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Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of Mycobacterium-non reactive classic TH1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αß T and non-classic CD4+ αß TH1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8+ αß T, and CD4+ αß TH1∗ cells unable to compensate for this deficit.
Assuntos
Imunidade Adaptativa , Imunidade Inata , Interferon gama/imunologia , Mycobacterium/imunologia , Proteínas com Domínio T/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Linhagem da Célula , Pré-Escolar , Cromatina/metabolismo , Ilhas de CpG/genética , Metilação de DNA/genética , Células Dendríticas/metabolismo , Epigênese Genética , Feminino , Homozigoto , Humanos , Mutação INDEL/genética , Lactente , Interferon gama/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Mutação com Perda de Função/genética , Masculino , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/microbiologia , Linhagem , Proteínas com Domínio T/química , Proteínas com Domínio T/deficiência , Proteínas com Domínio T/genética , Linfócitos T Auxiliares-Indutores/imunologia , Transcriptoma/genéticaRESUMO
PURPOSE: The first molecular evidence of a monogenic predisposition to mycobacteria came from the study of Mendelian susceptibility to mycobacterial disease (MSMD). We aimed to study this Mendelian susceptibility to mycobacterial diseases in Moroccan kindreds through clinical, immunological, and genetic analysis. METHODS: Patients presented with clinical features of MSMD were recruited into this study. We used whole blood samples from patients and age-matched healthy controls. To measure IL-12 and IFN-γ production, samples were activated by BCG plus recombinant human IFN-γ or recombinant human IL-12. Immunological assessments and genetic analysis were also done for patients and their relatives. RESULTS: Our study involved 22 cases from 15 unrelated Moroccan kindreds. The average age at diagnosis is 4 years. Fourteen patients (64%) were born to consanguineous parents. All patients were vaccinated with the BCG vaccine, and twelve of them (55%) developed locoregional or disseminated BCG infections. The other symptomatic patients had severe tuberculosis and/or recurrent salmonellosis. Genetic mutations were identified on the following genes: IL12RB1 in 8 patients, STAT1 in 7 patients; SPPL2A, IFNGR1, and TYK2 in two patients each; and TBX21 in one patient, with different modes of inheritance. All identified mutations/variants altered production or response to IFN-γ or both. CONCLUSION: Severe forms of tuberculosis and complications of BCG vaccination may imply a genetic predisposition present in the Moroccan population. In the presence of these infections, systematic genetic studies became necessary. BCG vaccination is contraindicated in MSMD patients and should be delayed in newborn siblings until the exclusion of a genetic predisposition to mycobacteria.
Assuntos
Infecções por Mycobacterium , Mycobacterium , Tuberculose , Recém-Nascido , Humanos , Pré-Escolar , Predisposição Genética para Doença , Vacina BCG , Infecções por Mycobacterium/etiologia , Tuberculose/genética , Interleucina-12 , Mutação/genéticaRESUMO
The constant progress of genomics and the establishment of new functional tests have paved the way for identifying monogenic defects conferring a selective predisposition to infections by certain microbes as a new type of inborn errors of immunity (IEIs). Mendelian susceptibility to mycobacterial diseases (MSMD) is the most characterized of these IEIs, with 36 different disorders found in 20 distinct genes (IFNGR1, IFNGR2, IFNG, IL12RB1, IL12RB2, IL23R, IL12B, ISG15, USP18, ZNFX1, TBX21, STAT1, TYK2, IRF8, IRF1, CYBB, JAK1, RORC, NEMO, and SPPL2A) over the last 20 years. MSMD confers a selective susceptibility to infections with weakly virulent mycobacteria, including the M. bovis Bacille Calmette-Guerin (BCG) vaccines and various environmental mycobacteria in patients, primarily children, without classical immune defects. These patients may also present severe forms of tuberculosis, and about half of them might develop non-typhoidal salmonellosis. In some cases, patients also suffer from chronic mucocutaneous candidiasis (CMC), while in others, patients also present severe viral, parasitic, fungal, and/or bacterial diseases. Despite this clinical and genetic heterogeneity, almost all genetic etiologies of MSMD alter the interferon-gamma (IFN-γ)- mediated immunity by impairing or abolishing IFN-γ production or the response to this cytokine. It was proven that the human IFN-γ level is a quantitative trait that defines the outcome of mycobacterial infection. The study of these monogenic defects contributes to understanding the molecular mechanism of mycobacterial diseases in humans and to the development of new diagnostic and therapeutic approaches to improve care and prognosis. For example, MSMD patients with impaired production of IFN-γ may benefit from injections of human recombinant IFN-γ, while for patients with abolished response to this cytokine, hematopoietic stem cell transplantation (HSCT) and promising gene therapy are the only current therapeutic options. These discoveries also bridge the gap between simple Mendelian inheritance and complex human genetics.
