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1.
Sci Immunol ; 7(73): eabq3277, 2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35867801

RESUMO

High-level expression of the transcription factor T-bet characterizes a phenotypically distinct murine B cell population known as "age-associated B cells" (ABCs). T-bet-deficient mice have reduced ABCs and impaired humoral immunity. We describe a patient with inherited T-bet deficiency and largely normal humoral immunity including intact somatic hypermutation, affinity maturation and memory B cell formation in vivo, and B cell differentiation into Ig-producing plasmablasts in vitro. Nevertheless, the patient exhibited skewed class switching to IgG1, IgG4, and IgE, along with reduced IgG2, both in vivo and in vitro. Moreover, T-bet was required for the in vivo and in vitro development of a distinct subset of human B cells characterized by reduced expression of CD21 and the concomitantly high expression of CD19, CD20, CD11c, FCRL5, and T-bet, a phenotype that shares many features with murine ABCs. Mechanistically, human T-bet governed CD21loCD11chi B cell differentiation by controlling the chromatin accessibility of lineage-defining genes in these cells: FAS, IL21R, SEC61B, DUSP4, DAPP1, SOX5, CD79B, and CXCR4. Thus, human T-bet is largely redundant for long-lived protective humoral immunity but is essential for the development of a distinct subset of human CD11chiCD21lo B cells.


Assuntos
Linfócitos B , Plasmócitos , Proteínas Adaptadoras de Transdução de Sinal , Animais , Antígeno CD11c/metabolismo , Regulação da Expressão Gênica , Humanos , Imunoglobulina G , Lipoproteínas/metabolismo , Ativação Linfocitária , Camundongos
2.
Nat Commun ; 13(1): 4344, 2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35896601

RESUMO

Innate lymphoid cells (ILCs) include cytotoxic natural killer cells and distinct groups of cytokine-producing innate helper cells which participate in immune defense and promote tissue homeostasis. Circulating human ILC precursors (ILCP) able to generate all canonical ILC subsets via multi-potent or uni-potent intermediates according to our previous work. Here we show potential cooperative roles for the Notch and IL-23 signaling pathways for human ILC differentiation from blood ILCP using single cell cloning analyses and validate these findings in patient samples with rare genetic deficiencies in IL12RB1 and RORC. Mechanistically, Notch signaling promotes upregulation of the transcription factor RORC, enabling acquisition of Group 1 (IFN-γ) and Group 3 (IL-17A, IL-22) effector functions in multi-potent and uni-potent ILCP. Interfering with RORC or signaling through its target IL-23R compromises ILC3 effector functions but also generally suppresses ILC production from multi-potent ILCP. Our results identify a Notch->RORC- > IL-23R pathway which operates during human ILC differentiation. These observations may help guide protocols to expand functional ILC subsets in vitro with an aim towards novel ILC therapies for human disease.


Assuntos
Imunidade Inata , Linfócitos , Diferenciação Celular , Humanos , Interleucina-23 , Células Matadoras Naturais , Células Progenitoras Linfoides/fisiologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Receptores Notch/metabolismo
3.
J Clin Immunol ; 2022 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-35748970

RESUMO

We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases.

4.
J Clin Immunol ; 2022 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-35585372

RESUMO

BACKGROUND: Autosomal recessive (AR) PKCδ deficiency is a rare inborn error of immunity (IEI) characterized by autoimmunity and susceptibility to bacterial, fungal, and viral infections. PKCδ is involved in the intracellular production of reactive oxidative species (ROS). MATERIAL AND METHODS: We studied a 5-year old girl presenting with a history of Burkholderia cepacia infection. She had no history of autoimmunity, lymphocyte counts were normal, and no auto-antibodies were detected in her plasma. We performed a targeted panel analysis of 407 immunity-related genes and immunological investigations of the underlying genetic condition in this patient. RESULTS: Consistent with a history suggestive of chronic granulomatous disease (CGD), oxidative burst impairment was observed in the patient's circulating phagocytes in a dihydrorhodamine 123 (DHR) assay. However, targeted genetic panel analysis identified no candidate variants of known CGD-causing genes. Two heterozygous candidate variants were detected in PRKCD: c.285C > A (p.C95*) and c.376G > T (p.D126Y). The missense variant was also predicted to cause abnormal splicing, as it is located at the splice donor site of exon 5. TOPO-TA cloning confirmed that exon 5 was completely skipped, resulting in a truncated protein. No PKCδ protein was detected in the patient's neutrophils and monocyte-derived macrophages. The monocyte-derived macrophages of the patient produced abnormally low levels of ROS, as shown in an Amplex Red assay. CONCLUSION: PKCδ deficiency should be considered in young patients with CGD-like clinical manifestations and abnormal DHR assay results, even in the absence of clinical and biological manifestations of autoimmunity.

