Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 158
Filtrar
Más filtros

Bases de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Nat Immunol ; 22(11): 1428-1439, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34471264

RESUMEN

Coordinated local mucosal and systemic immune responses following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection either protect against coronavirus disease 2019 (COVID-19) pathologies or fail, leading to severe clinical outcomes. To understand this process, we performed an integrated analysis of SARS-CoV-2 spike-specific antibodies, cytokines, viral load and bacterial communities in paired nasopharyngeal swabs and plasma samples from a cohort of clinically distinct patients with COVID-19 during acute infection. Plasma viral load was associated with systemic inflammatory cytokines that were elevated in severe COVID-19, and also with spike-specific neutralizing antibodies. By contrast, nasopharyngeal viral load correlated with SARS-CoV-2 humoral responses but inversely with interferon responses, the latter associating with protective microbial communities. Potential pathogenic microorganisms, often implicated in secondary respiratory infections, were associated with mucosal inflammation and elevated in severe COVID-19. Our results demonstrate distinct tissue compartmentalization of SARS-CoV-2 immune responses and highlight a role for the nasopharyngeal microbiome in regulating local and systemic immunity that determines COVID-19 clinical outcomes.


Asunto(s)
COVID-19/inmunología , Microbiota/inmunología , Nasofaringe/inmunología , SARS-CoV-2/fisiología , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anticuerpos Antivirales/sangre , Estudios de Cohortes , Femenino , Humanos , Inmunidad Humoral , Inmunidad Mucosa , Interferones/sangre , Masculino , Persona de Mediana Edad , Nasofaringe/microbiología , Glicoproteína de la Espiga del Coronavirus/inmunología , Carga Viral , Adulto Joven
2.
Nat Immunol ; 22(5): 607-619, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33833438

RESUMEN

FOXP3 deficiency in mice and in patients with immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome results in fatal autoimmunity by altering regulatory T (Treg) cells. CD4+ T cells in patients with IPEX syndrome and Foxp3-deficient mice were analyzed by single-cell cytometry and RNA-sequencing, revealing heterogeneous Treg-like cells, some very similar to normal Treg cells, others more distant. Conventional T cells showed no widespread activation or helper T cell bias, but a monomorphic disease signature affected all CD4+ T cells. This signature proved to be cell extrinsic since it was extinguished in mixed bone marrow chimeric mice and heterozygous mothers of patients with IPEX syndrome. Normal Treg cells exerted dominant suppression, quenching the disease signature and revealing in mutant Treg-like cells a small cluster of genes regulated cell-intrinsically by FOXP3, including key homeostatic regulators. We propose a two-step pathogenesis model: cell-intrinsic downregulation of core FOXP3-dependent genes destabilizes Treg cells, de-repressing systemic mediators that imprint the disease signature on all T cells, furthering Treg cell dysfunction. Accordingly, interleukin-2 treatment improved the Treg-like compartment and survival.


Asunto(s)
Diabetes Mellitus Tipo 1/congénito , Diarrea/genética , Factores de Transcripción Forkhead/deficiencia , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades del Sistema Inmune/congénito , Linfocitos T Reguladores/inmunología , Adolescente , Animales , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Conjuntos de Datos como Asunto , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Diarrea/sangre , Diarrea/inmunología , Modelos Animales de Enfermedad , Citometría de Flujo , Factores de Transcripción Forkhead/genética , Enfermedades Genéticas Ligadas al Cromosoma X/sangre , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Humanos , Enfermedades del Sistema Inmune/sangre , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/inmunología , Lactante , Masculino , Ratones , Ratones Transgénicos , Mutación , RNA-Seq , Análisis de la Célula Individual , Linfocitos T Reguladores/metabolismo , Adulto Joven
3.
J Allergy Clin Immunol ; 153(1): 67-76, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37977527

