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1.
Front Pediatr ; 7: 390, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31709200

RESUMO

A subset of patients with Ataxia-Telangiectasia (A-T) have dramatically reduced levels of IgG, IgA, and IgE with retained or elevated IgM levels. Several reports suggest that these A-T patients with a "hyper-IgM phenotype" (HIgM) suffer more clinical immunologic consequences than other A-T patients. The immunopathologic mechanism driving this phenomenon is unknown, making it difficult to predict response to immunomodulatory therapy. We describe an A-T patient with HIgM who underwent tumor necrosis factor (TNF) receptor blockade for cutaneous granuloma and after several months of successful therapy developed non-malignant lymphoproliferation, cytopenia, and increased serum immunoglobulin levels. This process was subsequently followed by an immune-complex-mediated intrarenal small vessel vasculitis that led to renal failure. The vasculitis was successfully treated with rituximab and corticosteroids. This case underscores the importance of HIgM as an unfavorable prognostic indicator in A-T and highlights the complexity of immunomodulatory treatment in this population, and the potential for a successful approach tailored to the immune defect.

2.
Am J Hum Genet ; 105(3): 549-561, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31447097

RESUMO

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.

3.
J Clin Invest ; 128(12): 5489-5504, 2018 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-30395541

RESUMO

We report the molecular, cellular, and clinical features of 5 patients from 3 kindreds with biallelic mutations in the autosomal LIG1 gene encoding DNA ligase 1. The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating γδT cells, and erythrocyte macrocytosis. Clinical severity ranged from a mild antibody deficiency to a combined immunodeficiency requiring hematopoietic stem cell transplantation. Using engineered LIG1-deficient cell lines, we demonstrated chemical and radiation defects associated with the mutant alleles, which variably impaired the DNA repair pathway. We further showed that these LIG1 mutant alleles are amorphic or hypomorphic, and exhibited variably decreased enzymatic activities, which lead to premature release of unligated adenylated DNA. The variability of the LIG1 genotypes in the patients was consistent with that of their immunological and clinical phenotypes. These data suggest that different forms of autosomal recessive, partial DNA ligase 1 deficiency underlie an immunodeficiency of variable severity.


Assuntos
Alelos , DNA Ligase Dependente de ATP , Síndromes de Imunodeficiência , Mutação , DNA Ligase Dependente de ATP/genética , DNA Ligase Dependente de ATP/imunologia , Células HEK293 , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia
4.
J Autoimmun ; 88: 114-120, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29129473

RESUMO

A genetic variant in the SAND domain of autoimmune regulator (AIRE), R247C, was identified in a patient with type I diabetes mellitus (T1DM) and his mother with rheumatoid arthritis. In vitro, the variant dominantly inhibited AIRE; however, typical features of Autoimmune Polyendocrinopathy Candidiasis and Ectodermal Dysplasia (APECED) were not seen in the subjects. Rather, early manifestation of autoimmunity appeared to be dependent on additional genetic factors. On a population level, diverse variants were identified in this region. Surprisingly, many likely pathogenic variants were seen disproportionately in Africans when compared to Europeans, reinforcing the importance of these variants in altering the immune repertoire. In light of these findings, we propose that R247C and other variants within the SAND-domain alter protein function in a dominant fashion and hold potential as drivers of autoimmunity.


Assuntos
Diabetes Mellitus Tipo 1/genética , Poliendocrinopatias Autoimunes/genética , Fatores de Transcrição/genética , Adolescente , Grupo com Ancestrais do Continente Africano/genética , Autoimunidade/genética , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Células HEK293 , Humanos , Mutação com Perda de Função , Masculino , Linhagem , Polimorfismo Genético , Domínios Proteicos/genética
6.
J Exp Med ; 214(7): 1949-1972, 2017 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-28606988

RESUMO

MDA5 is a cytosolic sensor of double-stranded RNA (ds)RNA including viral byproducts and intermediates. We studied a child with life-threatening, recurrent respiratory tract infections, caused by viruses including human rhinovirus (HRV), influenza virus, and respiratory syncytial virus (RSV). We identified in her a homozygous missense mutation in IFIH1 that encodes MDA5. Mutant MDA5 was expressed but did not recognize the synthetic MDA5 agonist/(ds)RNA mimic polyinosinic-polycytidylic acid. When overexpressed, mutant MDA5 failed to drive luciferase activity from the IFNB1 promoter or promoters containing ISRE or NF-κB sequence motifs. In respiratory epithelial cells or fibroblasts, wild-type but not knockdown of MDA5 restricted HRV infection while increasing IFN-stimulated gene expression and IFN-ß/λ. However, wild-type MDA5 did not restrict influenza virus or RSV replication. Moreover, nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV. Thus, human MDA5 deficiency is a novel inborn error of innate and/or intrinsic immunity that causes impaired (ds)RNA sensing, reduced IFN induction, and susceptibility to the common cold virus.