5.
J Fungi (Basel) ; 8(5)2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35628702

RESUMO

Phaeohyphomycoses comprise a heterogeneous group of fungal infections caused by dematiaceous fungi and have primarily been reported in patients with underlying acquired immunodeficiencies, such as hematological malignancies or solid-organ transplants. Over the past decade, a growing number of patients with phaeohyphomycosis but otherwise healthy were reported with autosomal recessive (AR) CARD9 deficiency. We report a 28-year-old woman who presented with invasive rhinosinusitis caused by Alternaria infectoria. Following a candidate gene sequencing approach, we identified a biallelic loss-of-function mutation of CARD9, thereby further broadening the spectrum of invasive fungal diseases found in patients with inherited CARD9 deficiency. In addition, we reviewed 17 other cases of phaeohyphomycosis associated with AR CARD9 deficiency. Physicians should maintain a high degree of suspicion for inborn errors of immunity, namely CARD9 deficiency, when caring for previously healthy patients with phaeohyphomycosis, regardless of age at first presentation.

6.
Front Immunol ; 13: 881352, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35558066

RESUMO

Objectives: We describe the clinical, mycological, immunological, and genetic characteristics of six HIV-negative patients presenting with invasive cryptococcosis. Methods: Patients with cryptococcosis without any of the classical risk factors, such as HIV infection, followed at Cayenne Hospital, were prospectively included. An immunologic and genetic assessment was performed. Results: Five male patients and one female patient, 5 adults and one child, were investigated. All presented a neuromeningeal localization. Cryptococcus neoformans var. gattii and C. neoformans var. grubii were isolated in two and three patients, respectively, whereas one patient could not be investigated. Overall, we did not observe any global leukocyte defect. Two patients were found with high levels of circulating autoantibodies against Granulocyte macrophage-colony stimulating factor (GM-CSF), and none had detectable levels of autoantibodies against Interferon gamma (IFN-γ) Sequencing of STAT1 exons and flanking regions performed for four patients was wild type. Conclusion: To better understand cryptococcosis in patients with cryptococcosis but otherwise healthy, further explorations are needed with repeated immune checkups and strain virulence studies.


Assuntos
Criptococose , Cryptococcus gattii , Cryptococcus neoformans , Infecções por HIV , Adulto , Autoanticorpos , Criança , Cryptococcus gattii/genética , Cryptococcus neoformans/genética , Feminino , Guiana Francesa , Infecções por HIV/complicações , Humanos , Masculino
7.
J Clin Immunol ; 42(2): 336-349, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34791587