RESUMEN

Chronic nonmalignant lymphoproliferation and autoimmune cytopenia are relevant manifestations of immunohematologic diseases of childhood. Their diagnostic classification is challenging but important for therapy. Autoimmune lymphoproliferative syndrome (ALPS) is a genetically defined inborn error of immunity combining these manifestations, but it can explain only a small proportion of cases. Diagnostic categories such as ALPS-like disease, common variable immunodeficiency, or Evans syndrome have therefore been used. Advances in genetics and increasing availablity of targeted therapies call for more therapy-oriented disease classification. Moreover, recent discoveries in the (re)analysis of genetic conditions affecting FAS signaling ask for a more precise definition of ALPS. In this review, we propose the term autoimmune lymphoproliferative immunodeficiencies for a disease phenotype that is enriched for patients with genetic diseases for which targeted therapies are available. For patients without a current molecular diagnosis, this term defines a subgroup of immune dysregulatory disorders for further studies. Within the concept of autoimmune lymphoproliferative immunodeficiencies, we propose a revision of the ALPS classification, restricting use of this term to conditions with clear evidence of perturbation of FAS signaling and resulting specific biologic and clinical consequences. This proposed approach to redefining ALPS and other lymphoproliferative conditions provides a framework for disease classification and diagnosis that is relevant for the many specialists confronted with these diseases.


Asunto(s)
Anemia Hemolítica Autoinmune , Enfermedades Autoinmunes , Síndrome Linfoproliferativo Autoinmune , Inmunodeficiencia Variable Común , Enfermedades del Sistema Inmune , Trastornos Linfoproliferativos , Humanos , Síndrome Linfoproliferativo Autoinmune/diagnóstico , Síndrome Linfoproliferativo Autoinmune/genética , Síndrome Linfoproliferativo Autoinmune/terapia , Fenotipo , Receptor fas/genética , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/terapia
4.
J Allergy Clin Immunol ; 154(1): 229-236.e2, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38438084

RESUMEN

BACKGROUND: Immune dysregulation often presents as autoimmunity, inflammation, and/or lymphoproliferation. Several germline genetic defects have been associated with immune dysregulation; they include heterozygous gain-of-function (GOF) mutations in IKZF1, an essential transcription factor for hematopoiesis containing zinc finger domains (ZFs). However, in a large percentage of patients, the genetic origin of their immunedysregulation remains undetermined. OBJECTIVE: A family with 2 members presenting immune dysregulation signs was studied to identify the genetic cause of their disease. METHODS: Whole exome sequencing, analysis of immunologic parameters, and functional assays (including Western blotting, electrophoretic mobility shift assay during the cell cycle, and TH cell differentiation) were performed. RESULTS: The 2 patients carried a novel heterozygous mutation in IKZF1 (IKZF1T398M). IKZF1 heterozygous mutations have previously been shown to be responsible for several distinct human immunologic diseases by directly affecting the ability of ZFs to bind to DNA or to dimerize. Herein, we showed that the IKZF1T398M, which is outside the ZFs, caused impaired phosphorylation of IKZF1, resulting in enhanced DNA-binding ability at the S phase of the cell cycle, reduction of the G1-S phase transition, and decreased proliferation. Confirming these data, similar functional alterations were observed with IKZF1T398A, but not with IKZF1T398D, mimicking dephosphorylation and phosphorylation, respectively. In T lymphocytes, expression of IKZF1T398M led to TH cell differentiation skewed toward TH2 cells. Thus, our data indicate that IKZF1T398M behaves as a GOF variant underlying immune dysregulation. CONCLUSION: Disturbed IKZF1 phosphorylation represents a novel GOF mechanism (GOF by loss of phosphorylation (termed as GOF-LOP) associated with immune dysregulation, highlighting the regulatory role of IKZF1 during cell cycle progression through phosphorylation.