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Objective: Common variable immunodeficiency (CVID) is a complex inborn error of humoral immunity with complications of both infectious and non-infectious origins. Classifications of CVID patients provide a clearer understanding of the pathogenesis, prediction, and management of non-infectious complications. This study aims to classify Moroccan CVID patients based on the European classification (EUROclass). Materials and Methods: We recruited 20 CVID patients meeting standard diagnostic criteria (5-6). After collecting clinical and demographic data, we used flow cytometry to analyze B-cell subsets and group patients and assess the relation of each group with clinical manifestations. Results: 90% of the patients in our cohort study had a history of respiratory infections. The noninfectious manifestations included splenomegaly, autoimmunity, lymphadenopathy, and granulomatous diseases diagnosed in 50%, 45%, 40%, and 25% of patients, respectively. We observed significant co-occurrence of splenomegaly with autoimmunity and granulomatous diseases to a lesser extent. Patients had a significant reduction in total, switched memory, marginal zone-like, plasma blasts, and a substantial increase in the percentage of activated B cells, suggesting a defect in the late phases of B-cell differentiation. This condition was linked with an increased occurrence of splenomegaly and granulomatous affections. Besides, patients also had an expansion of CD21low B-cells, which was strongly associated with splenomegaly. Conclusion: The classification of the first Moroccan cohort of CVID patients showed agreement with previous results. It suggests the possibility of adopting this approach on a global scale for better diagnosis and follow-up of CVID patients.
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INTRODUCTION: Morocco has made remarkable progress in the fight against tuberculosis, but the Covid-19 pandemic has affected tuberculosis control worldwide, with notable fluctuations in tuberculosis epidemiology during and after the pandemic. AIM: To describe the impact of the Covid-19 pandemic on the rate of hospitalization for tuberculosis and its different localizations in children. METHODS: We conducted a retrospective study based on the analysis of medical records of TB patients hospitalized within the Children's Hospital in Casablanca, during the periods before (2018-2019), during (2020) and after (2021-2022) Covid-19 quarantine. RESULTS: Throughout the study period (2018-2022), the total number of patients hospitalized in our department was 7390, including 283 children were hospitalized for tuberculosis, with a mean age of 6 years. Before the Covid-19 pandemic, the average number of tuberculosis cases was 49 per year, of which the percentage of pulmonary tuberculosis was 32% and extra-pulmonary tuberculosis 68%. The number of cases was 23 per year during the quarantine period, with a percentage of pulmonary tuberculosis of 26% and extra-pulmonary tuberculosis of 74%. After the quarantine period, this number rose to 81 cases per year, of which 21% were pulmonary tuberculosis and 79% extrapulmonary tuberculosis (pleural tuberculosis was predominant in 44.1% of cases). CONCLUSION: These results are consistent with data published by the World Health Organization, and with the findings of another study we carried out on the impact of COVID-19 on hospital admissions for acute lower respiratory tract infections. It is very likely that the reduction in the number of tuberculosis cases during the quarantine period is due to social distancing, which leads to a reduction in the transmission of tuberculosis between people as well as to the disruption of the national tuberculosis control program in Morocco, when positive cases are identified.
