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1.
N Engl J Med ; 388(19): 1755-1766, 2023 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-37163622

RESUMO

BACKGROUND: No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown. METHODS: We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo. RESULTS: Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P<0.001). Adverse events that occurred during the use of the intervention or placebo, irrespective of relatedness, were observed in 100% of the patients in the intervention group and 99.2% in the placebo group. Serious adverse events occurred in 8.6% of the patients in the intervention group and 2.5% of those in the placebo group; anaphylaxis occurred in 7.8% and 3.4%, respectively. Serious treatment-related adverse events occurred in 0.4% of patients in the intervention group and none in the placebo group. Treatment-related anaphylaxis occurred in 1.6% in the intervention group and none in the placebo group. CONCLUSIONS: In this trial involving children 1 to 3 years of age with peanut allergy, epicutaneous immunotherapy for 12 months was superior to placebo in desensitizing children to peanuts and increasing the peanut dose that triggered allergic symptoms. (Funded by DBV Technologies; EPITOPE ClinicalTrials.gov number, NCT03211247.).


Assuntos
Anafilaxia , Dessensibilização Imunológica , Hipersensibilidade a Amendoim , Pré-Escolar , Humanos , Lactente , Alérgenos/efeitos adversos , Anafilaxia/etiologia , Arachis/efeitos adversos , Dessensibilização Imunológica/efeitos adversos , Dessensibilização Imunológica/métodos , Hipersensibilidade a Amendoim/complicações , Hipersensibilidade a Amendoim/terapia , Administração Cutânea
2.
Blood ; 144(1): 35-45, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38643510

RESUMO

ABSTRACT: We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/µL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/µL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/µL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108.


Assuntos
Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Receptores CXCR4 , Verrugas , Humanos , Feminino , Receptores CXCR4/antagonistas & inibidores , Masculino , Doenças da Imunodeficiência Primária/tratamento farmacológico , Verrugas/tratamento farmacológico , Método Duplo-Cego , Adulto , Pessoa de Meia-Idade , Síndromes de Imunodeficiência/tratamento farmacológico , Quinolinas/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Adolescente , Adulto Jovem , Criança , Contagem de Linfócitos , Aminoquinolinas , Benzimidazóis , Butilaminas
3.
Am J Hum Genet ; 105(3): 549-561, 2019 09 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.


Assuntos
Fatores de Transcrição Forkhead/genética , Heterozigoto , Linfopenia/genética , Linfócitos T/metabolismo , Timo/citologia , Adulto , Idoso , Animais , Pré-Escolar , Feminino , Fatores de Transcrição Forkhead/fisiologia , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Adulto Jovem
4.
J Clin Immunol ; 42(1): 119-129, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34657245

RESUMO

Rare, biallelic loss-of-function mutations in DOCK8 result in a combined immune deficiency characterized by severe and recurrent cutaneous infections, eczema, allergies, and susceptibility to malignancy, as well as impaired humoral and cellular immunity and hyper-IgE. The advent of next-generation sequencing technologies has enabled the rapid molecular diagnosis of rare monogenic diseases, including inborn errors of immunity. These advances have resulted in the implementation of gene-guided treatments, such as hematopoietic stem cell transplant for DOCK8 deficiency. However, putative disease-causing variants revealed by next-generation sequencing need rigorous validation to demonstrate pathogenicity. Here, we report the eventual diagnosis of DOCK8 deficiency in a consanguineous family due to a novel homozygous intronic deletion variant that caused aberrant exon splicing and subsequent loss of expression of DOCK8 protein. Remarkably, the causative variant was not initially detected by clinical whole-genome sequencing but was subsequently identified and validated by combining advanced genomic analysis, RNA-seq, and flow cytometry. This case highlights the need to adopt multipronged confirmatory approaches to definitively solve complex genetic cases that result from variants outside protein-coding exons and conventional splice sites.