Asunto(s)
Mutación con Ganancia de Función , Factor de Transcripción Ikaros , Humanos , Factor de Transcripción Ikaros/genética , Fosforilación , Femenino , Masculino , Linaje , Adulto
5.
J Allergy Clin Immunol ; 153(1): 203-215, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37793571

RESUMEN

BACKGROUND: The autoimmune lymphoproliferative syndrome (ALPS) is a noninfectious and nonmalignant lymphoproliferative disease frequently associated with autoimmune cytopenia resulting from defective FAS signaling. We previously described germline monoallelic FAS (TNFRSF6) haploinsufficient mutations associated with somatic events, such as loss of heterozygosity on the second allele of FAS, as a cause of ALPS-FAS. These somatic events were identified by sequencing FAS in DNA from double-negative (DN) T cells, the pathognomonic T-cell subset in ALPS, in which the somatic events accumulated. OBJECTIVE: We sought to identify whether a somatic event affecting the FAS-associated death domain (FADD) gene could be related to the disease onset in 4 unrelated patients with ALPS carrying a germline monoallelic mutation of the FADD protein inherited from a healthy parent. METHODS: We sequenced FADD and performed array-based comparative genomic hybridization using DNA from sorted CD4+ or DN T cells. RESULTS: We found homozygous FADD mutations in the DN T cells from all 4 patients, which resulted from uniparental disomy. FADD deficiency caused by germline heterozygous FADD mutations associated with a somatic loss of heterozygosity was a phenocopy of ALPS-FAS without the more complex symptoms reported in patients with germline biallelic FADD mutations. CONCLUSIONS: The association of germline and somatic events affecting the FADD gene is a new genetic cause of ALPS.


Asunto(s)
Síndrome Linfoproliferativo Autoinmune , Proteína de Dominio de Muerte Asociada a Fas , Humanos , Apoptosis/genética , Enfermedades Autoinmunes/genética , Síndrome Linfoproliferativo Autoinmune/genética , Hibridación Genómica Comparativa , ADN , Receptor fas/genética , Proteína de Dominio de Muerte Asociada a Fas/genética , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Células Germinativas/patología , Mutación
6.
J Allergy Clin Immunol ; 153(1): 297-308.e12, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37979702

RESUMEN

BACKGROUND: Elevated TCRαß+CD4-CD8- double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U). OBJECTIVE: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway-related genes could explain these cases. METHODS: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway-related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss of heterozygosity (sLOH). RESULTS: Nine of 16 patients with ALPS-U lacked FAS expression on CD57+DNT predicting heterozygous "loss-of-expression" FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH. CONCLUSION: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing.


Asunto(s)
Síndrome Linfoproliferativo Autoinmune , Receptor fas , Humanos , Síndrome Linfoproliferativo Autoinmune/diagnóstico , Síndrome Linfoproliferativo Autoinmune/genética , Biomarcadores , Variaciones en el Número de Copia de ADN , Secuenciación del Exoma , Receptor fas/genética , Proteína de Dominio de Muerte Asociada a Fas/genética , Mutación
7.
J Allergy Clin Immunol ; 153(1): 275-286.e18, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37935260

RESUMEN

BACKGROUND: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited. OBJECTIVE: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers. METHODS: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months. RESULTS: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival. CONCLUSIONS: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.


Asunto(s)
Síndromes de Inmunodeficiencia , Inhibidores de las Cinasas Janus , Niño , Humanos , Inhibidores de las Cinasas Janus/uso terapéutico , Estudios Retrospectivos , Estudios Prospectivos , Síndromes de Inmunodeficiencia/terapia , Resultado del Tratamiento
8.
Clin Immunol ; 261: 110165, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38423196

RESUMEN

Mutations in NFkB pathway genes can cause inborn errors of immunity (IEI), with NFKB1 haploinsufficiency being a significant etiology for common variable immunodeficiency (CVID). Indeed, mutations in NFKB1 are found in 4 to 5% of in European and United States CVID cohorts, respectively; CVID representing almost » of IEI patients in European countries registries. This case study presents a 49-year-old patient with respiratory infections, chronic diarrhea, immune thrombocytopenia, hypogammaglobulinemia, and secondary lymphoma. Comprehensive genetic analysis, including high-throughput sequencing of 300 IEI-related genes and copy number variation analysis, identified a critical 2.6-kb deletion spanning the first untranslated exon and its upstream region. The region's importance was confirmed through genetic markers indicative of enhancers and promoters. The deletion was also found in the patient's brother, who displayed similar but milder symptoms. Functional analysis supported haploinsufficiency with reduced mRNA and protein expression in both patients. This case underscores the significance of copy number variation (CNV) analysis and targeting noncoding exons within custom gene panels, emphasizing the broader genomic approaches needed in medical genetics.


