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1.
Eur J Immunol ; 49(5): 790-800, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30801692

RESUMO

STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1-dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN-α were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN-α levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon-stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon-related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.

2.
BMC Immunol ; 19(1): 31, 2018 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-30390640

RESUMO

BACKGROUND: Down syndrome (DS) is the most common syndromic immunodeficiency with an increased risk of infection, mortality from sepsis, and autoinflammation. Innate immune function is altered in DS and therefore we examined responses in CD11b and Toll like receptor 4 (TLR-4), which are important immune cell surface markers upregulated in response to Lipopolysaccharide (LPS) endotoxin, and the immunomodulator melatonin. Neutrophil and monocyte responses to LPS and melatonin in children with Down syndrome (DS) who were clinically stable were compared to age-matched controls. Whole blood was incubated with LPS and melatonin and the relative expression of CD11b and TLR-4 evaluated by flow cytometry. RESULTS: Children with DS had an increased response to LPS in neutrophils and intermediate monocytes, while also having elevated TLR-4 expression on non-classical monocytes compared to controls at baseline. Melatonin reduced CD11b expression on neutrophils, total monocytes, both classical and intermediate sub-types, in children with DS and controls. CONCLUSION: Melatonin could represent a useful clinical adjunct in the treatment of sepsis as an immunomodulator. Children with DS had increased LPS responses which may contribute to the more adverse outcomes seen in sepsis.

4.
Immunol Cell Biol ; 96(10): 1060-1071, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29790605

RESUMO

Premature T-cell immunosenescence with CD57+ CD8+ T-cell accumulation has been linked to immunodeficiency and autoimmunity in primary immunodeficiencies including activated PI3 kinase delta syndrome (APDS). To address whether CD57 marks the typical senescent T-cell population seen in adult individuals or identifies a distinct population in APDS, we compared CD57+ CD8+ T cells from mostly pediatric APDS patients to those of healthy adults with similarly prominent senescent T cells. CD57+ CD8+ T cells from APDS patients were less differentiated with more CD27+ CD28+ effector memory T cells showing increased PD1 and Eomesodermin expression. In addition, transition of naïve to CD57+ CD8+ T cells was not associated with the characteristic telomere shortening. Nevertheless, they showed the increased interferon-gamma secretion, enhanced degranulation and reduced in vitro proliferation typical of senescent CD57+ CD8+ T cells. Thus, hyperactive PI3 kinase signaling favors premature accumulation of a CD57+ CD8+ T-cell population, which shows most functional features of typical senescent T cells, but is different in terms of differentiation and relative telomere shortening. Initial observations indicate that this specific differentiation state may offer the opportunity to revert premature T-cell immunosenescence and its potential contribution to inflammation and immunodeficiency in APDS.

5.
Pediatr Dermatol ; 34(5): e277-e278, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28730616

RESUMO

A healthy 5-year-old boy presented to the emergency department with an acute genital swelling. He had no relevant family history. His presentation and blood investigations were consistent with C1 esterase inhibitor deficiency, mostly likely arising de novo. A rare cause of acute genital swelling and its management are discussed.


Assuntos
Angioedemas Hereditários/diagnóstico , Proteína Inibidora do Complemento C1/análise , Ácido Tranexâmico/uso terapêutico , Angioedemas Hereditários/tratamento farmacológico , Pré-Escolar , Diagnóstico Diferencial , Edema/etiologia , Genitália/patologia , Humanos , Masculino
6.
J Allergy Clin Immunol ; 139(2): 597-606.e4, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27555459

RESUMO

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Síndromes de Imunodeficiência/genética , Transtornos Linfoproliferativos/genética , Mutação/genética , Infecções Respiratórias/genética , Adolescente , Adulto , Animais , Antibioticoprofilaxia , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Estudos de Coortes , Inibidores Enzimáticos/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/mortalidade , Infecções por Herpesviridae/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/mortalidade , Síndromes de Imunodeficiência/terapia , Lactente , Cooperação Internacional , Transtornos Linfoproliferativos/mortalidade , Transtornos Linfoproliferativos/terapia , Masculino , Camundongos , Pessoa de Meia-Idade , Recidiva , Infecções Respiratórias/mortalidade , Infecções Respiratórias/terapia , Inquéritos e Questionários , Análise de Sobrevida , Adulto Jovem
8.
Eur Respir J ; 47(3): 829-36, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26585432