RESUMO

BACKGROUND: CARD9 deficiency is an autosomal recessive primary immunodeficiency underlying increased susceptibility to fungal infection primarily presenting as invasive CNS Candida and/or cutaneous/invasive dermatophyte infections. More recently, a rare heterozygous dominant negative CARD9 variant c.1434 + 1G > C was reported to be protective from inflammatory bowel disease. OBJECTIVE: We studied two siblings carrying homozygous CARD9 variants (c.1434 + 1G > C) and born to heterozygous asymptomatic parents. One sibling was asymptomatic and the other presented with candida esophagitis, upper respiratory infections, hypogammaglobulinemia, and low class-switched memory B cells. METHODS AND RESULTS: The CARD9 c.1434 + 1G > C variant generated two mutant transcripts confirmed by mRNA and protein expression: an out-of-frame c.1358-1434 deletion/ ~ 55 kDa protein (CARD9Δex.11) and an in-frame c.1417-1434 deletion/ ~ 61 kDa protein (CARD9Δ18 nt.). Neither transcript was able to form a complete/functional CBM complex, which includes TRIM62. Based on the index patient's CVID-like phenotype, CARD9 expression was tested and detected in lymphocytes and monocytes from humans and mice. The functional impact of different CARD9 mutations and gene dosage conditions was evaluated in heterozygous and homozygous c.1434 + 1 G > C members of the index family, and in WT (two WT alleles), haploinsufficiency (one WT, one null allele), and null (two null alleles) individuals. CARD9 gene dosage impacted lymphocyte and monocyte functions including cytokine generation, MAPK activation, T-helper commitment, transcription, plasmablast differentiation, and immunoglobulin production in a differential manner. CONCLUSIONS: CARD9 exon 11 integrity is critical to CBM complex function. CARD9 is expressed and affects particular T and B cell functions in a gene dosage-dependent manner, which in turn may contribute to the phenotype of CARD9 deficiency.


Assuntos
Candidíase Mucocutânea Crônica , Alelos , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Dosagem de Genes , Homozigoto , Humanos , Camundongos , Fenótipo
8.
J Exp Med ; 219(4)2022 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-35319722

RESUMO

The vast interindividual clinical variability observed in any microbial infection-ranging from silent infection to lethal disease-is increasingly being explained by human genetic and immunological determinants. Autoantibodies neutralizing specific cytokines underlie the same infectious diseases as inborn errors of the corresponding cytokine or response pathway. Autoantibodies against type I IFNs underlie COVID-19 pneumonia and adverse reactions to the live attenuated yellow fever virus vaccine. Autoantibodies against type II IFN underlie severe disease caused by environmental or tuberculous mycobacteria, and other intra-macrophagic microbes. Autoantibodies against IL-17A/F and IL-6 are less common and underlie mucocutaneous candidiasis and staphylococcal diseases, respectively. Inborn errors of and autoantibodies against GM-CSF underlie pulmonary alveolar proteinosis; associated infections are less well characterized. In individual patients, autoantibodies against cytokines preexist infection with the pathogen concerned and underlie the infectious disease. Human antibody-driven autoimmunity can interfere with cytokines that are essential for protective immunity to specific infectious agents but that are otherwise redundant, thereby underlying specific infectious diseases.


Assuntos
COVID-19 , Candidíase Mucocutânea Crônica , Doenças Transmissíveis , Proteinose Alveolar Pulmonar , Autoanticorpos , Candidíase Mucocutânea Crônica/genética , Humanos
9.
Am J Hum Genet ; 108(12): 2301-2318, 2021 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-34762822

RESUMO

Identifying whether a given genetic mutation results in a gene product with increased (gain-of-function; GOF) or diminished (loss-of-function; LOF) activity is an important step toward understanding disease mechanisms because they may result in markedly different clinical phenotypes. Here, we generated an extensive database of documented germline GOF and LOF pathogenic variants by employing natural language processing (NLP) on the available abstracts in the Human Gene Mutation Database. We then investigated various gene- and protein-level features of GOF and LOF variants and applied machine learning and statistical analyses to identify discriminative features. We found that GOF variants were enriched in essential genes, for autosomal-dominant inheritance, and in protein binding and interaction domains, whereas LOF variants were enriched in singleton genes, for protein-truncating variants, and in protein core regions. We developed a user-friendly web-based interface that enables the extraction of selected subsets from the GOF/LOF database by a broad set of annotated features and downloading of up-to-date versions. These results improve our understanding of how variants affect gene/protein function and may ultimately guide future treatment options.


Assuntos
Bases de Dados Genéticas , Mutação com Ganho de Função , Mutação com Perda de Função , Proteínas/genética , Computação em Nuvem , Predisposição Genética para Doença , Genoma Humano , Mutação em Linhagem Germinativa , Humanos , Intervenção Baseada em Internet , Aprendizado de Máquina
10.
J Clin Invest ; 131(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623332

RESUMO

We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4+ T cells. In naive CD4+ T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient's naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.