Asunto(s)
Inmunodeficiencia Variable Común , Hermanos , Masculino , Adulto , Humanos , Persona de Mediana Edad , Haploinsuficiencia/genética , Variaciones en el Número de Copia de ADN , FN-kappa B/genética , Inmunodeficiencia Variable Común/genética , Secuencias Reguladoras de Ácidos Nucleicos , Subunidad p50 de NF-kappa B/genética
9.
Br J Haematol ; 2024 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-39233474

RESUMEN

MYSM1 deficiency causes inherited bone marrow failure syndrome (IBMFS). We have previously identified an IBMFS patient with a homozygous pathogenic variant in MYSM1 who recovered from cytopenia due to spontaneous correction of one MYSM1 variant in the haematopoietic compartment, an event called somatic genetic rescue (SGR). The study of the genetic and biological aspects of the patient's haematopoietic/lymphopoietic system over a decade after SGR shows that one genetically corrected haematopoietic stem cell (HSC) can restore a healthy and stable haematopoietic system. This supports in vivo gene correction of HSCs as a promising treatment for IBMFS, including MYSM1 deficiency.

10.
Br J Haematol ; 204(5): 1899-1907, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38432067

RESUMEN

Kabuki syndrome (KS) is now listed in the Human Inborn Errors of Immunity (IEI) Classification. It is a rare disease caused by KMT2D and KDM6A variants, dominated by intellectual disability and characteristic facial features. Recurrently, pathogenic variants are identified in those genes in patients examined for autoimmune cytopenia (AIC), but interpretation remains challenging. This study aims to describe the genetic diagnosis and the clinical management of patients with paediatric-onset AIC and KS. Among 11 patients with AIC and KS, all had chronic immune thrombocytopenic purpura, and seven had Evans syndrome. All had other associated immunopathological manifestations, mainly symptomatic hypogammaglobinaemia. They had a median of 8 (5-10) KS-associated manifestations. Pathogenic variants were detected in KMT2D gene without clustering, during the immunological work-up of AIC in three cases, and the clinical strategy to validate them is emphasized. Eight patients received second-line treatments, mainly rituximab and mycophenolate mofetil. With a median follow-up of 17 (2-31) years, 8/10 alive patients still needed treatment for AIC. First-line paediatricians should be able to recognize and confirm KS in children with ITP or multiple AIC, to provide early appropriate clinical management and specific long-term follow-up. The epigenetic immune dysregulation in KS opens exciting new perspectives.


Asunto(s)
Anomalías Múltiples , Proteínas de Unión al ADN , Cara , Enfermedades Hematológicas , Histona Demetilasas , Proteínas de Neoplasias , Enfermedades Vestibulares , Humanos , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/diagnóstico , Niño , Cara/anomalías , Femenino , Masculino , Preescolar , Anomalías Múltiples/genética , Adolescente , Histona Demetilasas/genética , Proteínas de Neoplasias/genética , Enfermedades Hematológicas/genética , Proteínas de Unión al ADN/genética , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/terapia , Púrpura Trombocitopénica Idiopática/diagnóstico , Lactante , Trombocitopenia/genética , Trombocitopenia/diagnóstico , Trombocitopenia/etiología , Trombocitopenia/terapia , Anemia Hemolítica Autoinmune/genética , Anemia Hemolítica Autoinmune/diagnóstico , Anemia Hemolítica Autoinmune/terapia , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/diagnóstico , Rituximab/uso terapéutico , Mutación , Citopenia
11.
J Clin Immunol ; 44(4): 99, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38619739

RESUMEN

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by its large heterogeneity in terms of clinical presentation and severity. The pathophysiology of SLE involves an aberrant autoimmune response against various tissues, an excess of apoptotic bodies, and an overproduction of type-I interferon. The genetic contribution to the disease is supported by studies of monozygotic twins, familial clustering, and genome-wide association studies (GWAS) that have identified numerous risk loci. In the early 70s, complement deficiencies led to the description of familial forms of SLE caused by a single gene defect. High-throughput sequencing has recently identified an increasing number of monogenic defects associated with lupus, shaping the concept of monogenic lupus and enhancing our insights into immune tolerance mechanisms. Monogenic lupus (moSLE) should be suspected in patients with either early-onset lupus or syndromic lupus, in male, or in familial cases of lupus. This review discusses the genetic basis of monogenic SLE and proposes its classification based on disrupted pathways. These pathways include defects in the clearance of apoptotic cells or immune complexes, interferonopathies, JAK-STATopathies, TLRopathies, and T and B cell dysregulations.


