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1.
Indian J Pathol Microbiol ; 62(2): 279-282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30971555

RESUMO

Griscelli syndrome is a rare autosomal recessive inherited disorder characterized by hypopigmentation, silver colored hair, and associated immunological deficiency, which proves fatal in the absence of timely intervention. Our patients diagnosed with Griscelli syndrome-2 presented with fever, hepatosplenomegaly, and deranged hematological and biochemical parameters. Both cases underwent detailed investigations comprising of hair mount microscopic examination, degranulation assay, and mutational studies. Our cases showed defective degranulation activity by NK cells and gene mutation analysis revealed RAB27A mutation that causes defect of cytotoxic granule exocytosis from natural killer (NK) and T-cells, manifesting clinically as hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplantation in one of the patients resulted in stable chimerism; however, the second case relapsed within a month after SCT. Stem cell transplantation is the only curative therapeutic option for GS2; thus, improvement in posttransplantation management may reduce mortality and posttransplant complications. Hence, any child who presents with partial albinism and clinical features suggestive of HLH, a peripheral blood, hair shaft mount examination along with basic immunological NK and T-cell cytotoxicity assay by flow cytometry will help clinch the diagnosis early. It can subsequently be confirmed by molecular study. Timely therapeutic intervention can prevent relapses and severe infection and improve outcome in these cases.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/terapia , Piebaldismo/genética , Piebaldismo/terapia , Pré-Escolar , Feminino , Cabelo , Humanos , Síndromes de Imunodeficiência/patologia , Células Matadoras Naturais/patologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , Mutação , Piebaldismo/patologia , Resultado do Tratamento , Proteínas rab27 de Ligação ao GTP/genética
2.
Orphanet J Rare Dis ; 14(1): 61, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819232

RESUMO

BACKGROUND: Warts Hypogammaglobulinemia Immunodeficiency Myelokathexis (WHIM) syndrome is a primary immunodeficiency characterized by recurrent bacterial infections, severe chronic neutropenia, with lymphopenia, monocytopenia and myelokathexis which is caused by heterozygous gain of functions mutations of the CXC chemokine receptor 4 (CXCR4). WHIM patients display an increased incidence of non-hematopoietic conditions, such as congenital heart disease suggesting that abnormal CXCR4 may put these patients at increased risk of congenital anomalies. Studies conducted on CXCR4 and SDF-1-deficient mice have demonstrated the role of CXCR4 signaling in neuronal cell migration and brain development. In particular, CXCR4 conditional knockout mice display abnormal cerebellar morphology and poor coordination and balance on motor testing. RESULTS: In order to evaluate a possible neurological involvement in WHIM syndrome subjects, we performed neurological examination, including International Cooperative Ataxia Rating Scale, cognitive and psychopathological assessment and brain Magnetic Resonance Imaging (MRI) in 6 WHIM patients (age range 8-51 years) with typical gain of functions mutations of CXCR4 (R334X or G336X). In three cases (P3, P5, P6) neurological evaluation revealed fine and global motor coordination disorders, balance disturbances, mild limb ataxia and excessive talkativeness. Brain MRI showed an abnormal orientation of the cerebellar folia involving bilaterally the gracilis and biventer lobules together with the tonsils in four subjects (P3, P4, P5, P6). The neuropsychiatric evaluation showed increased risk of internalizing and/or externalizing problems in four patients (P2, P3, P4, P6). CONCLUSIONS: Taken together, these observations suggest CXCR4 gain of function mutations can be associated with cerebellar malformation, mild neuromotor and psychopathological dysfunction in WHIM patients.


Assuntos
Cerebelo/anormalidades , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/diagnóstico por imagem , Imagem por Ressonância Magnética , Transtornos Mentais/etiologia , Malformações do Sistema Nervoso/etiologia , Verrugas/complicações , Verrugas/diagnóstico por imagem , Adolescente , Adulto , Cerebelo/diagnóstico por imagem , Criança , Feminino , Mutação com Ganho de Função , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Pessoa de Meia-Idade , Receptores CXCR4/genética , Verrugas/genética , Verrugas/patologia , Adulto Jovem
3.
Int J Hematol ; 109(4): 382-389, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30758723

