal/microbiologia , Caspofungina/administração & dosagem , Criança , Farmacorresistência Fúngica/efeitos dos fármacos , Farmacorresistência Fúngica/imunologia , Quimioterapia Combinada , Feminino , Humanos , Mutação , Nistatina/administração & dosagem , Fagócitos/efeitos dos fármacos , Fagócitos/imunologia , Resultado do Tratamento
4.
Nihon Rinsho Meneki Gakkai Kaishi ; 40(2): 109-117, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-28603201

RESUMO

Chronic mucocutaneous candidiasis (CMC) is an infectious phenotype which is characterized by recurrent or persistent infections affecting the nails, skin, and oral and genital mucosae caused by Candida species. Th17 cells produce interleukin-17 (IL-17) and play an important role in host mucosal immunity to Candida. Recent studies revealed that an impairment of IL-17 immunity underlies development of CMC. CMC disease (CMCD) is a primary immunodeficiency disease which is defined as CMC in patients in the absence of other prominent clinical signs. However, this definition is not strict. Thus, CMCD is currently used to refer to patients presenting with CMC as the main clinical phenotype. As well as CMCD, CMC is a major infectious phenotype in syndromic CMC. However, patients with syndromic CMC also present other clinical and infectious manifestations in addition to CMC. The genetic defects which affect development and/or proliferation of Th17 cells have been identified in patients with syndromic CMC. In contrast, germline mutations in the genes which directly involved in IL-17 signaling have been identified in patients with CMCD. Here, we review current knowledge of IL-17-signaling defects and the genetic etiologies of CMCD and syndromic CMC.


Assuntos
Candidíase Mucocutânea Crônica/imunologia , Interleucina-17 , Candidíase Mucocutânea Crônica/genética , Humanos , Síndromes de Imunodeficiência/imunologia , Interleucina-17/genética , Transdução de Sinais/genética , Células Th17/imunologia
5.
Acta Microbiol Immunol Hung ; 64(2): 191-201, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28597685

RESUMO

Heterozygous gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) have increasingly been identified as a genetic cause of autosomal-dominant (AD) chronic mucocutaneous candidiasis (CMC). In this article, we describe a 33-year-old man who experienced chronic refractory candidiasis, recurrent otitis media, and pneumonia resulting in bronchiectasis, severe oral and esophageal candidiases with strictures associated with hypothyroidism and immune hemolytic anemia. His son also suffered from persistent candidiasis, chronic diarrhea, poor weight gain, and pneumonia that resulted in his demise because of sepsis. The immunological workup showed that an inverse CD4/CD8 ratio and serum immunoglobulins were all within normal ranges. The laboratory data revealed failure in response to Candida lymphocyte transformation test. In addition, by Sanger sequencing method, we found a heterozygous mutation, Thr385Met (T385M), located in the DNA-binding domain of STAT1, which was previously shown to be GOF. These findings illustrate the broad and variable clinical phenotype of heterozygous STAT1 GOF mutations. However, more clinical information and phenotype-genotype studies are required to define the clinical phenotype caused by AD STAT1 GOF.


Assuntos
Candidíase Mucocutânea Crônica/genética , Mutação Puntual , Fator de Transcrição STAT1/genética , Adulto , Candida/genética , Candida/isolamento & purificação , Candida/fisiologia , Candidíase Mucocutânea Crônica/microbiologia , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Transdução de Sinais
6.
Respir Med ; 126: 39-45, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28427548

