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1.
Blood Adv ; 2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34920454

RESUMO

Helios, encoded by IKZF2, is a member of the Ikaros family of transcription factors with pivotal roles in T-follicular helper, NK- and T-regulatory cell physiology. Somatic IKZF2 mutations are frequently found in lymphoid malignancies. Although germline mutations in IKZF1 and IKZF3, encoding Ikaros and Aiolos, have recently been identified in patients with phenotypically similar immunodeficiency syndromes, the effect of germline mutations in IKZF2 on human hematopoiesis and immunity remains enigmatic. We identified germline IKZF2 mutations (one nonsense (p.R291X)- and 4 distinct missense variants) in six patients with systemic lupus erythematosus, immune thrombocytopenia or EBV-associated hemophagocytic lymphohistiocytosis. Patients exhibited hypogammaglobulinemia, decreased number of T-follicular helper and NK-cells. Single-cell RNA sequencing of PBMCs from the patient carrying the R291X variant revealed upregulation of pro-inflammatory genes associated with T-cell receptor activation and T-cell exhaustion. Functional assays revealed the inability of HeliosR291X to homodimerize and bind target DNA as dimers. Moreover, proteomic analysis by proximity-dependent Biotin Identification revealed aberrant interaction of 3/5 Helios mutants with core components of the NuRD complex conveying HELIOS-mediated epigenetic and transcriptional dysregulation.

2.
Curr Opin Pediatr ; 33(6): 648-656, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34734915

RESUMO

PURPOSE OF REVIEW: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused extreme concern for patients with inborn errors of immunity (IEIs). In the first 6  months of the pandemic, the case fatality rate among patients with IEIs resembled that of the general population (9%). This review aims at summarizing what we have learned about the course and outcome of coronavirus disease 2019 (COVID-19) in patients with different IEIs and what this can potentially teach us about the immune mechanisms that could confer protection or predisposition to severe disease. RECENT FINDINGS: A total of 649 patients with IEI and COVID-19 have been reported in the last year and a half, spanning all groups of the International Union of Immunological Societies classification of IEIs. For most patients, the underlying IEI does not represent an independent risk factor for severe COVID-19. In fact, some IEI may even be protective against the severe disease due to impaired inflammation resulting in less immune-mediated collateral tissue damage. SUMMARY: We review the characteristics of SARS-CoV-2 infection in a large number of patients with IEI. Overall, we found that combined immunodeficiencies, immune dysregulation disorders, and innate immune defects impairing type I interferon responses are associated with severe disease course.


Assuntos
COVID-19 , Doenças da Imunodeficiência Primária , Progressão da Doença , Suscetibilidade a Doenças , Humanos , SARS-CoV-2
3.
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
4.
J Clin Immunol ; 2021 Oct 17.
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.

5.
J Clin Immunol ; 41(8): 1915-1935, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34657246

RESUMO

PURPOSE: Deficiency of adenosine deaminase type 2 (ADA2) (DADA2) is a rare inborn error of immunity caused by deleterious biallelic mutations in ADA2. Clinical manifestations are diverse, ranging from severe vasculopathy with lacunar strokes to immunodeficiency with viral infections, hypogammaglobulinemia and bone marrow failure. Limited data are available on the phenotype and function of leukocytes from DADA2 patients. The aim of this study was to perform in-depth immunophenotyping and functional analysis of the impact of DADA2 on human lymphocytes. METHODS: In-depth immunophenotyping and functional analyses were performed on ten patients with confirmed DADA2 and compared to heterozygous carriers of pathogenic ADA2 mutations and normal healthy controls. RESULTS: The median age of the patients was 10 years (mean 20.7 years, range 1-44 years). Four out of ten patients were on treatment with steroids and/or etanercept or other immunosuppressives. We confirmed a defect in terminal B cell differentiation in DADA2 and reveal a block in B cell development in the bone marrow at the pro-B to pre-B cell stage. We also show impaired differentiation of CD4+ and CD8+ memory T cells, accelerated exhaustion/senescence, and impaired survival and granzyme production by ADA2 deficient CD8+ T cells. Unconventional T cells (i.e. iNKT, MAIT, Vδ2+ γδT) were diminished whereas pro-inflammatory monocytes and CD56bright immature NK cells were increased. Expression of the IFN-induced lectin SIGLEC1 was increased on all monocyte subsets in DADA2 patients compared to healthy donors. Interestingly, the phenotype and function of lymphocytes from healthy heterozygous carriers were often intermediate to that of healthy donors and ADA2-deficient patients. CONCLUSION: Extended immunophenotyping in DADA2 patients shows a complex immunophenotype. Our findings provide insight into the cellular mechanisms underlying some of the complex and heterogenous clinical features of DADA2. More research is needed to design targeted therapy to prevent viral infections in these patients with excessive inflammation as the overarching phenotype.