Asunto(s)
Autoinmunidad , Lupus Eritematoso Sistémico , Humanos , Masculino , Complejo Antígeno-Anticuerpo , Autoinmunidad/genética , Estudio de Asociación del Genoma Completo , Lupus Eritematoso Sistémico/genética , Fenotipo , Femenino , Estudios en Gemelos como Asunto
12.
J Autoimmun ; 142: 103152, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38071801

RESUMEN

Anti-nuclear antibodies are the hallmark of autoimmune diseases such as systemic lupus erythematosus (SLE) and scleroderma. However, the molecular mechanisms of B cell tolerance breakdown in these pathological contexts are poorly known. The study of rare familial forms of autoimmune diseases could therefore help to better describe common biological mechanisms leading to B cell tolerance breakdown. By Whole-Exome Sequencing, we identified a new heterozygous mutation (p.R594C) in ERN1 gene, encoding IRE1α (Inositol-Requiring Enzyme 1α), in a multiplex family with several members presenting autoantibody-mediated autoimmunity. Using human cell lines and a knock-in (KI) transgenic mouse model, we showed that this mutation led to a profound defect of IRE1α ribonuclease activity on X-Box Binding Protein 1 (XBP1) splicing. The KI mice developed a broad panel of autoantibodies, however in a subclinical manner. These results suggest that a decrease of spliced form of XBP1 (XBP1s) production could contribute to B cell tolerance breakdown and give new insights into the function of IRE1α which are important to consider for the development of IRE1α targeting strategies.


Asunto(s)
Enfermedades Autoinmunes , Proteínas Serina-Treonina Quinasas , Humanos , Ratones , Animales , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Transducción de Señal , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismo , Ratones Transgénicos
13.
J Allergy Clin Immunol ; 151(5): 1391-1401.e7, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36621650

RESUMEN

BACKGROUND: Fas ligand (FasL) is expressed by activated T cells and induces death in target cells upon binding to Fas. Loss-of-function FAS or FASLG mutations cause autoimmune-lymphoproliferative syndrome (ALPS) characterized by expanded double-negative T cells (DNT) and elevated serum biomarkers. While most ALPS patients carry heterozygous FAS mutations, FASLG mutations are rare and usually biallelic. Only 2 heterozygous variants were reported, associated with an atypical clinical phenotype. OBJECTIVE: We revisited the significance of heterozygous FASLG mutations as a cause of ALPS. METHODS: Clinical features and biomarkers were analyzed in 24 individuals with homozygous or heterozygous FASLG variants predicted to be deleterious. Cytotoxicity assays were performed with patient T cells and biochemical assays with recombinant FasL. RESULTS: Homozygous FASLG variants abrogated cytotoxicity and resulted in early-onset severe ALPS with elevated DNT, raised vitamin B12, and usually no soluble FasL. In contrast, heterozygous variants affected FasL function by reducing expression, impairing trimerization, or preventing Fas binding. However, they were not associated with elevated DNT and vitamin B12, and they did not affect FasL-mediated cytotoxicity. The dominant-negative effects of previously published variants could not be confirmed. Even Y166C, causing loss of Fas binding with a dominant-negative effect in biochemical assays, did not impair cellular cytotoxicity or cause vitamin B12 and DNT elevation. CONCLUSION: Heterozygous loss-of-function mutations are better tolerated for FASLG than for FAS, which may explain the low frequency of ALPS-FASLG.