Assuntos
Genes rel , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/imunologia , Proteínas Proto-Oncogênicas c-rel/deficiência , Proteínas Proto-Oncogênicas c-rel/genética , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Criança , Consanguinidade , Feminino , Transplante de Células-Tronco Hematopoéticas , Homozigoto , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Ativação Linfocitária , Linfócitos/classificação , Linfócitos/imunologia , Mutação , Células Mieloides/imunologia , Doenças da Imunodeficiência Primária/terapia , Isoformas de Proteínas
11.
J Exp Med ; 218(11)2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34473196

RESUMO

Autosomal dominant (AD) NFKB1 deficiency is thought to be the most common genetic etiology of common variable immunodeficiency (CVID). However, the causal link between NFKB1 variants and CVID has not been demonstrated experimentally and genetically, and there has been insufficient biochemical characterization and enrichment analysis. We show that the cotransfection of NFKB1-deficient HEK293T cells (lacking both p105 and its cleaved form p50) with a κB reporter, NFKB1/p105, and a homodimerization-defective RELA/p65 mutant results in p50:p65 heterodimer-dependent and p65:p65 homodimer-independent transcriptional activation. We found that 59 of the 90 variants in patients with CVID or related conditions were loss of function or hypomorphic. By contrast, 258 of 260 variants in the general population or patients with unrelated conditions were neutral. None of the deleterious variants displayed negative dominance. The enrichment in deleterious NFKB1 variants of patients with CVID was selective and highly significant (P = 2.78 × 10-15). NFKB1 variants disrupting NFKB1/p50 transcriptional activity thus underlie AD CVID by haploinsufficiency, whereas neutral variants in this assay should not be considered causal.


Assuntos
Imunodeficiência de Variável Comum/genética , Subunidade p50 de NF-kappa B/genética , Animais , Células COS , Linhagem Celular , Chlorocebus aethiops , Células HEK293 , Haploinsuficiência/genética , Humanos , NF-kappa B/genética , Fenótipo , Ativação Transcricional/genética
12.
Science ; 373(6561): eabi5459, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34529464

RESUMO

Break et al. (Research Articles, 15 January 2021, eaay5731) suggest that chronic mucocutaneous candidiasis in humans with inborn errors of AIRE and autoimmune polyendocrine syndrome type 1 is due to excessive interferon-γ production and not to autoantibodies neutralizing interleukin-17 cytokines. We argue that both claims are not conclusively supported by their data and are at odds with 35 years of study.


Assuntos
Micoses , Humanos , Membrana Mucosa
13.
Curr Opin Immunol ; 72: 318-323, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34455138

RESUMO

Chronic mucocutaneous candidiasis (CMC) is one of the earliest and most frequent clinical manifestations of autosomal recessive autoimmune polyendocrine syndrome type 1 (APS-1), a monogenic inborn error of immunity caused by deleterious variants of the autoimmune regulator (AIRE) gene. APS-1 patients suffer from various autoimmune diseases, due to the defective thymic deletion of autoreactive T cells, and the development of a large range of autoantibodies (auto-Abs) against various tissue antigens, and some cytokines. The mechanisms underlying CMC remained elusive for many years, until the description in 2010 of high serum titers of neutralizing auto-Abs against IL-17A, IL-17F, and/or IL-22, which are present in almost all APS-1 patients. Excessively high mucosal concentrations of IFN-γ were recently proposed as an alternative mechanism for CMC in APS-1.


Assuntos
Candidíase/etiologia , Predisposição Genética para Doença , Poliendocrinopatias Autoimunes/complicações , Poliendocrinopatias Autoimunes/genética , Animais , Autoanticorpos/imunologia , Autoimunidade/genética , Biomarcadores , Candidíase/diagnóstico , Candidíase/metabolismo , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-17/imunologia , Interleucina-17/metabolismo , Poliendocrinopatias Autoimunes/diagnóstico
14.
J Exp Med ; 218(9)2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34264265

RESUMO

Patients with autosomal recessive protein kinase C δ (PKCδ) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKCδ-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40phox normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients' circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKCδ in activation of the NADPH oxidase complex. Our findings thus show that patients with PKCδ deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype.