6.
Curr Opin Allergy Clin Immunol ; 21(6): 515-524, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34494617

RESUMO

PURPOSE OF REVIEW: The severe acute respiratory syndrome (SARS)-coronavirus 2 (CoV2)/COVID-19 pandemic has reminded us of the fundamental and nonredundant role played by the innate and adaptive immune systems in host defense against emerging pathogens. The study of rare 'experiments of nature' in the setting of inborn errors of immunity (IEI) caused by monogenic germline variants has revealed key insights into the molecular and cellular requirements for immune-mediated protection against infectious diseases. This review will provide an overview of the discoveries obtained from investigating severe COVID-19 in patients with defined IEI or otherwise healthy individuals. RECENT FINDINGS: Genetic, serological and cohort studies have provided key findings regarding host defense against SARS-CoV2 infection, and mechanisms of disease pathogenesis. Remarkably, the risk factors, severity of disease, and case fatality rate following SARS-CoV2 infection in patients with IEI were not too dissimilar to that observed for the general population. However, the type I interferon (IFN) signaling pathway - activated in innate immune cells in response to viral sensing - is critical for anti-SARS-CoV2 immunity. Indeed, genetic variants or autoAbs affecting type I IFN function account for up to 20% of all cases of life-threatening COVID-19. SUMMARY: The analysis of rare cases of severe COVID-19, coupled with assessing the impact of SARS-CoV2 infection in individuals with previously diagnosed IEI, has revealed fundamental aspects of human immunology, disease pathogenesis and immunopathology in the context of exposure to and infection with a novel pathogen. These findings can be leveraged to improve therapies for treating for emerging and established infectious diseases.


Assuntos
COVID-19/imunologia , Interações Hospedeiro-Patógeno/genética , Doenças da Imunodeficiência Primária/imunologia , SARS-CoV-2/imunologia , COVID-19/diagnóstico , COVID-19/mortalidade , COVID-19/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Doenças da Imunodeficiência Primária/complicações , Doenças da Imunodeficiência Primária/genética , Fatores de Risco , Índice de Gravidade de Doença
7.
Trends Immunol ; 42(8): 658-669, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34244056

RESUMO

T follicular helper (Tfh) cells cognately guide differentiation of antigen-primed B cells in secondary lymphoid tissues. 'Tfh-like' populations not expressing the canonical Tfh cell transcription factor BCL6 have also been described, which can aid particular aspects of B cell differentiation. Tfh and Tfh-like cells are essential for protective and pathological humoral immunity. These CD4+ T cells that help B cells are polarized to produce diverse combinations of cytokines and chemokine receptors and can be grouped into distinct subsets that promote antibodies of different isotype, affinity, and duration, according to the nature of immune challenge. However, unified nomenclature to describe the distinct functional Tfh and Tfh-like cells does not exist. While explicitly acknowledging cellular plasticity, we propose categorizing these cell states into three groups based on phenotype and function, paired with their anatomical site of action.