RESUMO

BACKGROUND: In a substantial number of patients with non-cystic fibrosis (CF) bronchiectasis an etiology cannot be found. Various complex immunodeficiency syndromes account for a significant portion of these patients but the mechanism elucidating the predisposition for suppurative lung disease often remains unknown. OBJECTIVE: To investigate the cause and mechanism predisposing a patient to severe bronchiectasis. METHODS: A patient presenting with severe non-CF bronchiectasis was investigated. Whole exome analysis (WES) was performed and complemented by extensive immunophenotyping. RESULTS: The genetic analysis revealed an autosomal dominant gain-of-function mutation (AD- GOF) in the signal transducer and activator of transcription 1 (STAT1) in the patient. STAT1 phosphorylation studies showed increased phosphorylation of STAT1 after stimulation with interferon γ (IFN-γ). Immunophenotyping showed normal counts of CD4 and CD8 T cells, B and NK cells, but a reduction of all memory B cells especially class switched memory B cells. Minor changes in the CD8 T cell subpopulations were seen. CONCLUSIONS: Early use of WES in the investigation of non-CF bronchiectasis was highly advantageous. The degree of impairment in class-switched memory B cells may predispose patients with AD- GOF mutations in STAT1 to suppurative sinopulmonary disease.


Assuntos
Bronquiectasia/genética , Mutação , Fator de Transcrição STAT1/genética , Sequenciamento Completo do Exoma/métodos , Adulto , Linfócitos B/citologia , Linfócitos B/imunologia , Bronquiectasia/diagnóstico por imagem , Bronquiectasia/epidemiologia , Bronquiectasia/imunologia , Candidíase Mucocutânea Crônica/diagnóstico por imagem , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Candidíase Mucocutânea Crônica/microbiologia , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Feminino , Humanos , Interferon gama/imunologia , Síndrome de Kartagener/diagnóstico , Masculino , Óxido Nítrico , Fosforilação , Prevalência , Fator de Transcrição STAT1/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Tomografia Computadorizada por Raios X , Estados Unidos/epidemiologia
7.
J Biol Chem ; 292(15): 6240-6254, 2017 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-28258222

RESUMO

Gain-of-function (GOF) mutations in the STAT1 gene are critical for the onset of chronic mucocutaneous candidiasis (CMC) disease. However, the molecular basis for the gain of STAT1 function remains largely unclear. Here, we investigated the structural features of STAT1 GOF residues to better understand the impact of these pathogenic mutations. We constructed STAT1 alanine mutants of the α3 helix residues of the coiled-coil domain, which are frequently found in CMC pathogenic mutations, and measured their transcriptional activities. Most of the identified GOF residues were located inside the coiled-coil domain stem structure or at the protein surface of the anti-parallel dimer interface. Unlike those, Arg-274 was adjacent to the DNA-binding domain. In addition, Arg-274 was found to functionally interact with Gln-441 in the DNA-binding domain. Because Gln-441 is located at the anti-parallel dimer contact site, Gln-441 reorientation by Arg-274 mutation probably impedes formation of the dimer. Further, the statistical analysis of RNA-seq data with STAT1-deficient epithelial cells and primary T cells from a CMC patient revealed that the R274Q mutation affected gene expression levels of 66 and 76 non-overlapping RefSeq genes, respectively. Because their transcription levels were only slightly modulated by wild-type STAT1, we concluded that the R274Q mutation increased transcriptional activity but did not change dramatically the repertoire of STAT1 targets. Hence, we provide a novel mechanism of STAT1 GOF triggered by a CMC pathogenic mutation.


Assuntos
Candidíase Mucocutânea Crônica , Regulação da Expressão Gênica , Mutação de Sentido Incorreto , Multimerização Proteica/genética , Fator de Transcrição STAT1 , Linfócitos T/metabolismo , Transcrição Genética , Substituição de Aminoácidos , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/metabolismo , Células HEK293 , Humanos , Domínios Proteicos , Estrutura Secundária de Proteína , Fator de Transcrição STAT1/biossíntese , Fator de Transcrição STAT1/genética
8.
Clin Immunol ; 178: 79-85, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28161409

RESUMO

Chronic mucocutaneous candidiasis, characterized by persistent or recurrent fungal infections, represents the clinical hallmark in gain-of-function (GOF) signal transducer and activator of transcription 1 (STAT1) mutation carriers. Several cases of intracranial aneurysms have been reported in patients with GOF STAT1 mutation but the paucity of reported cases likely suggested this association still as serendipity. In order to endorse this association, we link the development of intracranial aneurysms with STAT1 GOF mutation by presenting the two different cases of a patient and her mother, and demonstrate upregulated phosphorylated STAT4 and IL-12 receptor ß1 upon stimulation in patient's blood cells. We also detected increased transforming growth factor (TGF)-ß type 2 receptor expression, particularly in CD14+ cells, and a slightly higher phosphorylation rate of SMAD3. In addition, the mother of the patient developed disseminated bacille Calmette-Guérin disease after vaccination, speculating that GOF STAT1 mutations may confer a predisposition to weakly virulent mycobacteria.