RESUMO

Mutation in the gene encoding tRNA nucleotidyl transferase, CCA-adding 1 (TRNT1), an enzyme essential for the synthesis of the 3'-terminal CCA sequence in tRNA molecules, results in a disorder that features sideroblastic anemia, B-cell immunodeficiency, periodic fever, and developmental delay. Mutations in TRNT1 are also linked to phenotypes including retinitis pigmentosa, cataracts, and cardiomyopathy. To date, it has remained unclear how defective TRNT1 is linked to B-cell deficiency. Here we report the case of a 12-year-old boy without sideroblastic anemia who harbors novel compound heterozygous mutations in TRNT1. Immunophenotypic analysis revealed severely decreased levels of B cells and follicular helper T cells. In the bone marrow, B-cell maturation stopped at the CD19+CD10+CD20+/- pre-B-cell stage. Severe combined immunodeficiency mice transplanted with bone marrow hematopoietic stem cells from the patient showed largely normal B-cell engraftment and differentiation in the bone marrow and periphery at 24 weeks post-transplantation, comparable to those in mouse transplanted with healthy hematopoietic stem cells. Biochemical analysis revealed augmented endoplasmic reticulum (ER) stress response in activated T cells. Peripheral B-cell deficiency of TRNT1 deficiency may be associated with augmented ER stress in immature B cells in the bone marrow.


Assuntos
Heterozigoto , Síndromes de Imunodeficiência , Nucleotidiltransferases , Antígenos CD/sangue , Antígenos CD/genética , Linfócitos B/metabolismo , Linfócitos B/patologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Lactente , Masculino , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Auxiliares-Indutores/patologia
4.
N Engl J Med ; 380(2): 163-170, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30625055

RESUMO

WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), a primary immunodeficiency disorder involving panleukopenia, is caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Myelokathexis is neutropenia caused by neutrophil retention in bone marrow. Patients with WHIM syndrome are often treated with granulocyte colony-stimulating factor (G-CSF), which can increase neutrophil counts but does not affect cytopenias other than neutropenia. In this investigator-initiated, open-label study, three severely affected patients with WHIM syndrome who could not receive G-CSF were treated with low-dose plerixafor, a CXCR4 antagonist, for 19 to 52 months. Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus-associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly. Adverse events were mainly infections attributable to the underlying immunodeficiency. One patient died from complications of elective reconstructive surgery. (Funded by the National Institutes of Health.).


Assuntos
Medula Óssea/patologia , Compostos Heterocíclicos/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Receptores CXCR4/antagonistas & inibidores , Verrugas/tratamento farmacológico , Exame de Medula Óssea , Evolução Fatal , Humanos , Síndromes de Imunodeficiência/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias de Células Escamosas/tratamento farmacológico , Neoplasias de Células Escamosas/genética , Fenótipo , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/patologia , Receptores CXCR4/genética , Verrugas/patologia
5.
J Clin Invest ; 129(1): 78-92, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30307408

RESUMO

Mutations in CDCA7 and HELLS that respectively encode a CXXC-type zinc finger protein and an SNF2 family chromatin remodeler cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome types 3 and 4. Here, we demonstrate that the classical nonhomologous end joining (C-NHEJ) proteins Ku80 and Ku70, as well as HELLS, coimmunoprecipitated with CDCA7. The coimmunoprecipitation of the repair proteins was sensitive to nuclease treatment and an ICF3 mutation in CDCA7 that impairs its chromatin binding. The functional importance of these interactions was strongly suggested by the compromised C-NHEJ activity and significant delay in Ku80 accumulation at DNA damage sites in CDCA7- and HELLS-deficient HEK293 cells. Consistent with the repair defect, these cells displayed increased apoptosis, abnormal chromosome segregation, aneuploidy, centrosome amplification, and significant accumulation of γH2AX signals. Although less prominent, cells with mutations in the other ICF genes DNMT3B and ZBTB24 (responsible for ICF types 1 and 2, respectively) showed similar defects. Importantly, lymphoblastoid cells from ICF patients shared the same changes detected in the mutant HEK293 cells to varying degrees. Although the C-NHEJ defect alone did not cause CG hypomethylation, CDCA7 and HELLS are involved in maintaining CG methylation at centromeric and pericentromeric repeats. The defect in C-NHEJ may account for some common features of ICF cells, including centromeric instability, abnormal chromosome segregation, and apoptosis.