Asunto(s)
Síndrome Linfoproliferativo Autoinmune , Humanos , Síndrome Linfoproliferativo Autoinmune/genética , Proteína Ligando Fas/genética , Mutación , Biomarcadores , Vitaminas , Receptor fas/genética , Apoptosis/genética
14.
J Allergy Clin Immunol ; 151(6): 1634-1645, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36638922

RESUMEN

BACKGROUND: Allogenic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) are potentially curative treatments for severe combined immunodeficiency (SCID). Late-onset posttreatment manifestations (such as persistent hepatitis) are not uncommon. OBJECTIVE: We sought to characterize the prevalence and pathophysiology of persistent hepatitis in transplanted SCID patients (SCIDH+) and to evaluate risk factors and treatments. METHODS: We used various techniques (including pathology assessments, metagenomics, single-cell transcriptomics, and cytometry by time of flight) to perform an in-depth study of different tissues from patients in the SCIDH+ group and corresponding asymptomatic similarly transplanted SCID patients without hepatitis (SCIDH-). RESULTS: Eleven patients developed persistent hepatitis (median of 6 years after HSCT or GT). This condition was associated with the chronic detection of enteric viruses (human Aichi virus, norovirus, and sapovirus) in liver and/or stools, which were not found in stools from the SCIDH- group (n = 12). Multiomics analysis identified an expansion of effector memory CD8+ T cells with high type I and II interferon signatures. Hepatitis was associated with absence of myeloablation during conditioning, split chimerism, and defective B-cell function, representing 25% of the 44 patients with SCID having these characteristics. Partially myeloablative retransplantation or GT of patients with this condition (which we have named as "enteric virus infection associated with hepatitis") led to the reconstitution of T- and B-cell immunity and remission of hepatitis in 5 patients, concomitantly with viral clearance. CONCLUSIONS: Enteric virus infection associated with hepatitis is related to chronic enteric viral infection and immune dysregulation and is an important risk for transplanted SCID patients with defective B-cell function.


Asunto(s)
Infecciones por Enterovirus , Trasplante de Células Madre Hematopoyéticas , Hepatitis , Inmunodeficiencia Combinada Grave , Virosis , Humanos , Inmunodeficiencia Combinada Grave/terapia , Inmunodeficiencia Combinada Grave/etiología , Linfocitos T CD8-positivos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Virosis/etiología , Hepatitis/etiología
15.
Br J Haematol ; 203(1): 28-35, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37735545

RESUMEN

Since its first description by Evans in 1951, this syndrome has been linked to chronic immune thrombocytopenia with the concurrent or delayed onset of autoimmune haemolytic anaemia or neutropenia. For decades, the evolution of Evans syndrome (ES) has carried a poor prognosis and often resulted in chronic steroid exposure, multiple immune suppressing medications directed against T or B lymphocytes, and splenectomy. This paper presents a new view of ES based on recent advances in genomics which begin to classify patients based on their underlying molecular variants in previously described primary immune disorders. This has opened up new avenues of targeted therapy or bone marrow transplant at rather than broad long-term immune suppression or splenectomy. Importantly, recent studies of the full lifespan of ES suggest that at least 80% of those paediatric patients will progress to various clinical or biological immunopathological manifestations with age despite the resolution of their cytopenias. Those patients merit long-term follow-up and monitoring in dedicated transition programs to improve outcome at the adult age.


Asunto(s)
Anemia Hemolítica Autoinmune , Neutropenia , Púrpura Trombocitopénica Idiopática , Trombocitopenia , Adulto , Humanos , Niño , Anemia Hemolítica Autoinmune/diagnóstico , Anemia Hemolítica Autoinmune/terapia , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/terapia , Trombocitopenia/etiología , Trombocitopenia/terapia
16.
J Clin Immunol ; 43(1): 181-191, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36155879