Assuntos
Síndrome de Job , Consanguinidade , Fatores de Troca do Nucleotídeo Guanina/genética , Homozigoto , Humanos , Síndrome de Job/diagnóstico , Síndrome de Job/genética , Mutação/genética , Sequenciamento do Exoma
5.
J Paediatr Child Health ; 58(3): 404-408, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34499401

RESUMO

AIM: This study aims to evaluate the utility of genetic testing of patients diagnosed with periodic fever syndromes and to assess the validity of existing scoring criteria. METHODS: This study retrospectively reviewed the clinical history of patients diagnosed with periodic fever syndromes at Queensland Children's Hospital between November 2014 and June 2018. RESULTS: Forty-three patients were diagnosed with periodic fever syndromes. Diagnoses in the cohort included periodic fever, adenitis, pharyngitis and aphthous stomatitis (10), tumour necrosis factor receptor-associated periodic syndrome (9), cryopyrin-associated periodic syndrome (6), mevalonate kinase deficiency (4) while 14 remained unspecified. No presenting symptoms were uniquely associated with any particular diagnosis. Genetic testing of between 1 and 26 genes was performed in 26 (60%) patients. Two (7.7%) patients had pathogenic variants identified. Variants of uncertain significance which were insufficient to confirm a monogenic disorder were identified in a further 7 (27%) patients. The Eurofever classification criteria correlated with clinical diagnosis for patients diagnosed with cryopyrin-associated periodic syndrome (P = 0.046) and tumour necrosis factor receptor-associated periodic syndrome (P = 0.025) but not for patients diagnosed with mevalonate kinase deficiency (P = 0.47); however, the Eurofever classification criteria were often positive for more than one diagnosis in these patients. CONCLUSION: The European classification criteria can form a potentially useful tool to guide diagnosis; however, clinical judgement remains essential, because the score is often positive for multiple diagnoses. The diagnostic yield of genetic testing in this cohort was low and genetic testing may be more useful to confirm a strong clinical suspicion than to clarify a diagnosis for patients with less clear symptoms.


Assuntos
Febre Familiar do Mediterrâneo , Linfadenite , Deficiência de Mevalonato Quinase , Faringite , Estomatite Aftosa , Criança , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Humanos , Linfadenite/diagnóstico , Linfadenite/genética , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/genética , Estudos Retrospectivos , Estomatite Aftosa/diagnóstico , Estomatite Aftosa/genética
6.
J Paediatr Child Health ; 56(10): 1508-1513, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33099818

RESUMO

This consensus document outlines the recommendations from the Australasian Society of Clinical Immunology and Allergy Transplantation and Primary Immunodeficiency group for the diagnosis and management of patients with severe combined immunodeficiency. It also provides a proposed framework for the early investigation, management and supportive care prior to haematopoietic stem cell transplantation.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência , Imunodeficiência Combinada Severa , Austrália , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/terapia , Nova Zelândia , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/terapia
7.
J Immunol ; 2017 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-28794229

RESUMO

Mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause an autosomal recessive form of hyper-IgE syndrome, characterized by chronic immunodeficiency with persistent microbial infection and increased incidence of malignancy. These manifestations suggest a defect in cytotoxic lymphocyte function and immune surveillance. However, how DOCK8 regulates NK cell-driven immune responses remains unclear. In this article, we demonstrate that DOCK8 regulates NK cell cytotoxicity and cytokine production in response to target cell engagement or receptor ligation. Genetic ablation of DOCK8 in human NK cells attenuated cytokine transcription and secretion through inhibition of Src family kinase activation, particularly Lck, downstream of target cell engagement or NKp30 ligation. PMA/Ionomycin treatment of DOCK8-deficient NK cells rescued cytokine production, indicating a defect proximal to receptor ligation. Importantly, NK cells from DOCK8-deficient patients had attenuated production of IFN-γ and TNF-α upon NKp30 stimulation. Taken together, we reveal a novel molecular mechanism by which DOCK8 regulates NK cell-driven immunity.