Assuntos
Candidíase Mucocutânea Crônica/genética , Aneurisma Intracraniano/genética , Fator de Transcrição STAT1/genética , Adjuvantes Imunológicos/efeitos adversos , Adulto , Angiografia Digital , Vacina BCG/efeitos adversos , Candidíase Mucocutânea Crônica/complicações , Candidíase Mucocutânea Crônica/imunologia , Candidíase Mucocutânea Crônica/metabolismo , Angiografia Cerebral , Feminino , Humanos , Aneurisma Intracraniano/complicações , Aneurisma Intracraniano/diagnóstico por imagem , Aneurisma Intracraniano/metabolismo , Mães , Mutação , Fosfoproteínas/imunologia , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Interleucina-12/imunologia , Receptores de Interleucina-12/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/imunologia , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Transcrição STAT4/imunologia , Fator de Transcrição STAT4/metabolismo , Proteína Smad3/imunologia , Proteína Smad3/metabolismo , Tuberculose/induzido quimicamente , Tuberculose/imunologia , Adulto Jovem
9.
J Allergy Clin Immunol ; 139(5): 1629-1640.e2, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28139313

RESUMO

BACKGROUND: 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. OBJECTIVE: 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. METHODS: We used in vitro polarization assays, as well as phenotypic and functional analysis of STAT1-mutated patient cells. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Anemia Hemolítica Autoimune/genética , Inibidores de Proteínas Quinases/farmacologia , Púrpura Trombocitopênica Idiopática/genética , Pirazóis/farmacologia , Fator de Transcrição STAT1/genética , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Anemia Hemolítica Autoimune/imunologia , Autoimunidade/efeitos dos fármacos , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Criança , Citocinas/imunologia , Feminino , Humanos , Janus Quinases/antagonistas & inibidores , Mutação , Púrpura Trombocitopênica Idiopática/imunologia , Fator de Transcrição STAT1/imunologia , Células Th1/imunologia , Células Th17/imunologia
10.
J Allergy Clin Immunol ; 140(2): 553-564.e4, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28069426

RESUMO

BACKGROUND: Gain-of-function (GOF) mutations affecting the coiled-coil domain or the DNA-binding domain of signal transducer and activator of transcription 1 (STAT1) cause chronic mucocutaneous candidiasis disease. This condition is characterized by fungal and bacterial infections caused by impaired generation of TH17 cells; meanwhile, some patients with chronic mucocutaneous candidiasis disease might also have viral or intracellular pathogen infections. OBJECTIVE: We sought to investigate the effect of STAT1 GOF mutations on the functioning of natural killer (NK) cells. METHODS: Because STAT1 is involved in the signaling response to several cytokines, we studied NK cell functional activities and STAT1 signaling in 8 patients with STAT1 GOF mutations. RESULTS: Functional analysis of NK cells shows a significant impairment of cytolytic and degranulation activities in patients with STAT1 GOF mutations. Moreover, NK cells from these patients display lower production of IFN-γ in response to IL-15 and reduced proliferation after stimulation with IL-2 or IL-15, suggesting that STAT5 signaling is affected. In addition, signaling studies demonstrate that the increased phosphorylation of STAT1 in response to IFN-α is associated with detectable activation of STAT1 and increased STAT1 binding to the interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) promoter in response to IL-15, whereas STAT5 phosphorylation and DNA binding to IL-2 receptor α (IL2RA) are reduced or not affected in response to the same cytokine. CONCLUSION: These observations suggest that persistent activation of STAT1 might affect NK cell proliferation and functional activities.