RESUMEN

PURPOSE: Hypogammaglobulinemia in a context of lymphoma is usually considered as secondary and prior lymphoma remains an exclusion criterion for a common variable immunodeficiency (CVID) diagnosis. We hypothesized that lymphoma could be the revealing symptom of an underlying primary immunodeficiency (PID), challenging the distinction between primary and secondary hypogammaglobulinemia. METHODS: Within a French cohort of adult patients with hypogammaglobulinemia, patients who developed a lymphoma either during follow-up or before the diagnosis of hypogammaglobulinemia were identified. These two chronology groups were then compared. For patients without previous genetic diagnosis, a targeted next-generation sequencing of 300 PID-associated genes was performed. RESULTS: A total of forty-seven patients had developed 54 distinct lymphomas: non-Hodgkin B cell lymphoma (67%), Hodgkin lymphoma (26%), and T cell lymphoma (7%). In 25 patients, lymphoma developed prior to the diagnosis of hypogammaglobulinemia. In this group of patients, Hodgkin lymphoma was overrepresented compared to the group of patients in whom lymphoma occurred during follow-up (48% versus 9%), whereas MALT lymphoma was absent (0 versus 32%). Despite the histopathological differences, both groups presented with similar characteristics in terms of age at hypogammaglobulinemia diagnosis, consanguinity rate, or severe T cell defect. Overall, genetic analyses identified a molecular diagnosis in 10/47 patients (21%), distributed in both groups and without peculiar gene recurrence. Most of these patients presented with a late onset combined immunodeficiency (LOCID) phenotype. CONCLUSION: Prior or concomitant lymphoma should not be used as an exclusion criteria for CVID diagnosis, and these patients should be investigated accordingly.


Asunto(s)
Agammaglobulinemia , Inmunodeficiencia Variable Común , Enfermedad de Hodgkin , Humanos , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/complicaciones , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/complicaciones , Enfermedad de Hodgkin/diagnóstico , Linfocitos T , Fenotipo
17.
J Clin Immunol ; 44(1): 2, 2023 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-38099988

RESUMEN

The DNA polymerase δ complex (PolD), comprising catalytic subunit POLD1 and accessory subunits POLD2, POLD3, and POLD4, is essential for DNA synthesis and is central to genome integrity. We identified, by whole exome sequencing, a homozygous missense mutation (c.1118A > C; p.K373T) in POLD3 in a patient with Omenn syndrome. The patient exhibited severely decreased numbers of naïve T cells associated with a restricted T-cell receptor repertoire and a defect in the early stages of TCR recombination. The patient received hematopoietic stem cell transplantation at age 6 months. He manifested progressive neurological regression and ultimately died at age 4 years. We performed molecular and functional analysis of the mutant POLD3 and assessed cell cycle progression as well as replication-associated DNA damage. Patient fibroblasts showed a marked defect in S-phase entry and an enhanced number of double-stranded DNA break-associated foci despite normal expression levels of PolD components. The cell cycle defect was rescued by transduction with WT POLD3. This study validates autosomal recessive POLD3 deficiency as a novel cause of profound T-cell deficiency and Omenn syndrome.


Asunto(s)
ADN Polimerasa III , Inmunodeficiencia Combinada Grave , Masculino , Humanos , Lactante , Preescolar , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/terapia , Ciclo Celular , Daño del ADN , Fibroblastos
18.
J Allergy Clin Immunol ; 149(2): 550-556.e2, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34800432

RESUMEN

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) is characterized by impaired type I interferon activity and a state of hyperinflammation leading to acute respiratory distress syndrome. The complement system has recently emerged as a key player in triggering and maintaining the inflammatory state, but the role of this molecular cascade in severe COVID-19 is still poorly characterized. OBJECTIVE: We aimed at assessing the contribution of complement pathways at both the protein and transcriptomic levels. METHODS: To this end, we systematically assessed the RNA levels of 28 complement genes in the circulating whole blood of patients with COVID-19 and healthy controls, including genes of the alternative pathway, for which data remain scarce. RESULTS: We found differential expression of genes involved in the complement system, yet with various expression patterns: whereas patients displaying moderate disease had elevated expression of classical pathway genes, severe disease was associated with increased lectin and alternative pathway activation, which correlated with inflammation and coagulopathy markers. Additionally, properdin, a pivotal positive regulator of the alternative pathway, showed high RNA expression but was found at low protein concentrations in patients with a severe and critical disease, suggesting its deposition at the sites of complement activation. Notably, low properdin levels were significantly associated with the use of mechanical ventilation (area under the curve = 0.82; P = .002). CONCLUSION: This study sheds light on the role of the alternative pathway in severe COVID-19 and provides additional rationale for the testing of drugs inhibiting the alternative pathway of the complement system.