Assuntos
Reparo do DNA por Junção de Extremidades , DNA Helicases/metabolismo , Metilação de DNA , Face/anormalidades , Síndromes de Imunodeficiência/metabolismo , Mutação , Proteínas Nucleares/metabolismo , Apoptose/genética , Centrômero/genética , Centrômero/metabolismo , Centrômero/patologia , Segregação de Cromossomos/genética , Ilhas de CpG , Dano ao DNA , DNA Helicases/genética , Face/patologia , Feminino , Células HEK293 , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Autoantígeno Ku/genética , Autoantígeno Ku/metabolismo , Masculino , Proteínas Nucleares/genética
6.
Diagn Microbiol Infect Dis ; 93(1): 69-73, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30174143

RESUMO

OBJECTIVE: Predictive factors associated with clinical outcomes of chronic norovirus infection (CNI) in primary immunodeficiency diseases (PIDD) are lacking. METHOD: We sought to characterize CNI using a multi-institutional cohort of patients with PIDD and CNI using the Clinical Immunology Society's CIS-PIDD Listserv e-mail group. RESULTS: Thirty-four subjects (21 males and 13 females) were reported from centers across North America, Europe, and Asia. All subjects were receiving high doses (median IgG dose: 1200 mg/kg/month) of supplemental immunoglobulin therapy. Fifty-three percent had a complete absence of B cells (median B-cell count 0; range 0-139 cells/µL). Common Variable Immune Deficiency (CVID) subjects manifested a unique phenotype with B-cell lymphopenia, non O+ blood type, and villous atrophy (logistic regression model, P = 0.01). Five subjects died, all of whom had no evidence of villous atrophy. CONCLUSION: While Norovirus (NoV) is thought to replicate in B cells, in this PIDD cohort of CNI, B-cell lymphopenia was common, indicating that the presence of B lymphocytes is not essential for CNI.


Assuntos
Infecções por Caliciviridae/imunologia , Síndromes de Imunodeficiência/virologia , Norovirus/fisiologia , Adolescente , Adulto , Linfócitos B/patologia , Infecções por Caliciviridae/mortalidade , Infecções por Caliciviridae/patologia , Doença Crônica , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/patologia , Imunodeficiência de Variável Comum/terapia , Imunodeficiência de Variável Comum/virologia , Feminino , Gastroenterite/imunologia , Gastroenterite/mortalidade , Gastroenterite/patologia , Humanos , Imunização Passiva , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/terapia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Norovirus/genética , Estudos Retrospectivos , Adulto Jovem
7.
J Clin Immunol ; 39(1): 45-54, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30547383

RESUMO

Studies of chest computed tomography (CT) in patients with primary antibody deficiency syndromes (ADS) suggest a broad range of bronchial pathology. However, there are as yet no multicentre studies to assess the variety of bronchial pathology in this patient group. One of the underlying reasons is the lack of a consensus methodology, a prerequisite to jointly document chest CT findings. We aimed to establish an international platform for the evaluation of bronchial pathology as assessed by chest CT and to describe the range of bronchial pathologies in patients with antibody deficiency. Ffteen immunodeficiency centres from 9 countries evaluated chest CT scans of patients with ADS using a predefined list of potential findings including an extent score for bronchiectasis. Data of 282 patients with ADS were collected. Patients with common variable immunodeficiency disorders (CVID) comprised the largest subgroup (232 patients, 82.3%). Eighty percent of CVID patients had radiological evidence of bronchial pathology including bronchiectasis in 61%, bronchial wall thickening in 44% and mucus plugging in 29%. Bronchiectasis was detected in 44% of CVID patients aged less than 20 years. Cough was a better predictor for bronchiectasis than spirometry values. Delay of diagnosis as well as duration of disease correlated positively with presence of bronchiectasis. The use of consensus diagnostic criteria and a pre-defined list of bronchial pathologies allows for comparison of chest CT data in multicentre studies. Our data suggest a high prevalence of bronchial pathology in CVID due to late diagnosis or duration of disease.


Assuntos
Brônquios/patologia , Síndromes de Imunodeficiência/patologia , Parede Torácica/patologia , Adolescente , Adulto , Idoso , Bronquiectasia/patologia , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/patologia , Feminino , Humanos , Lactente , Masculino , Espirometria/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto Jovem
8.
J Allergy Clin Immunol ; 143(1): 266-275, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29778502