Assuntos
Candidíase Mucocutânea Crônica/genética , Células Matadoras Naturais/imunologia , Fator de Transcrição STAT1/genética , Adolescente , Adulto , Candidíase Mucocutânea Crônica/imunologia , Criança , Citocinas/farmacologia , Feminino , Expressão Gênica , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Fosforilação , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT5/metabolismo
11.
J Oral Pathol Med ; 46(5): 393-397, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27682444

RESUMO

OBJECTIVE: The aim of this study was to investigate whether a variation in the genomic copy number (CNV) of the ß-defensin cluster could be associated with the pre-disposition to chronic mucocutaneous candidiasis (CMC) in Sardinian APECED patients. SUBJECTS AND METHODS: The ß-defensin copy number variation was determined by MLPA analysis in 18 Sardinian APECED patients with CMC and in 21 Sardinian controls. Statistical analyses were performed with one-way ANOVA test. RESULTS: No statistically significant results were observed between the patients and controls groups. CONCLUSIONS: According to the results we have obtained, it appears that either ß-defensin genomic CNV is not a modifier locus for CMC susceptibility in APECED patients, or any effect is too small for it to be detected using such sample size. An extensive study on APECED patients from different geographical areas might reveal the real implication of the ß-defensin CNV in the susceptibility to Candida albicans infections.


Assuntos
Candidíase Mucocutânea Crônica/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença/genética , Poliendocrinopatias Autoimunes/genética , beta-Defensinas/genética , Adolescente , Adulto , Candida albicans , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/fisiologia , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Poliendocrinopatias Autoimunes/microbiologia
13.
Int J Mol Sci ; 17(12)2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27916941

RESUMO

Autoimmune regulator (Aire) mutations result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), which manifests as multi-organ autoimmunity and chronic mucocutaneous candidiasis (CMC). Indendritic cells (DCs), pattern recognition receptors (PRR), such as Toll-like receptors (TLRs), are closely involved in the recognition of various pathogens, activating the intercellular signaling pathway, followed by the activation of transcription factors and the expression of downstream genes, which take part in mediating the immune response and maintaining immune tolerance. In this study, we found that Aire up-regulated TLR3 expression and modulated the downstream cytokine expression and nuclear factor-κB (NF-κB) of the TLR3 signaling pathway.


Assuntos
Candidíase Mucocutânea Crônica/genética , Poliendocrinopatias Autoimunes/genética , Receptor 3 Toll-Like/biossíntese , Fatores de Transcrição/biossíntese , Animais , Autoimunidade/genética , Autoimunidade/imunologia , Candida/imunologia , Candida/patogenicidade , Candidíase Mucocutânea Crônica/imunologia , Candidíase Mucocutânea Crônica/microbiologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Regulação da Expressão Gênica , Humanos , Tolerância Imunológica/genética , Camundongos , Mutação , NF-kappa B/genética , Poliendocrinopatias Autoimunes/imunologia , Poliendocrinopatias Autoimunes/microbiologia , Receptor 3 Toll-Like/imunologia , Fatores de Transcrição/genética
14.
J Infect ; 72 Suppl: S56-60, 2016 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-27161991

RESUMO

Autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) is a rare and severe primary immunodeficiency that is characterized by mucocutaneous fungal infection, autoimmunity, cerebral aneurysms, and oropharyngeal and esophageal cancer. Recently, it was discovered that STAT1 mutations are responsible for AD-CMC. These mutations lead to the inability of STAT1 to be dephosphorylated, resulting in hyperphosphorylation, increased binding to the DNA, and gain of function (GOF) effects on STAT1 signaling. Furthermore, a characteristic feature of AD-CMC patients is deficiency in the T-helper 17 (Th17) responses, which is believed to be the immunological cause of the mucocutaneous fungal infection. No targeted treatment other than lifelong antifungal prophylaxis exists for AD-CMC. However, the discovery of the genetic and immunological defects makes it now possible to explore new treatment strategies. This review will discuss immunomodulatory treatment options that can be explored in patients with STAT1 GOF mutations.