Assuntos
Linfócitos B , Centro Germinativo , Diferenciação Celular , Imunidade Humoral , Ativação Linfocitária , Linfócitos T Auxiliares-Indutores
8.
Curr Opin Immunol ; 72: 249-261, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34284230

RESUMO

The production of high-affinity antibodies is a key feature of the vertebrate immune system. Antibodies neutralize and clear pathogens, thereby protecting against infectious diseases. However, dysregulated production of antibodies can cause immune pathologies, such as autoimmunity and immune deficiency. Long-lived humoral immunity depends on B-cell help provided by T follicular helper (Tfh) cells, which support the differentiation of antigen (Ag)-specific B cells into memory and plasma cells. Tfh cells are generated from naïve CD4+ T cells following the receipt of inputs from various cell surface receptors, and can undergo further differentiation into subsets with specialised effector functions to induce and maintain serological memory. While genetically modified mice have provided great understanding of the requirements for generating Tfh cells, it is critical that requirements for human Tfh cell generation and function are also established. Key insights into the molecular requirements for human Tfh cells have been elucidated from the systematic analysis of humans with monogenic germline variants that cause inborn errors of immunity characterised by impaired humoral immunity following infection or vaccination or immune dysregulation and autoimmunity. In this review we will discuss how studying rare 'experiments of nature' has enabled discovery of non-redundant molecules and pathways necessary for Tfh cell generation, differentiation, regulation and function in humans, and how these findings inform us about basic and clinical immunology.

9.
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
10.
Expert Rev Clin Immunol ; 17(8): 905-914, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34157234

RESUMO

INTRODUCTION: Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that plays a fundamental role in cell survival, metabolism, proliferation and differentiation. Thus, balanced PI3K signalling is critical for multiple aspects of human health. The discovery that germline variants in genes in the PI3K pathway caused inborn errors of immunity highlighted the non-redundant role of these signalling proteins in the human immune system. The subsequent identification and characterisation of >300 individuals with a novel immune dysregulatory disorder, termed activated PI3K-delta syndrome (APDS), has reinforced the status of PI3K as a key pathway regulating immune function. Studies of APDS have demonstrated that dysregulated PI3K function is disruptive for immune cell development, activation, differentiation, effector function and self-tolerance, which are all important in supporting effective, long-term immune responses. AREAS COVERED: In this review, we recount recent findings regarding humans with germline variants in PI3K genes and discuss the underlying cellular and molecular pathologies, with a focus on implications for therapy in APDS patients. EXPERT OPINION: Modulating PI3K immune cell signalling by offers opportunities for therapeutic interventions in settings of immunodeficiency, autoimmunity and malignancy, but also highlights potential adverse events that may result from overt pharmacological or intrinsic inhibition of PI3K function.

11.
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
13.
Nat Commun ; 12(1): 2931, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006841

RESUMO

Indigenous people worldwide are at high risk of developing severe influenza disease. HLA-A*24:02 allele, highly prevalent in Indigenous populations, is associated with influenza-induced mortality, although the basis for this association is unclear. Here, we define CD8+ T-cell immune landscapes against influenza A (IAV) and B (IBV) viruses in HLA-A*24:02-expressing Indigenous and non-Indigenous individuals, human tissues, influenza-infected patients and HLA-A*24:02-transgenic mice. We identify immunodominant protective CD8+ T-cell epitopes, one towards IAV and six towards IBV, with A24/PB2550-558-specific CD8+ T cells being cross-reactive between IAV and IBV. Memory CD8+ T cells towards these specificities are present in blood (CD27+CD45RA- phenotype) and tissues (CD103+CD69+ phenotype) of healthy individuals, and effector CD27-CD45RA-PD-1+CD38+CD8+ T cells in IAV/IBV patients. Our data show influenza-specific CD8+ T-cell responses in Indigenous Australians, and advocate for T-cell-mediated vaccines that target and boost the breadth of IAV/IBV-specific CD8+ T cells to protect high-risk HLA-A*24:02-expressing Indigenous and non-Indigenous populations from severe influenza disease.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Epitopos de Linfócito T/genética , Antígeno HLA-A24/genética , Povos Indígenas/genética , Adulto , Alelos , Sequência de Aminoácidos , Animais , Austrália , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Cães , Epitopos de Linfócito T/imunologia , Feminino , Frequência do Gene , Antígeno HLA-A24/imunologia , Humanos , Vírus da Influenza A/imunologia , Vírus da Influenza A/fisiologia , Vírus da Influenza B/imunologia , Vírus da Influenza B/fisiologia , Influenza Humana/imunologia , Influenza Humana/virologia , Masculino , Camundongos Transgênicos , Pessoa de Meia-Idade
14.
J Clin Immunol ; 41(6): 1272-1290, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33929673