RESUMO

BACKGROUND: Activated phosphatidylinositol-3-OH kinase δ syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory tract infections, lymphoid hyperplasia, and Herpesviridae infections caused by germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) can be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, methods, and outcomes of HSCT for APDS1 remain undefined. OBJECTIVE: Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT. METHODS: We reviewed retrospectively the medical records of cohorts undergoing HSCT at collaborating facilities. RESULTS: Thirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced-intensity conditioning. Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT. CONCLUSION: Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based reduced-intensity conditioning-HSCT ameliorated clinical symptoms, but transplantation-related complications were frequent, including graft failure.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência , Transtornos Linfoproliferativos , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Intervalo Livre de Doença , Feminino , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/mortalidade , Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/terapia , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/mortalidade , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/terapia , Masculino , Taxa de Sobrevida
9.
Dig Dis ; 37(1): 45-52, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30153682

RESUMO

BACKGROUND: It has been reported that 5-50% of patients with primary immune deficiencies (PID) may present with or develop gastrointestinal (GI) manifestations. OBJECTIVE: This study was aimed at analyzing GI and related endoscopic, histopathological findings in children with PID. METHODS: Children with PID who were evaluated by endoscopy between 2005 and 2016 were enrolled in this study. Demographic data, growth parameters, signs and symptoms at diagnosis were obtained. RESULTS: Of 425 children with PID, 195 had GI manifestations. Forty-seven of 195 children required endoscopic investigation, 30 (63.8%) were male, and the mean age was 7.7 ± 5 years. The rate of consanguinity was 61.7%, and the most common symptom was chronic diarrhea (57.4%). Seventy-two percent of the patients were malnourished. Giardia intestinalis was detected in 4, and Helicobacter pylori was confirmed in 8/45 (17.7%) patients. Non-celiac villous flatting was discovered in 15.5% of patients. Twelve patients were diagnosed as having immunodeficiency associated inflammatory bowel disease (IBD)-like colitis. CONCLUSIONS: PID may present with GI manifestations or develop during the course of the disease. Investigating immunodeficiency in patients with atypical GI symptoms can provide an appropriate therapeutic option, and an improved quality of life, particularly in populations with a high rate of consanguinity.


Assuntos
Gastroenteropatias/complicações , Gastroenteropatias/imunologia , Síndromes de Imunodeficiência/complicações , Adolescente , Criança , Pré-Escolar , Endoscopia , Feminino , Gastroenteropatias/patologia , Humanos , Síndromes de Imunodeficiência/patologia , Lactente , Masculino , Fenótipo , Qualidade de Vida
10.
J Allergy Clin Immunol ; 143(1): 325-334.e2, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29906526

RESUMO

BACKGROUND: V(D)J recombination ensures the diversity of the adaptive immune system. Although its complete defect causes severe combined immunodeficiency (ie, T-B- severe combined immunodeficiency), its suboptimal activity is associated with a broad spectrum of immune manifestations, such as late-onset combined immunodeficiency and autoimmunity. The earliest molecular diagnosis of these patients is required to adopt the best therapy strategy, particularly when it involves a myeloablative conditioning regimen for hematopoietic stem cell transplantation. OBJECTIVE: We aimed at developing biomarkers based on analysis of the T-cell receptor (TCR) α repertoire to assist in the diagnosis of patients with primary immunodeficiencies with V(D)J recombination and DNA repair deficiencies. METHODS: We used flow cytometric (fluorescence-activated cell sorting) analysis to quantify TCR-Vα7.2-expressing T lymphocytes in peripheral blood and developed PROMIDISα, a multiplex RT-PCR/next-generation sequencing assay, to evaluate a subset of the TCRα repertoire in T lymphocytes. RESULTS: The combined fluorescence-activated cell sorting and PROMIDISα analyses revealed specific signatures in patients with V(D)J recombination-defective primary immunodeficiencies or ataxia telangiectasia/Nijmegen breakage syndromes. CONCLUSION: Analysis of the TCRα repertoire is particularly appropriate in a prospective way to identify patients with partial immune defects caused by suboptimal V(D)J recombination activity, a DNA repair defect, or both. It also constitutes a valuable tool for the retrospective in vivo functional validation of variants identified through exome or panel sequencing. Its broader implementation might be of interest to assist early diagnosis of patients presenting with hypomorphic DNA repair defects inclined to experience acute toxicity during prehematopoietic stem cell transplantation conditioning.