8.
Pediatr Diabetes ; 19(1): 171-179, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28370959

RESUMO

BACKGROUND: Insulin autoimmune syndrome (IAS), characterized by glycemic dysregulation and life-threatening hypoglycemia, can occur in patients with type 1 diabetes (T1D). Diagnostic confirmation is complex but important in order to ensure timely initiation of definitive therapy. AIMS: We aimed to quantitate the degree of immunoglobulin-insulin complex (IIC) formation and its effects on glycemic control in a patient with T1D and IAS compared with T1D and non-T1D controls and before and after therapeutic plasma exchange (TPE). MATERIALS & METHODS: The prospective descriptive study was conducted between June 2015 and December 2015 in a quaternary children's hospital in Brisbane, Australia. Percent Free "Immunoreactive" Insulin (%FII) as assessed by polyethylene glycol precipitation studies and its relationship to plasma glucose and serum insulin concentration. RESULTS: Samples from the patient with T1D and IAS demonstrated lower mean %FII compared to T1D (23.8 ± 2.0 vs 52.0 ± 6.7; P < .0001) and non-T1D (23.8 ± 2.0 vs 102.9 ± 2.7; P < .0001) controls. This was associated with loss of glycemic predictability and frequent severe hypoglycemia. TPE increased %FII (23.8 ± 2.0 before TPE vs 83.6 ± 2.5 after TPE, P < .0001) and reestablished plasma glucose responsiveness to exogenous insulin. DISCUSSION: IAS should be considered in T1D patients with unexplained glycemic instability and hypoglycemia. The laboratory plays an integral diagnostic role. CONCLUSION: TPE is an effective method for removing IICs and normalizing insulin-mediated glucose responses.


Assuntos
Doenças Autoimunes/terapia , Diabetes Mellitus Tipo 1/complicações , Hipoglicemia/imunologia , Insulina/imunologia , Troca Plasmática , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/etiologia , Criança , Diabetes Mellitus Tipo 1/imunologia , Humanos , Masculino , Estudos Prospectivos
9.
J Allergy Clin Immunol ; 139(3): 933-949, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27554822

RESUMO

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency caused by autosomal recessive loss-of-function mutations in DOCK8. This disorder is characterized by recurrent cutaneous infections, increased serum IgE levels, and severe atopic disease, including food-induced anaphylaxis. However, the contribution of defects in CD4+ T cells to disease pathogenesis in these patients has not been thoroughly investigated. OBJECTIVE: We sought to investigate the phenotype and function of DOCK8-deficient CD4+ T cells to determine (1) intrinsic and extrinsic CD4+ T-cell defects and (2) how defects account for the clinical features of DOCK8 deficiency. METHODS: We performed in-depth analysis of the CD4+ T-cell compartment of DOCK8-deficient patients. We enumerated subsets of CD4+ T helper cells and assessed cytokine production and transcription factor expression. Finally, we determined the levels of IgE specific for staple foods and house dust mite allergens in DOCK8-deficient patients and healthy control subjects. RESULTS: DOCK8-deficient memory CD4+ T cells were biased toward a TH2 type, and this was at the expense of TH1 and TH17 cells. In vitro polarization of DOCK8-deficient naive CD4+ T cells revealed the TH2 bias and TH17 defect to be T-cell intrinsic. Examination of allergen-specific IgE revealed plasma IgE from DOCK8-deficient patients is directed against staple food antigens but not house dust mites. CONCLUSION: Investigations into the DOCK8-deficient CD4+ T cells provided an explanation for some of the clinical features of this disorder: the TH2 bias is likely to contribute to atopic disease, whereas defects in TH1 and TH17 cells compromise antiviral and antifungal immunity, respectively, explaining the infectious susceptibility of DOCK8-deficient patients.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/deficiência , Síndromes de Imunodeficiência/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Alérgenos/imunologia , Criança , Pré-Escolar , Citocinas/imunologia , Feminino , Fatores de Troca do Nucleotídeo Guanina/imunologia , Humanos , Imunoglobulina E/sangue , Leucócitos Mononucleares/imunologia , Masculino , Adulto Jovem
10.
Blood ; 119(17): 3997-4008, 2012 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-22403255

RESUMO

T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4(+) T cells to the Tfh lineage, because IL-12 induces naive human CD4(+) T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4(+) T cells from patients deficient in IL-12Rß1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4(+) T cells. Defective expression of IL-21 by STAT3-deficient CD4(+) T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4(+)CXCR5(+) T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.