RESUMO

Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections. While eight IL-21R-deficient patients have been reported previously, the natural course, immune characteristics of disease, and response to hematopoietic stem cell transplantation (HSCT) remain to be comprehensively examined. In our study, we have collected clinical histories of 13 patients with IL-21R deficiency from eight families across seven centers worldwide, including five novel patients identified by exome or NGS panel sequencing. Eight unique mutations in IL21R were identified in these patients, including two novel mutations. Median age at disease onset was 2.5 years (0.5-7 years). The main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was 33.3%, with pre-existing organ damage constituting a negative prognostic factor. Mortality of non-transplanted patients (n = 7) was 57.1%. Our detailed analysis of the largest cohort of IL-21R-deficient patients to date provides in-depth clinical, immunological and immunophenotypic features of these patients, thereby establishing critical non-redundant functions of IL-21/IL-21R signaling in lymphocyte differentiation, humoral immunity and host defense against infection, and mechanisms of disease pathogenesis due to IL-21R deficiency. Outcome following HSCT depends on prior chronic infections and organ damage, which should thus be considered as early as possible following molecular diagnosis.

15.
J Exp Med ; 218(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33904890

RESUMO

Multisystem inflammatory syndrome in children (MIS-C) emerged in April 2020 in communities with high COVID-19 rates. This new condition is heterogenous but resembles Kawasaki disease (KD), a well-known but poorly understood and clinically heterogenous pediatric inflammatory condition for which weak associations have been found with a myriad of viral illnesses. Epidemiological data clearly indicate that SARS-CoV-2 is the trigger for MIS-C, which typically occurs about 1 mo after infection. These findings support the hypothesis of viral triggers for the various forms of classic KD. We further suggest that rare inborn errors of immunity (IEIs) altering the immune response to SARS-CoV-2 may underlie the pathogenesis of MIS-C in some children. The discovery of monogenic IEIs underlying MIS-C would shed light on its pathogenesis, paving the way for a new genetic approach to classic KD, revisited as a heterogeneous collection of IEIs to viruses.


Assuntos
COVID-19/etiologia , Síndrome de Linfonodos Mucocutâneos/genética , Síndrome de Linfonodos Mucocutâneos/virologia , SARS-CoV-2/patogenicidade , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Biomarcadores/sangue , COVID-19/epidemiologia , COVID-19/imunologia , Criança , Citocinas/sangue , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Inflamação/etiologia , Inflamação/genética , Inflamação/imunologia , Mediadores da Inflamação/sangue , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/virologia , Modelos Biológicos , Síndrome de Linfonodos Mucocutâneos/epidemiologia , Pandemias , SARS-CoV-2/imunologia , Síndrome de Resposta Inflamatória Sistêmica/epidemiologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia
16.
J Clin Immunol ; 41(3): 666-679, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33598806

RESUMO

The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.

18.
Stem Cells ; 39(4): 389-402, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33400834

RESUMO

Hematopoietic stem cells (HSCs) are the progenitor cells that give rise to the diverse repertoire of all immune cells. As they differentiate, HSCs yield a series of cell states that undergo gradual commitment to become mature blood cells. Studies of hematopoiesis in murine models have provided critical insights about the lineage relationships among stem cells, progenitors, and mature cells, and these have guided investigations of the molecular basis for these distinct developmental stages. Primary immune deficiencies are caused by inborn errors of immunity that result in immune dysfunction and subsequent susceptibility to severe and recurrent infection(s). Over the last decade there has been a dramatic increase in the number and depth of the molecular, cellular, and clinical characterization of such genetically defined causes of immune dysfunction. Patients harboring inborn errors of immunity thus represent a unique resource to improve our understanding of the multilayered and complex mechanisms underlying lymphocyte development in humans. These breakthrough discoveries not only enable significant advances in the diagnosis of such rare and complex conditions but also provide substantial improvement in the development of personalized treatments. Here, we will discuss the clinical, cellular, and molecular phenotypes, and treatments of selected inborn errors of immunity that impede, either intrinsically or extrinsically, the development of B- or T-cells at different stages.

19.
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
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