Assuntos
Síndromes de Imunodeficiência , Receptores de Antígenos de Linfócitos T alfa-beta , Recombinação V(D)J/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Estudos Retrospectivos
11.
J Exp Med ; 215(12): 3151-3164, 2018 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-30498080

RESUMO

Primary immunodeficiencies represent naturally occurring experimental models to decipher human immunobiology. We report a patient with combined immunodeficiency, marked by recurrent respiratory tract and DNA-based viral infections, hypogammaglobulinemia, and panlymphopenia. He also developed moderate neutropenia but without prototypical pyogenic infections. Using whole-exome sequencing, we identified a homozygous mutation in the inducible T cell costimulator ligand gene (ICOSLG; c.657C>G; p.N219K). Whereas WT ICOSL is expressed at the cell surface, the ICOSLN219K mutation abrogates surface localization: mutant protein is retained in the endoplasmic reticulum/Golgi apparatus, which is predicted to result from deleterious conformational and biochemical changes. ICOSLN219K diminished B cell costimulation of T cells, providing a compelling basis for the observed defect in antibody and memory B cell generation. Interestingly, ICOSLN219K also impaired migration of lymphocytes and neutrophils across endothelial cells, which normally express ICOSL. These defects likely contributed to the altered adaptive immunity and neutropenia observed in the patient, respectively. Our study identifies human ICOSLG deficiency as a novel cause of a combined immunodeficiency.


Assuntos
Síndromes de Imunodeficiência , Ligante Coestimulador de Linfócitos T Induzíveis/deficiência , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Linfócitos B/imunologia , Linfócitos B/patologia , Linhagem Celular Transformada , Células Endoteliais/imunologia , Células Endoteliais/patologia , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Memória Imunológica , Ligante Coestimulador de Linfócitos T Induzíveis/imunologia , Masculino , Linfócitos T/imunologia , Linfócitos T/patologia , Sequenciamento Completo do Genoma
12.
Front Immunol ; 9: 2741, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30534129

RESUMO

Leptin, a pleiotropic protein has long been recognized to play an important role in the regulation of energy homeostasis, metabolism, neuroendocrine function, and other physiological functions through its effects on the central nervous system (CNS) and peripheral tissues. Leptin is secreted by adipose tissue and encoded by the obese (ob) gene. Leptin acts as a central mediator which regulates immunity as well as nutrition. Importantly, leptin can modulate both innate and adaptive immune responses. Leptin deficiency/resistance is associated with dysregulation of cytokine production, increased susceptibility toward infectious diseases, autoimmune disorders, malnutrition and inflammatory responses. Malnutrition induces a state of immunodeficiency and an inclination to death from communicable diseases. Infectious diseases are the disease of poor who invariably suffer from malnutrition that could result from reduced serum leptin levels. Thus, leptin has been placed at the center of many interrelated functions in various pathogenic conditions, such as bacterial, viruses and parasitic infections. We review herein, the recent advances on the role of leptin in malnutrition in pathogenesis of infectious diseases with a particular emphasis on parasitic diseases such as Leishmaniasis, Trypanosomiasis, Amoebiasis, and Malaria.


Assuntos
Doenças Autoimunes/imunologia , Doenças Transmissíveis/imunologia , Síndromes de Imunodeficiência/imunologia , Leptina/imunologia , Desnutrição/imunologia , Imunidade Adaptativa , Animais , Doenças Autoimunes/patologia , Doenças Transmissíveis/patologia , Humanos , Imunidade Inata , Síndromes de Imunodeficiência/patologia , Desnutrição/patologia
13.
Elife ; 72018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30484769

RESUMO

Pericentromeric satellite repeats are enriched in 5-methylcytosine (5mC). Loss of 5mC at these sequences is common in cancer and is a hallmark of Immunodeficiency, Centromere and Facial abnormalities (ICF) syndrome. While the general importance of 5mC is well-established, the specific functions of 5mC at pericentromeres are less clear. To address this deficiency, we generated a viable animal model of pericentromeric hypomethylation through mutation of the ICF-gene ZBTB24. Deletion of zebrafish zbtb24 caused a progressive loss of 5mC at pericentromeres and ICF-like phenotypes. Hypomethylation of these repeats triggered derepression of pericentromeric transcripts and activation of an interferon-based innate immune response. Injection of pericentromeric RNA is sufficient to elicit this response in wild-type embryos, and mutation of the MDA5-MAVS dsRNA-sensing machinery blocks the response in mutants. These findings identify activation of the innate immune system as an early consequence of pericentromeric hypomethylation, implicating derepression of pericentromeric transcripts as a trigger of autoimmunity. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).