Assuntos
Diferenciação Celular , Interleucina-12/farmacologia , Mutação/genética , Receptores de Interleucina-12/genética , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética , Linfócitos T Auxiliares-Indutores/citologia , TYK2 Quinase/genética , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Citocinas/metabolismo , Humanos , Hospedeiro Imunocomprometido , Ativação Linfocitária , Camundongos , Receptores de Interleucina-12/deficiência , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/deficiência , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , TYK2 Quinase/metabolismo , Fatores de Transcrição/metabolismo
11.
J Allergy Clin Immunol ; 132(2): 400-11.e9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23830147

RESUMO

BACKGROUND: The capacity of CD8(+) T cells to control infections and mediate antitumor immunity requires the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer of CD8(+) T-cell effector function and memory development in mouse models of infectious disease. However, the role of IL-21 and associated signaling pathways in protective CD8(+) T-cell immunity in human subjects is unknown. OBJECTIVE: We sought to determine which signaling pathways mediate the effects of IL-21 on human CD8(+) T cells and whether defects in these pathways contribute to disease pathogenesis in patients with primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade. METHODS: Human primary immunodeficiencies resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Lymphocytes from patients with loss-of-function mutations in signal transducer and activator of transcription 1 (STAT1), STAT3, or IL-21 receptor (IL21R) were used to assess the respective roles of these genes in human CD8(+) T-cell differentiation in vivo and in vitro. RESULTS: Mutations in STAT3 and IL21R, but not STAT1, led to a decrease in multiple memory CD8(+) T-cell subsets in vivo, indicating that STAT3 signaling, possibly downstream of IL-21R, regulates the memory cell pool. Furthermore, STAT3 was important for inducing the lytic machinery in IL-21-stimulated naive CD8(+) T cells. However, this defect was overcome by T-cell receptor engagement. CONCLUSION: The IL-21R/STAT3 pathway is required for many aspects of human CD8(+) T-cell behavior but in some cases can be compensated by other signals. This helps explain the relatively mild susceptibility to viral disease observed in STAT3- and IL-21R-deficient subjects.


Assuntos
Linfócitos T CD8-Positivos/citologia , Diferenciação Celular , Memória Imunológica , Síndrome de Job/genética , Mutação , Fator de Transcrição STAT3/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Humanos , Interleucinas/genética , Interleucinas/imunologia , Interleucinas/metabolismo , Síndrome de Job/imunologia , Síndrome de Job/patologia , Receptores de Interleucina-21/genética , Receptores de Interleucina-21/imunologia , Receptores de Interleucina-21/metabolismo , Fator de Transcrição STAT3/genética
12.
Blood ; 118(26): 6824-35, 2011 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-22039266

RESUMO

SCID resulting from mutations in IL2RG or JAK3 is characterized by lack of T and natural killer cells; B cells are present in normal number, but antibody responses are defective. Hematopoietic cell transplantation (HCT) is curative for SCID. However, B-cell dysfunction persists in a substantial proportion of patients. We hypothesized that impaired B-cell responses after HCT in IL2RG/JAK3 deficiency results from poor donor B-cell engraftment and defective γc-dependent cytokine signaling in host B cells. To test this, and to identify which γc cytokine(s) is critical for humoral immunity, we studied 28 transplanted patients with IL2RG/JAK3 deficiency. Lack of donor B-cell engraftment associated with persistent humoral dysfunction and significantly reduced memory B cells. B-cell proliferation induced by CD40L alone or together with CpG, anti-Ig, IL-4, IL-10, or IL-13 was comparable in healthy controls and in post-HCT SCID patients, irrespective of their chimerism status. However, in vitro stimulation with CD40L/IL-21 induced B-cell proliferation, plasmablast differentiation, and antibody secretion in patients with donor B cells, but not in patients with autologous B cells. These data imply that IL-21-mediated signaling is critical for long-lived humoral immunity and to restore antibody responses in IL2RG/JAK3-deficient patients after HCT. Furthermore, in vitro stimulation with CD40L/IL-21 can predict in vivo B-cell immunity in IL2RG/JAK3 SCID after transplantation.