RESUMO

Lung disease in patients with both primary ciliary dyskinesia (PCD) or cystic fibrosis (CF) is associated with impaired mucociliary clearance; however, clinical outcomes are typically worse in CF patients. We assessed whether CF and PCD patients differ in inflammatory response in the airways during pulmonary exacerbation.We first studied clinically stable PCD patients with a spectrum of bacterial pathogens to assess inflammatory response to different pathogens. Subsequently, PCD and CF patients with similar bacterial pathogens were studied at the time of a pulmonary exacerbation and after 21 days of antibiotics treatment. Qualitative and quantitative microbiology, cell counts, interleukin-8 concentrations, and neutrophil elastase activity were assessed in sputum samples obtained before and after treatment.In stable PCD patients, no significant differences were found in sputum inflammatory markers between individuals colonised with different bacterial pathogens. Pulmonary exacerbation severity assessed by a pulmonary exacerbation score and lung function decline from their previous baseline did not differ between CF and PCD patients. Bacterial density for Staphylococcus aureus and Haemophilus influenzae was higher in CF versus PCD (p<0.05), but absolute neutrophil counts were higher in PCD patients (p=0.02). While sputum elastase activity was similar in PCD and CF at the time of exacerbation, it decreased with antibiotic therapy in PCD (p<0.05) but not CF patients.PCD patients differ from those with CF in their responses to treatment of pulmonary exacerbations, with higher neutrophil elastase activity persisting in the CF airways at the end of treatment.


Assuntos
Fibrose Cística/fisiopatologia , Inflamação/microbiologia , Síndrome de Kartagener/fisiopatologia , Pulmão/fisiopatologia , Escarro/microbiologia , Adolescente , Biomarcadores/análise , Criança , Fibrose Cística/microbiologia , Progressão da Doença , Feminino , Haemophilus influenzae/isolamento & purificação , Humanos , Interleucina-8/sangue , Síndrome de Kartagener/microbiologia , Masculino , Neutrófilos/citologia , Ontário , Testes de Função Respiratória , Staphylococcus aureus/isolamento & purificação
10.
J Cyst Fibros ; 14(2): 262-6, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25453872

RESUMO

This study aimed to determine whether antimicrobial susceptibility testing of Pseudomonas aeruginosa grown as a biofilm, rather than planktonically, improves efficacy of antibiotic treatment for pulmonary exacerbations. This was a multicenter randomized, double-blind controlled trial of 14 days of intravenous antibiotic treatment for pulmonary exacerbations chosen based on conventional vs. biofilm antimicrobial susceptibility results in CF patients with chronic P. aeruginosa infection. There were 74 exacerbations in 39 patients. A total of 46% (12/26) exacerbations in the conventional group compared to 40% (19/48) exacerbations in the biofilm group achieved a ≥3 log drop in P. aeruginosa sputum density (difference -0.03, 95% CI -0.5 to 0.4, p=0.9). Lung function improvements were similar in both groups. Biofilm antimicrobial susceptibility testing did not lead to improved microbiological or clinical outcomes compared to conventional methods in the treatment of pulmonary exacerbations in CF patients with chronic P. aeruginosa.


Assuntos
Antibacterianos , Biofilmes , Fibrose Cística , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas , Pseudomonas aeruginosa , Antibacterianos/classificação , Antibacterianos/uso terapêutico , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Canadá , Criança , Fibrose Cística/complicações , Fibrose Cística/microbiologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana/métodos , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Infecções por Pseudomonas/diagnóstico , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/etiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Reprodutibilidade dos Testes , Testes de Função Respiratória/métodos , Escarro/efeitos dos fármacos , Escarro/microbiologia , Resultado do Tratamento
11.
Blood ; 124(12): 1894-904, 2014 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-25122610

RESUMO

We have previously reported on a unique patient in whom homozygosity for a mutation at IRF8 (IRF8(K108E)) causes a severe immunodeficiency. Laboratory evaluation revealed a highly unusual myeloid compartment, remarkable for the complete absence of CD141 and CD161 monocytes, absence of CD11c1 conventional dendritic cells (DCs) and CD11c1/CD1231 plasmacytoid DCs, and striking granulocytic hyperplasia. The patient initially presented with severe disseminated mycobacterial and mucocutaneous fungal infections and was ultimately cured by cord blood transplant. Sequencing RNA from the IRF8(K108E) patient's primary blood cells prior to transplant shows not only depletion of IRF8-bound and IRF8-regulated transcriptional targets, in keeping with the distorted composition of the myeloid compartment, but also a paucity of transcripts associated with activated CD41 and CD81 T lymphocytes. This suggests that T cells reared in the absence of a functional antigen-presenting compartment in IRF8(K108E) are anergic. Biochemical characterization of the IRF8(K108E) mutant in vitro shows that loss of the positively charged side chain at K108 causes loss of nuclear localization and loss of transcriptional activity, which is concomitant with decreased protein stability, increased ubiquitination, increased small ubiquitin-like modification, and enhanced proteasomal degradation. These findings provide functional insight into the molecular basis of immunodeficiency associated with loss of IRF8.