Assuntos
Centrômero , Metilação de DNA , Face/anormalidades , Síndromes de Imunodeficiência/patologia , Interferons/metabolismo , Animais , Modelos Animais de Doenças , Face/patologia , Técnicas de Inativação de Genes , Imunidade Inata , Peixe-Zebra
14.
Orphanet J Rare Dis ; 13(1): 207, 2018 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-30445974

RESUMO

BACKGROUND: Patients with cartilage-hair hypoplasia (CHH), a rare metaphyseal chondrodysplasia, manifest severe growth failure, variable immunodeficiency and increased risk of malignancies. The impact of CHH on gynecologic and reproductive health is unknown. Vulnerability to genital infections may predispose CHH patients to prolonged human papillomavirus (HPV) infections potentially leading to cervical, vaginal and vulvar cancer. METHODS: We carried out gynecologic evaluation, pelvic ultrasound and laboratory assessment in 19 women with genetically confirmed CHH. All patients were clinically examined and retrospective data were collected from hospital records. RESULTS: The women ranged in age from 19.2 to 70.8 years (median 40.8 years) and in height from 103 to 150 cm (median 123 cm). All women had undergone normal pubertal development as assessed by breast development according to Tanner scale and by age of menarche (mean 12.5 yrs., range 11-14 yrs). Despite significant short stature and potentially small pelvic diameters, a well-developed uterus with fairly normal size and shape was found by pelvic ultrasound in most of the patients. Ovarian follicle reserve, assessed by ultrasound was normal in relation to age in all premenopausal women it could be assessed (12 cases). Anti-Müllerian hormone was normal in relation to age in 17 women (89%). HPV was detected in 44% (8/18) and three women carried more than one HPV serotype; findings did not associate with immunological parameters. Three patients had a concurrent cell atypia in Pap smear. CONCLUSIONS: Pubertal development, reproductive hormones and ovarian structure and function were usually normal in women with CHH suggesting fairly normal reproductive health. However, the immunodeficiency characteristic to CHH may predispose the patients to HPV infections. High prevalence of HPV infections detected in this series highlights the importance of careful gynecologic follow up of these patients.


Assuntos
Cabelo/anormalidades , Doença de Hirschsprung/patologia , Doença de Hirschsprung/virologia , Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/virologia , Osteocondrodisplasias/congênito , Papillomaviridae/patogenicidade , Adulto , Idoso , Feminino , Genótipo , Cabelo/patologia , Cabelo/virologia , Doença de Hirschsprung/genética , Humanos , Síndromes de Imunodeficiência/genética , Pessoa de Meia-Idade , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Osteocondrodisplasias/virologia , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Estudos Retrospectivos , Sorogrupo
15.
Nat Med ; 24(12): 1815-1821, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30397357

RESUMO

Human microbiome studies have revealed the intricate interplay of host immunity and bacterial communities to achieve homeostatic balance. Healthy skin microbial communities are dominated by bacteria with low viral representation1-3, mainly bacteriophage. Specific eukaryotic viruses have been implicated in both common and rare skin diseases, but cataloging skin viral communities has been limited. Alterations in host immunity provide an opportunity to expand our understanding of microbial-host interactions. Primary immunodeficient patients manifest with various viral, bacterial, fungal, and parasitic infections, including skin infections4. Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare primary human immunodeficiency characterized by recurrent cutaneous and systemic infections, as well as atopy and cancer susceptibility5. DOCK8, encoding a guanine nucleotide exchange factor highly expressed in lymphocytes, regulates actin cytoskeleton, which is critical for migration through collagen-dense tissues such as skin6. Analyzing deep metagenomic sequencing data from DOCK8-deficient skin samples demonstrated a notable increase in eukaryotic viral representation and diversity compared with healthy volunteers. De novo assembly approaches identified hundreds of novel human papillomavirus genomes, illuminating microbial dark matter. Expansion of the skin virome in DOCK8-deficient patients underscores the importance of immune surveillance in controlling eukaryotic viral colonization and infection.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Síndromes de Imunodeficiência/virologia , Dermatopatias/virologia , Pele/virologia , Adolescente , Bacteriófagos/genética , Criança , Feminino , Genoma Viral/genética , Fatores de Troca do Nucleotídeo Guanina/deficiência , Voluntários Saudáveis , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunidade/genética , Síndromes de Imunodeficiência/microbiologia , Síndromes de Imunodeficiência/patologia , Linfócitos/virologia , Masculino , Metagenoma/genética , Metagenoma/imunologia , Microbiota/genética , Papillomaviridae/isolamento & purificação , Papillomaviridae/patogenicidade , Pele/microbiologia , Dermatopatias/genética , Dermatopatias/microbiologia , Dermatopatias/patologia
16.
Curr Opin Allergy Clin Immunol ; 18(6): 470-480, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30299396

