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1.
J Allergy Clin Immunol ; 153(1): 297-308.e12, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37979702

RESUMO

BACKGROUND: Elevated TCRαß+CD4-CD8- double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U). OBJECTIVE: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway-related genes could explain these cases. METHODS: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway-related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss of heterozygosity (sLOH). RESULTS: Nine of 16 patients with ALPS-U lacked FAS expression on CD57+DNT predicting heterozygous "loss-of-expression" FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH. CONCLUSION: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing.


Assuntos
Síndrome Linfoproliferativa Autoimune , Receptor fas , Humanos , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética , Biomarcadores , Variações do Número de Cópias de DNA , Sequenciamento do Exoma , Receptor fas/genética , Proteína de Domínio de Morte Associada a Fas/genética , Mutação
2.
J Clin Immunol ; 44(6): 129, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38773012

RESUMO

Mutations in genes of the DNA polymerase complex have been linked to impaired immunological function next to distinct syndromic features. Biallelic mutations in PRIM1 are associated with a primordial dwarfism syndrome with variable hypogammaglobulinemia. The disease is mostly lethal in infancy due to pulmonary infections as well as hepatic cirrhosis. We studied 3 novel patients with PRIM1-deficiency with a focus on immunological consequences. All three shared dysmorphic features including a prominent forehead, triangular face and bilateral cryptorchidism. P1 carried the novel homozygous PRIM1 splice variant c.103+2T>G, allowing residual protein expression and associated with a mild clinical phenotype. P2 and P3 carried the known homozygous variant c.638+36C>G and died in infancy. Paradoxically, B cell lymphopenia was most pronounced in P1. No other significant lymphocyte abnormalities were detected. Interestingly, all 3 patients showed variable, but intermittently excessive Type I interferon signatures. In summary, the B-cell deficiency in PRIM1-deficiency is markedly variable and the severity of syndromic manifestations is not predictive of the immunological phenotype. We highlight a potential contribution of pathological type I interferon activation to disease pathogenesis which warrants further investigations.


Assuntos
Alelos , Linfócitos B , Mutação , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Linfócitos B/imunologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/diagnóstico , Interferon Tipo I/metabolismo , Mutação/genética , Fenótipo
3.
BMC Public Health ; 23(1): 1003, 2023 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-37254143

RESUMO

BACKGROUND: A recurrent feature of infectious diseases is the observation that different individuals show different levels of secondary transmission. This inter-individual variation in transmission potential is often quantified by the dispersion parameter k. Low values of k indicate a high degree of variability and a greater probability of superspreading events. Understanding k for COVID-19 across contexts can assist policy makers prepare for future pandemics. METHODS: A literature search following a systematic approach was carried out in PubMed, Embase, Web of Science, Cochrane Library, medRxiv, bioRxiv and arXiv to identify publications containing epidemiological findings on superspreading in COVID-19. Study characteristics, epidemiological data, including estimates for k and R0, and public health recommendations were extracted from relevant records. RESULTS: The literature search yielded 28 peer-reviewed studies. The mean k estimates ranged from 0.04 to 2.97. Among the 28 studies, 93% reported mean k estimates lower than one, which is considered as marked heterogeneity in inter-individual transmission potential. Recommended control measures were specifically aimed at preventing superspreading events. The combination of forward and backward contact tracing, timely confirmation of cases, rapid case isolation, vaccination and preventive measures were suggested as important components to suppress superspreading. CONCLUSIONS: Superspreading events were a major feature in the pandemic of SARS-CoV-2. On the one hand, this made outbreaks potentially more explosive but on the other hand also more responsive to public health interventions. Going forward, understanding k is critical for tailoring public health measures to high-risk groups and settings where superspreading events occur.


Assuntos
COVID-19 , Humanos , COVID-19/epidemiologia , SARS-CoV-2 , Pandemias/prevenção & controle , Saúde Pública , Busca de Comunicante
4.
Pediatr Blood Cancer ; 67(6): e28302, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32285995

RESUMO

This report offers novel clinical and diagnostic aspects of the association between germline mutations in HAVCR2 and subcutaneous panniculitis-like T-cell lymphoma (SPTCL). The patient presented with panniculitis-like T-cell lymphoma involving mesenteric fatty tissue associated with hemophagocytic lymphohistiocytosis (HLH). Five years later, he developed a clonally unrelated SPTCL and underwent hematopoietic stem cell transplantation. Retrospectively, he was found to carry germline mutations in HAVCR2 associated with reduced T-cell immunoglobulin mucin-3 (TIM-3) expression. We show that mesenteric fatty tissue localization of SPTCL can be the presenting manifestation of TIM-3 deficiency, that this condition predisposes to recurrent lymphoma, and that flow cytometry is a possible screening tool.