Assuntos
Células Dendríticas/imunologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/genética , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Anergia Clonal/genética , Anergia Clonal/imunologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Feminino , Células HEK293 , Homozigoto , Humanos , Síndromes de Imunodeficiência/terapia , Lactente , Fatores Reguladores de Interferon/metabolismo , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/terapia , Proteínas Mutantes/genética , Proteínas Mutantes/imunologia , Proteínas Mutantes/metabolismo , Processamento de Proteína Pós-Traducional , Estabilidade Proteica , RNA/genética , Subpopulações de Linfócitos T/imunologia
12.
Can J Infect Dis Med Microbiol ; 23(3): 137-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23997782

RESUMO

A three-year-old boy presented with community-acquired pneumonia complicated by empyema. Streptococcus pyogenes (group A streptococcus) was identified on culture of the pleural fluid. The patient improved with antibiotic therapy and drainage of the empyema. During his convalescence, the patient developed persistent fever, lethargy and anorexia. His inflammatory markers were elevated, and repeat cultures were negative. Although the patient had none of the classical mucocutaneous features of Kawasaki disease, an echocardiogram was performed, which revealed coronary artery dilation. The patient was diagnosed with incomplete Kawasaki disease and treated with intravenous immunoglobulin and high-dose acetylsalicylic acid. The fever subsided within 48 h. To the authors' knowledge, the present report is the first report of Kawasaki disease associated with complicated S pyogenes pneumonia. It emphasizes the importance of considering incomplete Kawasaki disease among children with persistent fever, the role of echocardiography in diagnosis, and the potential link between Kawasaki disease and superantigen-producing organisms such as S pyogenes.

13.
Pediatr Pulmonol ; 46(5): 489-96, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21337531

RESUMO

A single-center retrospective study was undertaken in children with cystic fibrosis (CF) to evaluate (1) risk factors for acquisition; (2) molecular epidemiology; and (3) impact on disease progression of borderline oxacillin-resistant Staphylococcus aureus (BORSA) versus mecA-positive methicillin-resistant Staphylococcus aureus (MRSA). The study comprised of (1) identification of all children with at least one respiratory specimen positive for either BORSA or MRSA during the study period; (2) compilation of relevant clinical and epidemiological data from 12-month period leading up to first positive (index) culture; (3) microbiological and molecular characterization of index isolates and (4) measurement of subsequent clinical outcome. Thirty-eight children were identified with at least one positive isolate; 4 were excluded due to insufficient clinical or laboratory data. Eighteen children (53%) grew BORSA in their index culture. Children who acquired BORSA only (n = 16) were more likely to have had prior MSSA colonization (P < 0.0001). Usage of oral cephalexin (P < 0.01) and inhaled tobramycin (P < 0.03) prior to index culture was significantly and independently associated with acquisition of BORSA. The majority of BORSA isolates were hyper ß-lactamase producers and susceptible to a greater range of antibiotics. Strain relatedness was not evident within the BORSA group. There was no difference in disease progression between the two groups. This is the first study to demonstrate that a significant proportion of S. aureus isolates with methicillin resistance in the CF population are BORSAs that lack mecA. Antibiotic pressure may lead to the development of BORSA in CF patients. Prospective studies are needed to assess its clinical impact.


Assuntos
Fibrose Cística/epidemiologia , Oxacilina , Resistência às Penicilinas , Infecções Estafilocócicas/epidemiologia , Adolescente , Antibacterianos/uso terapêutico , Proteínas de Bactérias/genética , Cefalexina/uso terapêutico , Criança , Pré-Escolar , Fibrose Cística/microbiologia , Feminino , Humanos , Lactente , Masculino , Meticilina , Proteínas de Ligação às Penicilinas/genética , Estudos Retrospectivos , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Staphylococcus aureus/isolamento & purificação , Tobramicina/uso terapêutico
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