Assuntos
Candidíase Mucocutânea Crônica/imunologia , Candidíase Mucocutânea Crônica/terapia , Síndromes de Imunodeficiência/microbiologia , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/microbiologia , Humanos , Síndromes de Imunodeficiência/complicações , Imunomodulação , Mutação , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Células Th17/imunologia
15.
Blood ; 127(25): 3154-64, 2016 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-27114460

RESUMO

Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guérin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis.


Assuntos
Candidíase Mucocutânea Crônica/genética , Estudos de Associação Genética , Mutação , Fator de Transcrição STAT1/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
17.
J Clin Immunol ; 36(3): 204-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26961233

RESUMO

Chronic mucocutaneous or invasive fungal infections are generally the result of primary or secondary immune dysfunction. Patients with autosomal recessive CARD9 mutations are also predisposed to recurrent mucocutaneous and invasive fungal infections with Candida spp., dermatophytes (e.g., Trichophyton spp.) and phaeohyphomycetes (Exophiala spp., Phialophora verrucosa). We study a consanguineous family of Turkish origin in which three members present with distinct clinical phenotypes of chronic mucocutaneous and invasive fungal infections, ranging from chronic mucocutaneous candidiasis (CMC) in one patient, treatment-resistant cutaneous dermatophytosis and deep dermatophytosis in a second patient, to CMC with Candida encephalitis and endocrinopathy in a third patient. Two patients consented to genetic testing and were found to have a previously reported homozygous R70W CARD9 mutation. Circulating IL-17 and IL-22 producing T cells were decreased as was IL-6 and granulocyte/macrophage colony-stimulating factor (GM-CSF) secretion upon stimulation with Candida albicans. Patients with recurrent fungal infections in the absence of known immunodeficiencies should be analyzed for CARD9 gene mutations as the cause of fungal infection predisposition.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Candidíase Mucocutânea Crônica/genética , Síndromes de Imunodeficiência/genética , Infecções Fúngicas Invasivas/genética , Tinha/genética , Proteínas Adaptadoras de Sinalização CARD/deficiência , Proteínas Adaptadoras de Sinalização CARD/imunologia , Candida/crescimento & desenvolvimento , Candida/patogenicidade , Candidíase Mucocutânea Crônica/imunologia , Candidíase Mucocutânea Crônica/patologia , Criança , Consanguinidade , Feminino , Expressão Gênica , Genes Recessivos , Predisposição Genética para Doença , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Homozigoto , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucinas/genética , Interleucinas/imunologia , Infecções Fúngicas Invasivas/imunologia , Infecções Fúngicas Invasivas/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Linfócitos T , Tinha/imunologia , Tinha/patologia , Trichophyton/crescimento & desenvolvimento , Trichophyton/patogenicidade , Turquia
18.
Clin Immunol ; 164: 1-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26732859

RESUMO

In gain-of-function STAT1 mutations, chronic mucocutaneous candidiasis disease (CMCD) represents the phenotypic manifestation of a complex immunodeficiency characterized by clinical and immunological heterogeneity. We aimed to study clinical manifestations, long-term complications, molecular basis, and immune profile of patients with dominant CMCD. We identified nine patients with heterozygous mutations in STAT1, including novel amino acid substitutions (L283M, L351F, L400V). High risk of azole-resistance was observed, particularly when intermittent regimens of antifungal treatment or use of suboptimal dosage occurs. We report a case of Cryptococcosis and various bacterial and viral infections. Risk of developing bronchiectasis in early childhood or gradually evolving to chronic lung disease in adolescent or adult ages emerges. Lymphopenia is variable, likely progressing by adulthood. We conclude that continuous antifungal prophylaxis associated to drug monitoring might prevent resistance to treatment; prompt diagnosis and therapy of lung disease might control long-term progression; careful monitoring of lymphopenia-related infections might improve prognosis.