Assuntos
Helicase IFIH1 Induzida por Interferon/genética , Mutação , Infecções por Picornaviridae/genética , Infecções por Picornaviridae/virologia , Rhinovirus/fisiologia , Antivirais/farmacologia , Sequência de Bases , Células Cultivadas , Pré-Escolar , Análise Mutacional de DNA/métodos , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/virologia , Expressão Gênica/efeitos dos fármacos , Genes Recessivos/genética , Heterozigoto , Homozigoto , Interações Hospedeiro-Patógeno , Humanos , Helicase IFIH1 Induzida por Interferon/deficiência , Interferons/farmacologia , Masculino , Linhagem
7.
Nat Genet ; 49(8): 1192-1201, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28628108

RESUMO

Few monogenic causes for severe manifestations of common allergic diseases have been identified. Through next-generation sequencing on a cohort of patients with severe atopic dermatitis with and without comorbid infections, we found eight individuals, from four families, with novel heterozygous mutations in CARD11, which encodes a scaffolding protein involved in lymphocyte receptor signaling. Disease improved over time in most patients. Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor-induced activation of nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1). Patient T cells had similar defects, as well as low production of the cytokine interferon-γ (IFN-γ). The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells. Our findings indicate that a single hypomorphic mutation in CARD11 can cause potentially correctable cellular defects that lead to atopic dermatitis.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Dermatite Atópica/genética , Mutação em Linhagem Germinativa , Guanilato Ciclase/genética , Sistema ASC de Transporte de Aminoácidos/metabolismo , Estudos de Coortes , Análise Mutacional de DNA , Dermatite Atópica/imunologia , Feminino , Genes Dominantes , Glutamina/metabolismo , Humanos , Células Jurkat , Ativação Linfocitária , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Antígenos de Histocompatibilidade Menor/metabolismo , Complexos Multiproteicos/metabolismo , NF-kappa B/metabolismo , Linhagem , Linfócitos T/imunologia , Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/metabolismo
8.
J Pediatric Infect Dis Soc ; 6(3): e140-e143, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28339562

RESUMO

We performed a retrospective chart review for all cases of recurrent Stevens Johnson Syndrome (SJS) from March 2013 to March 2016. Nine children had 29 episodes of SJS or incomplete SJS; all children were male and 8 (88%) were white. Episodes affected mucus membranes with minimal skin involvement. Mycoplasma infections and HLA-B27/-B51 were common.


Assuntos
Síndrome de Stevens-Johnson/etiologia , Síndrome de Stevens-Johnson/microbiologia , Adolescente , Criança , Pré-Escolar , Chlamydophila pneumoniae/isolamento & purificação , Chlamydophila pneumoniae/patogenicidade , Grupos Étnicos , Humanos , Inflamação , Masculino , Mucosa Bucal , Infecções por Mycoplasma , Mycoplasma pneumoniae/isolamento & purificação , Mycoplasma pneumoniae/patogenicidade , Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/imunologia
9.
J Allergy Clin Immunol ; 139(4): 1282-1292, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27697500

RESUMO

BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. OBJECTIVES: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. METHODS: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. RESULTS: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. CONCLUSION: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.


Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Síndrome de Imunodeficiência com Hiper-IgM/mortalidade , Síndrome de Imunodeficiência com Hiper-IgM/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Tempo , Adulto Jovem
10.
J Allergy Clin Immunol ; 139(4): 1331-1342, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27542981

RESUMO

BACKGROUND: Regulatory T cells attenuate development of asthma in wild-type (WT) mice, with both naturally occurring regulatory T (nTreg) cells and inducible regulatory T (iTreg) cells exhibiting suppressive activity. When transferred into CD8-deficient (CD8-/-) recipients, both cell types enhanced development of allergen-induced airway hyperresponsiveness. OBJECTIVE: We sought to determine whether the pathways leading to enhancement of lung allergic responses by transferred nTreg and iTreg cells differed. METHODS: nTreg cells (CD4+CD25+) were isolated from WT mice and iTreg cells were generated from WT CD4+CD25- T cells after activation in the presence of TGF-ß and transferred into sensitized CD8-/- recipients before challenge. Development of airway hyperresponsiveness, cytokine levels, and airway inflammation were monitored. RESULTS: Transfer of nTreg cells enhanced lung allergic responses, as did transfer of iTreg cells. Although anti-IL-13 reduced nTreg cell-mediated enhancement, it was ineffective in iTreg cell-mediated enhancement; conversely, anti-IL-17, but not anti-IL-13, attenuated the enhancement by iTreg cells. Recovered iTreg cells from the lungs of CD8-/- recipients were capable of IL-17 production and expressed high levels of signature genes of the TH17 pathway, RORγt and Il17, whereas reduced expression of the Treg cell key transcription factor forkhead box p3 (Foxp3) was observed. In vitro exogenous IL-6-induced IL-17 production in iTreg cells, and in vivo conversion of transferred iTreg cells was dependent on recipient IL-6. CONCLUSIONS: iTreg cells, similar to nTreg cells, exhibit functional plasticity and can be converted from suppressor cells to pathogenic effector cells, enhancing lung allergic responses, but these effects were mediated through different pathways.