Assuntos
Infecções/genética , Proteína Quinase C-delta/genética , Explosão Respiratória/fisiologia , Linfócitos B/enzimologia , Feminino , Humanos , Lactente , Infecções/tratamento farmacológico , Infecções/etiologia , Infecções/patologia , Masculino , NADPH Oxidases/metabolismo , Linhagem , Fagocitose , Fosforilação , Isoformas de Proteínas , Proteína Quinase C-delta/deficiência , Proteína Quinase C-delta/metabolismo
15.
Front Immunol ; 12: 696350, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248995

RESUMO

X-linked severe combined immunodeficiency (X-SCID) is caused by mutations of IL2RG, the gene encoding the interleukin common gamma chain (IL-2Rγ or γc) of cytokine receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Hypomorphic mutations of IL2RG may cause combined immunodeficiencies with atypical clinical and immunological presentations. Here, we report a clinical, immunological, and functional characterization of a missense mutation in exon 1 (c.115G>A; p. Asp39Asn) of IL2RG in a 7-year-old boy. The patient suffered from recurrent sinopulmonary infections and refractory eczema. His total lymphocyte counts have remained normal despite skewed T cell subsets, with a pronounced serum IgE elevation. Surface expression of IL-2Rγ was reduced on his lymphocytes. Signal transducer and activator of transcription (STAT) phosphorylation in response to IL-2, IL-4, and IL-7 showed a partially preserved receptor function. T-cell proliferation in response to mitogens and anti-CD3/anti-CD28 monoclonal antibodies was significantly reduced. Further analysis revealed a decreased percentage of CD4+ T cells capable of secreting IFN-γ, but not IL-4 or IL-17. Studies on the functional consequences of IL-2Rγ variants are important to get more insight into the pathogenesis of atypical phenotypes which may lay the ground for novel therapeutic strategies.


Assuntos
Subunidade gama Comum de Receptores de Interleucina/genética , Síndrome de Job/genética , Mutação de Sentido Incorreto , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Proliferação de Células , Criança , Predisposição Genética para Doença , Humanos , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Síndrome de Job/diagnóstico , Síndrome de Job/imunologia , Ativação Linfocitária , Masculino , Fenótipo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/diagnóstico , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia
16.
Pediatr Allergy Immunol ; 32(8): 1804-1812, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34289170

RESUMO

BACKGROUND: Inherited chronic mucocutaneous candidiasis (CMC) is often caused by inborn errors of immunity, impairing the response to, or the production of IL-17A and IL-17F. About half of the cases carry STAT1 gain-of-function (GOF) mutations. Only few patients have been reported with mutations of TRAF3IP2, a gene encoding the adaptor ACT1 essential for IL-17 receptor(R) signaling. We investigated a 10-year-old girl with CMC, carrying a heterozygous variant of STAT1 and compound heterozygous variants of TRAF3IP2. METHODS: By flow cytometry, STAT1 levels and phosphorylation (CD14+) as well as IL-17A, IL-22, IFN-γ, and IL-4 production (memory CD4+ T cells) were determined. ACT1 expression and binding to IL-17RA were assessed by Western blot and co-immunoprecipitation in HEK-293T cells transfected with plasmids encoding wild-type or mutant HA-tagged ACT1 and Flag-IL-17RA. We evaluated IL-17A responses by measuring luciferase induction under a NF-κB-driven reporter system in HEK-293T cells and Gro-α secretion in fibroblasts. RESULTS: A STAT1 variant (c.1363G>A/p.V455I) was identified by next-generation sequencing and classified as likely non-pathogenic as functional testing revealed normal STAT1 expression and phosphorylation upon IFN-γ. We also found compound heterozygous variants (c.1325A>G/p.D451G and c.1335delA/p.K454fs11*) of TRAF3IP2. By overexpression, despite normal protein expression, and impaired (K454fs11*) or normal (D451G) interaction with IL-17RA, both mutant alleles resulted in impaired NF-κB activation. Patient's fibroblasts displayed abolished GRO-α secretion upon IL-17A stimulation. Finally, ex vivo CD4+ T cells showed increased IL-17A, IL-22, and IL-4 and normal low IFN-γ expression upon stimulation. CONCLUSION: We identify novel compound heterozygous variants of TRAFP3IP2 causing autosomal recessive ACT1 deficiency in a child with CMC and provide a review of the current literature.