RESUMO

PURPOSE OF REVIEW: To summarize the current understanding and recent advances on the genetic aetiology in the pathogenesis of very early onset inflammatory bowel disease (VEO-IBD). RECENT FINDINGS: IBD is a chronic disorder of the gastrointestinal tract whose manifestation is a result of complex interactions between genetics, environment, immune system and microbial flora. Over 230 IBD risk loci have been reported in genome wide association studies but the genetic contribution of the majority of these loci in the manifestation of IBD is very low. Patients with VEO-IBD present with a more severe disease than older patients, characterized by poor prognosis and failure of conventional therapy. Recent studies have reported several monogenic diseases with high penetrance that present with IBD and IBD-like intestinal manifestations and overlap with primary immunodeficiencies. Increasing body of evidence supports a prominent role of genetics in the onset of VEO-IBD. New genetic variants and diagnoses in VEO-IBD are reviewed and current challenges in therapy with potential strategy to manage the disease are discussed. SUMMARY: Functional analysis of the genes implicated in monogenic IBD has increased the understanding of the underlying pathobiological mechanism of the disease. This knowledge can be used to personalize medicine for specific patients, improving the standard of care and quality of life.


Assuntos
Predisposição Genética para Doença , Doenças Inflamatórias Intestinais , Qualidade de Vida , Estudo de Associação Genômica Ampla , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia
17.
Pediatr Dermatol ; 35(6): 780-783, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30338556

RESUMO

BACKGROUND/OBJECTIVES: Silvery hair syndrome is a rare, autosomal-recessive entity characterized by silvery gray hair, eyebrows, and eyelashes and may be associated or not with immunologic or neurologic alterations. Two main types have been recognized: Chediak-Higashi syndrome and Griscelli syndrome. Hair shaft examination under light microscopy has been a useful tool to differentiate Chediak-Higashi syndrome from Griscelli syndrome, although distribution of melanin varies according to hair color related to ethnicity. The objective was to compare the pattern of melanin in the skin and with the pattern of melanin distribution in the hair shaft. METHODS: Sixteen patients with silvery hair syndrome were selected (Chediak-Higashi syndrome 5, Griscelli syndrome 11). The distribution of melanin granules in skin and hair shafts was compared and correlated with clinical diagnoses. RESULTS: Chediak-Higashi syndrome was characterized by small granules of melanin uniformly distributed throughout the thickness of the epidermis. Griscelli syndrome was characterized by an irregular pigment distribution in the epidermal basal layer with large and dense granules alternating with areas lacking melanin pigment. In two cases, study of the hair was not conclusive, but the skin showed the characteristic pattern of Griscelli syndrome. CONCLUSION: Skin biopsy is a useful tool in differentiating Chediak-Higashi syndrome from Griscelli syndrome and as a complementary study in cases in which hair shaft pigment distribution does not support the diagnosis, especially in patients with fair hair. The distribution of melanin granules in the skin correlates with that observed in the hair shaft, allowing Chediak-Higashi syndrome to be differentiated from Griscelli syndrome, at any age.


Assuntos
Síndrome de Chediak-Higashi/diagnóstico , Cabelo/patologia , Perda Auditiva Neurossensorial/diagnóstico , Síndromes de Imunodeficiência/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Piebaldismo/diagnóstico , Transtornos da Pigmentação/diagnóstico , Adolescente , Biópsia , Síndrome de Chediak-Higashi/patologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Perda Auditiva Neurossensorial/patologia , Humanos , Síndromes de Imunodeficiência/patologia , Lactente , Recém-Nascido , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , Piebaldismo/patologia , Transtornos da Pigmentação/patologia , Estudos Retrospectivos , Pele/patologia
18.
Blood ; 132(22): 2362-2374, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30254128

RESUMO

ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complex that is involved in actin branching from an existing filament. Germline biallelic mutations in ARPC1B have been recently described in 6 patients with clinical features of combined immunodeficiency (CID), whose neutrophils and platelets but not T lymphocytes were studied. We hypothesized that ARPC1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in ARPC1B in 6 unrelated patients with early onset disease characterized by severe infections, autoimmune manifestations, and thrombocytopenia. Immunological features included T-cell lymphopenia, low numbers of naïve T cells, and hyper-immunoglobulin E. Alteration in ARPC1B protein structure led to absent/low expression by flow cytometry and confocal microscopy. This molecular defect was associated with the inability of patient-derived T cells to extend an actin-rich lamellipodia upon T-cell receptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cells additionally displayed impaired TCR-mediated proliferation and SDF1-α-directed migration. Gene transfer of ARPC1B in patients' T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In 1 revertant patient, memory CD8+ T cells expressing normal levels of ARPC1B displayed improved T-cell migration. Inherited ARPC1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID.