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COVID-19 , Hospitalização , Tuberculose , Humanos , COVID-19/epidemiologia , Criança , Hospitalização/estatística & dados numéricos , Estudos Retrospectivos , Marrocos/epidemiologia , Feminino , Masculino , Tuberculose/epidemiologia , Pré-Escolar , Adolescente , Quarentena , Tuberculose Pulmonar/epidemiologia , Lactente , Hospitais Pediátricos/estatística & dados numéricosRESUMO
Tuberculous meningitis, a severe form of tuberculosis caused by Mycobacterium tuberculosis (BK), remains a major public health challenge worldwide. In addition to the complex mechanisms of the innate and adaptive immune response against Mycobacterium tuberculosis, there is a crucial genetic dimension to consider. Individuals with specific genetic variations may have altered immune responses that make them more susceptible to this form of tuberculosis. Genetic mutations in genes encoding surface receptors, adaptor proteins, kinases, transcription factors, nucleic receptors and other molecules involved in cellular interactions and molecular mechanisms have been associated with susceptibility to TB. Understanding the molecular mechanisms of immune interactions in host response to Mycobacterium tuberculosis is crucial to understanding the genetic dimension in susceptibility to tuberculosis, particularly its dreaded form of tuberculous meningitis. The aim of this update is to explore in details the key interactions between the main players in innate and adaptive immunity during infection with Mycobacterium tuberculosis, with particular emphasis on the genetic factors associated with susceptibility to tuberculosis, especially its dreaded form of tuberculous meningitis.
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Predisposição Genética para Doença , Mycobacterium tuberculosis , Tuberculose Meníngea , Humanos , Tuberculose Meníngea/genética , Tuberculose Meníngea/imunologia , Mycobacterium tuberculosis/imunologia , Imunidade Inata/genética , Imunidade Adaptativa/genéticaRESUMO
INTRODUCTION: The future of the COVID-19 pandemic depends on the evolution of the virus and immune protection stimulated by vaccination or upon exposure to natural infection. While most research focuses on vaccine efficacy, data remain unclear on the efficacy and duration of natural immune protection against infection. AIM: In this article, we aim to determine the efficacy of natural immune protection against reinfection with COVID-19 or severe COVID-19. METHODS: We performed a systematic review of available studies in electronic databases followed by a meta-analysis to determine the efficacy of natural immune protection against COVID-19 reinfection and severe infection. RESULTS: Of the 414 studies identified for the full review, 8 studies met the inclusion criteria and were analyzed. The total number of individuals participating in the 8 studies included 19,837,147 people. Individuals with a history of SARS-CoV-2 infection (1,9% [0,6%-3,1%]) had a lower rate of infection than individuals without a history of infection (7,1% [3,9%-10,1%]). The mean efficacy of natural immune protection against reinfection was 84,7% [78,5%-90,9%], while the mean efficacy of natural immune protection against severe COVID-19 infection was 96,9% [94%-99,6%]. CONCLUSION: These results indicate that natural immune protection against reinfection is high, particularly against severe COVID-19. However, further research is needed to determine the duration of natural immune protection and the impact of different variants of SARS-CoV-2.
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COVID-19 , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , SARS-CoV-2 , Pandemias , Reinfecção/epidemiologia , Reinfecção/prevenção & controleRESUMO
Objective: SSc is a CTD characterized by excessive fibrosis of the skin and internal organs, along with microvascular damage, and is often associated with typical autoantibodies. The aim of this study was to analyse the correlation between specific autoantibody profiles, clinical and paraclinical features in Moroccan patients with SSc. Methods: We analysed the presence of specific autoantibodies in 46 SSc patients using IIF on HEp-2 cells and immunodot. We then correlated the types of autoantibodies with clinical and laboratory manifestations. Results: Among our patients, 86.9% were females. The mean age of patients at diagnosis was 50.21 years, with an average delay to diagnosis of 5 years. The main clinical manifestations found were RP (89.2%), sclerodactyly (84.8%), proximal scleroderma (67.4%), gastrointestinal involvement (50%) and interstitial lung disease (30.4%). According to the specific autoantibody profile, 14 patients were anti-topo I positive (30.4%), 8 anti-RNP (68 kDa/A/C) positive (17.4%) and 6 anti-RNA polymerase III positive (13%). We found a significant association of anti-RNA polymerase III with sclerodactyly and pulmonary arterial hypertension (P < 0.05). We also found an association between anti-topo I and interstitial lung disease in 30.4% of patients. There was no significant association between the positivity for the autoantibodies and other diagnosed clinical manifestations. Conclusion: Some clinical manifestations of SSc might be positively correlated with the presence of specific autoantibodies. Environmental factors, ethnicity and gene interaction might also influence this correlation.
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Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/ß (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.