Assuntos
Linfócitos B/imunologia , Diferenciação Celular/imunologia , Subunidade gama Comum de Receptores de Interleucina/imunologia , Interleucinas/imunologia , Linfócitos B/metabolismo , Ligante de CD40/imunologia , Ligante de CD40/metabolismo , Células Cultivadas , Citometria de Fluxo , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Memória Imunológica/imunologia , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Interleucinas/metabolismo , Janus Quinase 3/genética , Janus Quinase 3/imunologia , Janus Quinase 3/metabolismo , Mutação , Ligação Proteica , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/metabolismo , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/metabolismo
13.
Eur J Hum Genet ; 31(10): 1125-1132, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-36864115

RESUMO

Molecular diagnosis of paediatric inborn errors of immunity (IEI) influences management decisions and alters clinical outcomes, through early use of targeted and curative therapies. The increasing demand for genetic services has resulted in growing waitlists and delayed access to vital genomic testing. To address this issue, the Queensland Paediatric Immunology and Allergy Service, Australia, developed and evaluated a mainstreaming model of care to support point-of-care genomic testing for paediatric IEI. Key features of the model of care included a genetic counsellor embedded in the department, state-wide multidisciplinary team meetings, and variant prioritisation meetings to review whole exome sequencing (WES) data. Of the 62 children presented at the MDT, 43 proceeded to WES, of which nine (21%) received a confirmed molecular diagnosis. Changes to treatment and management were reported for all children with a positive result, including curative hematopoietic stem cell transplantation (n = 4). Four children were also referred for further investigations of variants of uncertain significance or additional testing due to ongoing suspicion of genetic cause after negative result. Demonstrating engagement with the model of care, 45% of the patients were from regional areas and on average, 14 healthcare providers attended the state-wide multidisciplinary team meetings. Parents demonstrated understanding of the implications of testing, reported minimal decisional regret post-test, and identified benefits to genomic testing. Overall, our program demonstrated the feasibility of a mainstreaming model of care for paediatric IEI, improved access to genomic testing, facilitated treatment decision-making, and was acceptable to parents and clinicians alike.


Assuntos
Genômica , Pais , Humanos , Criança , Sequenciamento do Exoma , Austrália , Testes Genéticos
14.
J Exp Med ; 220(1)2023 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-36342455

RESUMO

Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)-specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines.


Assuntos
Linfócitos B , Vacinas contra COVID-19 , COVID-19 , Interferon Tipo I , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , Autoanticorpos , COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética , Receptor 7 Toll-Like/genética , Vacinação , Vacinas de mRNA , Vacinas contra COVID-19/imunologia , Linfócitos B/imunologia , Interferon Tipo I/deficiência
15.
Nutrients ; 14(11)2022 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-35684099

RESUMO

This open-label, non-randomized, multicenter trial (Registration: NCT03661736) aimed to assess if an amino acid-based formula (AAF) supplemented with two human milk oligosaccharides (HMO) supports normal growth and is well tolerated in infants with a cow's milk protein allergy (CMPA). Term infants aged 1-8 months with moderate-to-severe CMPA were enrolled. The study formula was an AAF supplemented with 2'-fucosyllactose (2'-FL) and lacto-N-neotetraose (LNnT). Infants were fed the study formula for 4 months and were offered to remain on the formula until 12 months of age. Tolerance and safety were assessed throughout the trial. Out of 32 infants (mean age 18.6 weeks; 20 (62.5%) male), 29 completed the trial. During the 4-month principal study period, the mean weight-for-age Z score (WAZ) increased from -0.31 at the baseline to +0.28 at the 4-months' follow-up. Linear and head growth also progressed along the WHO child growth reference, with a similar small upward trend. The formula was well tolerated and had an excellent safety profile. When comparing the microbiome at the baseline to the subsequent visits, there was a significant on-treatment enrichment in HMO-utilizing bifidobacteria, which was associated with a significant increase in fecal short-chain fatty acids. In addition, we observed a significant reduction in the abundance of fecal Proteobacteria, suggesting that the HMO-supplemented study formula partially corrected the gut microbial dysbiosis in infants with CMPA.