Assuntos
Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Mutação em Linhagem Germinativa , Síndromes de Imunodeficiência/genética , Linfócitos T/patologia , Complexo 2-3 de Proteínas Relacionadas à Actina/química , Feminino , Homozigoto , Humanos , Síndromes de Imunodeficiência/patologia , Masculino , Modelos Moleculares , Linhagem , Conformação Proteica , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/patologia , Linfócitos T/metabolismo
19.
J Exp Med ; 215(10): 2485-2496, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30194267

RESUMO

Activated PI3K-delta syndrome (APDS) is an immunodeficiency caused by gain-of-function mutations in PIK3CD. This disease exhibits complex immune phenotypes including increased IgM, recurrent infection, and impaired vaccine responses. To better understand the impact of B cells in this disease, we generated an inducible model of the common APDS mutation (hPIK3CD-E1021K; referred to as aPIK3CD) and intercrossed these mice with B cell-specific Cre models. Mb1-aPIK3CD mice exhibited bone marrow B lymphopenia and, conversely, expansion of the peripheral innate B1a and MZ B cell compartments. aPIK3CD B cells manifest increased pS6 and increased survival at several stages, without alterations in cycling, and baseline increases in plasma cells, natural IgM, and IgG3. Finally, Mb1-aPIK3CD mice exhibited blunted T cell-independent immune responses, and both AID- and CD21-aPIK3CD mice displayed reduced class-switched antibodies following T cell-dependent immunization. Thus, aPIK3CD alters B cell development and function and is counter-productive during immune responses, providing insight into B cell-intrinsic contributions to the APDS phenotype.


Assuntos
Mutação com Ganho de Função , Doenças Genéticas Inatas/imunologia , Imunidade Inata , Síndromes de Imunodeficiência/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Plasmócitos/imunologia , Animais , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Ativação Enzimática/genética , Ativação Enzimática/imunologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Camundongos , Camundongos Knockout , Fosfatidilinositol 3-Quinases/genética , Plasmócitos/patologia
20.
Blood ; 132(18): 1871-1878, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30082493

RESUMO

Immunodeficiency-associated lymphoproliferative disorders (IA-LPDs) are pathologically and clinically heterogeneous. In many instances, similar features are shared by a spectrum of IA-LPDs in clinically diverse settings. However, the World Health Organization (WHO) classifies IA-LPDs by their immunodeficiency setting largely according to the paradigm of posttransplant lymphoproliferative disorders but with inconsistent terminology and disease definitions. The field currently lacks standardization and would greatly benefit from thinking across immunodeficiency categories by adopting a common working vocabulary to better understand these disorders and guide clinical management. We propose a 3-part unifying nomenclature that includes the name of the lesion, associated virus, and the specific immunodeficiency setting for all IA-LPDs. B-cell lymphoproliferative disorders (LPDs) are usually Epstein-Barr virus (EBV)+ and show a spectrum of lesions, including hyperplasias, polymorphic LPDs, aggressive lymphomas, and, rarely, indolent lymphomas. Human herpes virus 8-associated LPDs also include polyclonal and monoclonal proliferations. EBV- B-cell LPDs and T- and NK-cell LPDs are rare and less well characterized. Recognition of any immunodeficiency is important because it impacts the choice of treatment options. There is an urgent need for reappraisal of IA-LPDs because a common framework will facilitate meaningful biological insights and pave the way for future work in the field.


Assuntos
Síndromes de Imunodeficiência/complicações , Transtornos Linfoproliferativos/etiologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/patologia , Infecções por Herpesviridae/complicações , Infecções por Herpesviridae/patologia , Herpesvirus Humano 4/isolamento & purificação , Herpesvirus Humano 8/isolamento & purificação , Humanos , Síndromes de Imunodeficiência/classificação , Síndromes de Imunodeficiência/patologia , Células Matadoras Naturais/patologia , Transtornos Linfoproliferativos/classificação , Transtornos Linfoproliferativos/patologia , Linfócitos T/patologia
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