Assuntos
Candidíase Mucocutânea Crônica , Proteínas Adaptadoras de Transdução de Sinal , Alelos , Candidíase Mucocutânea Crônica/genética , Criança , Feminino , Humanos , Mutação , Fosforilação , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Linfócitos T/metabolismo
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 Exp Med ; 218(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34160550

RESUMO

We have described a child suffering from Mendelian susceptibility to mycobacterial disease (MSMD) due to autosomal recessive, complete T-bet deficiency, which impairs IFN-γ production by innate and innate-like adaptive, but not mycobacterial-reactive purely adaptive, lymphocytes. Here, we explore the persistent upper airway inflammation (UAI) and blood eosinophilia of this patient. Unlike wild-type (WT) T-bet, the mutant form of T-bet from this patient did not inhibit the production of Th2 cytokines, including IL-4, IL-5, IL-9, and IL-13, when overexpressed in T helper 2 (Th2) cells. Moreover, Herpesvirus saimiri-immortalized T cells from the patient produced abnormally large amounts of Th2 cytokines, and the patient had markedly high plasma IL-5 and IL-13 concentrations. Finally, the patient's CD4+ αß T cells produced most of the Th2 cytokines in response to chronic stimulation, regardless of their antigen specificities, a phenotype reversed by the expression of WT T-bet. T-bet deficiency thus underlies the excessive production of Th2 cytokines, particularly IL-5 and IL-13, by CD4+ αß T cells, causing blood eosinophilia and UAI. The MSMD of this patient results from defective IFN-γ production by innate and innate-like adaptive lymphocytes, whereas the UAI and eosinophilia result from excessive Th2 cytokine production by adaptive CD4+ αß T lymphocytes.


Assuntos
Citocinas/metabolismo , Pneumonia/imunologia , Proteínas com Domínio T/deficiência , Células Th2/imunologia , Animais , Citocinas/sangue , Epigênese Genética , Epitopos/imunologia , Feminino , Humanos , Memória Imunológica , Masculino , Camundongos Endogâmicos C57BL , Mutação/genética , Linhagem , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Hipersensibilidade Respiratória/sangue , Hipersensibilidade Respiratória/imunologia , Análise de Sequência de RNA , Análise de Célula Única , Proteínas com Domínio T/genética
19.
NAR Genom Bioinform ; 3(2): lqab037, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34046589

RESUMO

The detection of copy number variations (CNVs) in whole-exome sequencing (WES) data is important, as CNVs may underlie a number of human genetic disorders. The recently developed HMZDelFinder algorithm can detect rare homozygous and hemizygous (HMZ) deletions in WES data more effectively than other widely used tools. Here, we present HMZDelFinder_opt, an approach that outperforms HMZDelFinder for the detection of HMZ deletions, including partial exon deletions in particular, in WES data from laboratory patient collections that were generated over time in different experimental conditions. We show that using an optimized reference control set of WES data, based on a PCA-derived Euclidean distance for coverage, strongly improves the detection of HMZ complete exon deletions both in real patients carrying validated disease-causing deletions and in simulated data. Furthermore, we develop a sliding window approach enabling HMZDelFinder_opt to identify HMZ partial deletions of exons that are undiscovered by HMZDelFinder. HMZDelFinder_opt is a timely and powerful approach for detecting HMZ deletions, particularly partial exon deletions, in WES data from inherently heterogeneous laboratory patient collections.

20.
J Clin Immunol ; 41(6): 1376-1379, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33825088

RESUMO

Inborn errors of the IL-17-mediated signaling have been associated with chronic mucocutaneous candidiasis (CMC). We describe a patient with CMC, atopic dermatitis, enamel dysplasia, and recurrent parotitis harboring a novel compound heterozygous mutation of TRAF3IP2, leading to autosomal recessive ACT1 deficiency and deficient IL-17 signaling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Candidíase Mucocutânea Crônica/genética , Mutação/genética , Criança , Predisposição Genética para Doença/genética , Humanos , Interleucina-17/genética , Masculino
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