Assuntos
Mutação em Linhagem Germinativa , Receptor Celular 2 do Vírus da Hepatite A/deficiência , Receptor Celular 2 do Vírus da Hepatite A/genética , Linfo-Histiocitose Hemofagocítica/patologia , Linfoma de Células T/patologia , Mesentério/patologia , Paniculite/patologia , Adolescente , Humanos , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/metabolismo , Linfoma de Células T/complicações , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , Masculino , Mesentério/metabolismo , Paniculite/complicações , Paniculite/genética , Paniculite/metabolismo , Prognóstico
8.
Eur J Cancer ; 159: 78-86, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34736044

RESUMO

PURPOSE: There are limited data on SARS-CoV-2 (COVID-19) infection in children with cancer or after haematopoietic stem cell transplant (HSCT). We describe the severity and outcomes of SARS-COV-2 in these patients and identify factors associated with severe disease. METHODS: This was a multinational, observational study of children (aged <19 years) with cancer or HSCT and SARS-CoV-2 confirmed by polymerase chain reaction. COVID-19 was classified as asymptomatic, mild, moderate, severe or critical (≥1 organ support). Exact polytomous regression was used to determine the relationship between clinical variables and disease severity. RESULTS: One hundred and thirty-one patients with COVID-19 across 10 countries were identified (median age 8 years). Seventy-eight (60%) had leukaemia/lymphoma, 48 (37%) had solid tumour and five had primary immunodeficiency and HSCT. Fever (71%), cough (47%) and coryza (29%) were the most frequent symptoms. The median duration of detectable virus was 16 days (range, 1-79 days). Forty-nine patients (37%) were hospitalised for COVID-19 symptoms, and 15 (11%) required intensive care unit-level care. Chemotherapy was delayed/modified in 35% of patients. COVID-19 was asymptomatic in 32% of patients, mild in 47%, moderate in 8%, severe in 4% and critical in 9%. In 124 patients (95%), a full recovery was documented, and four (3%) died due to COVID-19. Any comorbidity (odds ratio, 2.94; 95% confidence interval [CI], 1.81-5.21), any coinfection (1.74; 95% CI 1.03-3.03) and severe baseline neutropenia (1.82; 95% CI 1.13-3.09) were independently and significantly associated with increasing disease severity. CONCLUSION: Although most children with cancer had asymptomatic/mild disease, 13% had severe COVID-19 and 3% died. Comorbidity, coinfection and neutropenia may increase the risk of severe disease. Our data may help management decisions in this vulnerable population.


Assuntos
COVID-19/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Neoplasias/epidemiologia , Adolescente , Fatores Etários , COVID-19/diagnóstico , COVID-19/mortalidade , Criança , Pré-Escolar , Coinfecção , Comorbidade , Feminino , Humanos , Masculino , Neoplasias/diagnóstico , Neoplasias/mortalidade , Neutropenia/epidemiologia , Prognóstico , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo
9.
Front Immunol ; 11: 808, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32457750

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous hyperinflammatory syndrome with different pathways of pathogenesis resulting in similar clinical presentations. It is best defined and understood if presenting in the context of genetic immunodeficiencies associated with defects of lymphocyte cytotoxicity. In these "primary" forms of HLH, cellular and soluble immune effectors are relatively well characterized. While etoposide-based broad cell-directed therapies remain standard of care, more specific therapies targeting these effectors individually are increasingly available. Anti-CD52 as a cell-directed therapy and anti-IFN-gamma, IL-18BP, and JAK-inhibition as cytokine-directed therapies are expected to broaden the therapeutic options, but the precise role of these drugs in first-line and rescue treatment indications remains to be defined. A number of additional inborn errors of immunity are associated with episodes of immune activation fulfilling the clinical criteria of HLH. Impaired pathogen control is a key driver of hyperinflammation in some conditions, while others are characterized by a strong autoinflammatory component. This heterogeneity of disease-driving factors and the variable severity in disease progression in these conditions do not allow a simple adaptation of protocols established for "primary" HLH to HLH in the context of other inborn errors of immunity. Cytokine-directed therapies hold significant promise in these increasingly recognized disorders.


Assuntos
Citocinas/uso terapêutico , Síndromes de Imunodeficiência/terapia , Linfo-Histiocitose Hemofagocítica/terapia , Animais , Ensaios Clínicos como Assunto , Humanos , Síndromes de Imunodeficiência/genética , Imunoterapia , Linfo-Histiocitose Hemofagocítica/imunologia , Camundongos
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