Assuntos
Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Citocinas/biossíntese , Citocinas/imunologia , Modelos Animais de Doenças , Citometria de Fluxo , Hipersensibilidade/imunologia , Pulmão/citologia , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real
11.
Immunol Allergy Clin North Am ; 35(4): 637-58, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26454311

RESUMO

Common variable immunodeficiency (CVID) refers to a grouping of antibody deficiencies that lack a more specific genetic or phenotypic classification. It is the immunodeficiency classification with the greatest number of constituents, likely because of the numerous ways in which antibody production can be impaired and the frequency in which antibody production becomes impaired in human beings. CVID comprises a heterogeneous group of rare diseases. Consequently, CVID presents a significant challenge for researchers and clinicians. Despite these difficulties, both our understanding of and ability to manage this grouping of complex immune diseases has advanced significantly over the past 60 years.


Assuntos
Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/terapia , Imunodeficiência de Variável Comum/etiologia , Imunodeficiência de Variável Comum/metabolismo , Diagnóstico Diferencial , Gerenciamento Clínico , Humanos
12.
J Clin Immunol ; 35(2): 189-98, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25627830

RESUMO

Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.


Assuntos
Estudos de Associação Genética , Fatores de Troca do Nucleotídeo Guanina/deficiência , Fatores de Troca do Nucleotídeo Guanina/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Incidência , Lactente , /epidemiologia , Síndrome de Job/complicações , Síndrome de Job/diagnóstico , Síndrome de Job/genética , Síndrome de Job/imunologia , Síndrome de Job/mortalidade , Síndrome de Job/terapia , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias/epidemiologia , Neoplasias/etiologia , Fenótipo , Adulto Jovem
13.
JAMA ; 312(7): 729-38, 2014 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-25138334

RESUMO

IMPORTANCE: Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100,000 births. OBJECTIVES: To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments. DESIGN: Epidemiological and retrospective observational study. SETTING: Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3,030,083 newborns screened with a TREC test. MAIN OUTCOMES AND MEASURES: Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked. RESULTS: Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58,000 infants (95% CI, 1/46,000-1/80,000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87% (45/52), 92% (45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia. CONCLUSIONS AND RELEVANCE: Newborn screening in 11 programs in the United States identified SCID in 1 in 58,000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.


Assuntos
Linfopenia/diagnóstico , Triagem Neonatal/métodos , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/epidemiologia , Feminino , Humanos , Incidência , Recém-Nascido , Masculino , Prognóstico , Receptores de Antígenos de Linfócitos T/genética , Estudos Retrospectivos , Imunodeficiência Combinada Severa/terapia , Análise de Sobrevida , Linfócitos T/imunologia , Estados Unidos
14.
Laryngoscope ; 124(11): 2568-73, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24984601

RESUMO

OBJECTIVES/HYPOTHESIS: Paradoxical vocal fold motion and exercise-induced paradoxical vocal fold motion (EIPVFM) are two related conditions that do not have definitive diagnostic criteria. Much of the EIPVFM literature describes patients with characteristic physiologic findings of severe upper airway obstruction or obvious airflow limitation in the clinical context of exertional dyspnea with audible stridor. The objective of this study was to highlight a group of patients who demonstrate important clinical findings of EIPVFM (exertional dyspnea with audible stridor) without simultaneously definitive physiologic findings (mild glottic adduction and normal flow volume loops). STUDY DESIGN: Retrospective medical record review. METHODS: We reviewed the records of 150 patients who performed continuous laryngoscopy during exercise for inclusion in a case series. We excluded patients for technical (incomplete records) and physiologic (extremes of disease severity) reasons. Three blinded physicians (practicing in laryngology, pulmonology, and allergy/immunology) independently evaluated isolated audio tracks, video tracks, and flow volume loops of the remaining patients for the presence or absence of stridor, the glottic configuration, and the presence or absence of inspiratory limitation on exercise flow volume loops at peak work capacity. RESULTS: Exercise laryngoscopy and flow volume loops were fully evaluated for 23 patients. Five patients with exertional dyspnea were unanimously described as having audible stridor, open glottic configuration, and normal flow volume loops. CONCLUSIONS: EIPVFM can occur in the absence of widely recognized confirmatory physiologic measures. Improved quantitative metrics are needed to better characterize patients with EIPVFM. LEVEL OF EVIDENCE: 4.


Assuntos
Teste de Esforço/efeitos adversos , Laringoscopia/métodos , Sons Respiratórios/diagnóstico , Sons Respiratórios/etiologia , Disfunção da Prega Vocal/etiologia , Adolescente , Asma Induzida por Exercício/diagnóstico , Índice de Massa Corporal , Teste de Esforço/métodos , Feminino , Glote/fisiopatologia , Humanos , Masculino , Variações Dependentes do Observador , Consumo de Oxigênio/fisiologia , Estudos Retrospectivos , Disfunção da Prega Vocal/diagnóstico , Adulto Jovem
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