Assuntos
Microbioma Gastrointestinal , Hipersensibilidade a Leite , Aminoácidos , Animais , Bovinos , Feminino , Humanos , Lactente , Fórmulas Infantis , Masculino , Leite Humano , Oligossacarídeos
16.
J Exp Med ; 219(6)2022 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-35442418

RESUMO

Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses. We report seven children from five unrelated kindreds of western Polynesian ancestry who suffered from severe viral diseases. All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*). This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function. The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-ß). Remarkably, this IFNAR1 variant has a minor allele frequency >1% in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region. Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses.


Assuntos
Receptor de Interferon alfa e beta , Viroses , Alelos , Criança , Homozigoto , Humanos , Polinésia
17.
J Exp Med ; 218(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34137790

RESUMO

Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.


Assuntos
Genes Dominantes , Síndrome de Job/genética , Mutação/genética , Fator de Transcrição STAT3/genética , Adolescente , Adulto , Alelos , Processamento Alternativo/genética , Criança , Pré-Escolar , Códon sem Sentido/genética , Evolução Molecular , Família , Feminino , Mutação da Fase de Leitura/genética , Genética Populacional , Células HEK293 , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Linhagem , Biossíntese de Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
18.
J Clin Invest ; 131(3)2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33290277

RESUMO

Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy, and malignancy. Somatic reversion refers to the spontaneous repair of a pathogenic germline genetic variant and has been reported to occur in a number of inborn errors of immunity, with a range of impacts on clinical outcomes of these conditions. DOCK8 deficiency due to biallelic inactivating mutations in DOCK8 causes a combined immunodeficiency characterized by severe bacterial, viral, and fungal infections, as well as allergic disease and some cancers. Here, we describe the clinical, genetic, and cellular features of 3 patients with biallelic DOCK8 variants who, following somatic reversion in multiple lymphocyte subsets, exhibited improved clinical features, including complete resolution of infection and allergic disease, and cure over time. Acquisition of DOCK8 expression restored defective lymphocyte signalling, survival and proliferation, as well as CD8+ T cell cytotoxicity, CD4+ T cell cytokine production, and memory B cell generation compared with typical DOCK8-deficient patients. Our temporal analysis of DOCK8-revertant and DOCK8-deficient cells within the same individual established mechanisms of clinical improvement in these patients following somatic reversion and revealed further nonredundant functions of DOCK8 in human lymphocyte biology. Last, our findings have significant implications for future therapeutic options for the treatment of DOCK8 deficiency.


Assuntos
Diferenciação Celular , Fatores de Troca do Nucleotídeo Guanina/deficiência , Memória Imunológica/genética , Ativação Linfocitária/genética , Linfócitos/imunologia , Imunodeficiência Combinada Severa , Adulto , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Feminino , Humanos , Masculino , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia
20.
J Paediatr Child Health ; 45(9): 481-6, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19702611

RESUMO

Cow's milk protein allergy is a condition commonly managed by general practitioners and paediatricians. The diagnosis is usually made in the first 12 months of life. Management of immediate allergic reactions and anaphylaxis includes the prevention of accidental food ingestion and provision of an adrenaline autoinjector, if appropriate. By contrast, the clinical course of delayed food-allergic manifestations is characterised by chronicity, and is often associated with nutritional or behavioural sequelae. Correct diagnosis of these non-IgE-mediated conditions may be delayed due to a lack of reliable diagnostic markers. This review aims to guide clinicians in the: (i) diagnostic evaluation (skin prick testing or measurement of food-specific serum IgE levels; indications for diagnostic challenges for suspected IgE- and non-IgE-mediated food allergy), (ii) dietary treatment, (iii) assessment of response to treatment, (iv) differential diagnosis and further diagnostic work-up in non-responders, (v) follow-up assessment of tolerance development and (vi) recommendations for further referral.


Assuntos
Hipersensibilidade a Leite/tratamento farmacológico , Proteínas do Leite/efeitos adversos , Anafilaxia , Animais , Austrália , Bovinos , Pré-Escolar , Protocolos Clínicos , Humanos , Hipersensibilidade Imediata/induzido quimicamente , Lactente , Recém-Nascido , Hipersensibilidade a Leite/diagnóstico , Hipersensibilidade a Leite/fisiopatologia
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