Assuntos
Candidíase Mucocutânea Crônica/genética , Fator de Transcrição STAT1/genética , Adolescente , Adulto , Antifúngicos/uso terapêutico , Autoimunidade , Azóis/uso terapêutico , Infecções Bacterianas/complicações , Candidíase Mucocutânea Crônica/complicações , Candidíase Mucocutânea Crônica/tratamento farmacológico , Criança , Doença Crônica , Criptococose/complicações , Cryptococcus neoformans , Resistência a Medicamentos , Feminino , Humanos , Leishmaniose Visceral/complicações , Pneumopatias/complicações , Pneumopatias/tratamento farmacológico , Pneumopatias/genética , Linfopenia/complicações , Masculino , Pessoa de Meia-Idade , Mutação , Fosforilação , Fator de Transcrição STAT1/metabolismo , Viroses/complicações , Adulto Jovem
19.
J Clin Immunol ; 36(1): 73-84, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26604104

RESUMO

PURPOSE: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients. METHODS: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients. RESULTS: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61%). Out of 39 familial cases from 11 families, 26 patients (67%) from 9 families and out of 18 sporadic cases, 9 patients (50%) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients. CONCLUSION: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.


Assuntos
Candidíase Mucocutânea Crônica/diagnóstico , Síndromes de Imunodeficiência/diagnóstico , Leucócitos Mononucleares/imunologia , Mutação/genética , Fator de Transcrição STAT1/metabolismo , Adulto , Candidíase Mucocutânea Crônica/genética , Células Cultivadas , Citocinas/metabolismo , Análise Mutacional de DNA , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Masculino , Linhagem , Fenótipo , Estrutura Terciária de Proteína/genética , Fator de Transcrição STAT1/genética
20.
Clin Exp Immunol ; 184(2): 216-27, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26621323

RESUMO

Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent and persistent superficial infections, with Candida albicans affecting the mucous membranes, skin and nails. It can be acquired or caused by primary immune deficiencies, particularly those that impair interleukin (IL)-17 and IL-22 immunity. We describe a single kindred with CMC and the identification of a STAT1 GOF mutation by whole exome sequencing (WES). We show how detailed clinical and immunological phenotyping of this family in the context of WES has enabled revision of disease status and clinical management. Together with analysis of other CMC cases within our cohort of patients, we used knowledge arising from the characterization of this family to develop a rapid ex-vivo screening assay for the detection of T helper type 17 (Th17) deficiency better suited to the routine diagnostic setting than established in-vitro techniques, such as intracellular cytokine staining and enzyme-linked immunosorbent assay (ELISA) using cell culture supernatants. We demonstrate that cell surface staining of unstimulated whole blood for CCR6⁺ CXCR3⁻ CCR4⁺ CD161⁺ T helper cells generates results that correlate with intracellular cytokine staining for IL-17A, and is able to discriminate between patients with molecularly defined CMC and healthy controls with 100% sensitivity and specificity within the cohort tested. Furthermore, removal of CCR4 and CD161 from the antibody staining panel did not affect assay performance, suggesting that the enumeration of CCR6⁺ CXCR3⁻ CD4⁺ T cells is sufficient for screening for Th17 deficiency in patients with CMC and could be used to guide further investigation aimed at identifying the underlying molecular cause.


Assuntos
Candida albicans/imunologia , Candidíase Mucocutânea Crônica/diagnóstico , Candidíase Mucocutânea Crônica/genética , Fator de Transcrição STAT1/genética , Células Th17/imunologia , Adolescente , Adulto , Sequência de Bases , Antígenos CD4/metabolismo , Candidíase Mucocutânea Crônica/microbiologia , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Exoma/genética , Família , Feminino , Humanos , Lactente , Interleucina-17/imunologia , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/imunologia , Membrana Mucosa/microbiologia , Receptores CCR6/metabolismo , Receptores CXCR3/metabolismo , Análise de Sequência de DNA , Coloração e Rotulagem , Adulto Jovem
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