Asunto(s)
COVID-19/inmunología , Activación de Complemento/genética , Vía Alternativa del Complemento/genética , Proteínas del Sistema Complemento/genética , Coagulación Intravascular Diseminada/inmunología , SARS-CoV-2/patogenicidad , COVID-19/genética , COVID-19/terapia , COVID-19/virología , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/terapia , Enfermedades Cardiovasculares/virología , Estudios de Casos y Controles , Comorbilidad , Proteínas del Sistema Complemento/inmunología , Diabetes Mellitus/genética , Diabetes Mellitus/inmunología , Diabetes Mellitus/terapia , Diabetes Mellitus/virología , Coagulación Intravascular Diseminada/genética , Coagulación Intravascular Diseminada/terapia , Coagulación Intravascular Diseminada/virología , Femenino , Regulación de la Expresión Génica , Humanos , Hipertensión/genética , Hipertensión/inmunología , Hipertensión/terapia , Hipertensión/virología , Lectinas/genética , Lectinas/inmunología , Masculino , Persona de Mediana Edad , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/virología , Properdina/genética , Properdina/inmunología , Respiración Artificial , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Índice de Severidad de la Enfermedad
19.
Immunol Rev ; 287(1): 50-61, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30565243

RESUMEN

The human adaptive immune system recognizes almost all the pathogens that we encounter and all the tumor antigens that may arise during our lifetime. Primary immunodeficiencies affecting lymphocyte development or function therefore lead to severe infections and tumor susceptibility. Furthermore, the fact that autoimmunity is a frequent feature of primary immunodeficiencies reveals a third function of the adaptive immune system: its self-regulation. Indeed, the generation of a broad repertoire of antigen receptors (via a unique strategy of random somatic rearrangements of gene segments in T cell and B cell receptor loci) inevitably creates receptors with specificity for self-antigens and thus leads to the presence of autoreactive lymphocytes. There are many different mechanisms for controlling the emergence or action of autoreactive lymphocytes, including clonal deletion in the primary lymphoid organs, receptor editing, anergy, suppression of effector lymphocytes by regulatory lymphocytes, and programmed cell death. Here, we review the genetic defects affecting lymphocyte apoptosis and that are associated with lymphoproliferation and autoimmunity, together with the role of somatic mutations and their potential involvement in more common autoimmune diseases.


Asunto(s)
Apoptosis/genética , Autoinmunidad/genética , Linfocitos B/inmunología , Leucemia/genética , Linfocitos T/inmunología , Receptor fas/genética , Proteínas ras/genética , Animales , Autoantígenos/inmunología , Humanos , Mutación/genética , Receptores de Antígenos/genética
20.
Ann Rheum Dis ; 81(5): 720-728, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35022159

RESUMEN

OBJECTIVES: The emergence of strains of SARS-CoV-2 exhibiting increase viral fitness and immune escape potential, such as the Delta variant (B.1.617.2), raises concerns in immunocompromised patients. We aimed to evaluate seroconversion, cross-neutralisation and T-cell responses induced by BNT162b2 in immunocompromised patients with systemic inflammatory diseases. METHODS: Prospective monocentric study including patients with systemic inflammatory diseases and healthcare immunocompetent workers as controls. Primary endpoints were anti-spike antibodies levels and cross-neutralisation of Alpha and Delta variants after BNT162b2 vaccine. Secondary endpoints were T-cell responses, breakthrough infections and safety. RESULTS: Sixty-four cases and 21 controls not previously infected with SARS-CoV-2 were analysed. Kinetics of anti-spike IgG after BNT162b2 vaccine showed lower and delayed induction in cases, more pronounced with rituximab. Administration of two doses of BNT162b2 generated a neutralising response against Alpha and Delta in 100% of controls, while sera from only one of rituximab-treated patients neutralised Alpha (5%) and none Delta. Other therapeutic regimens induced a partial neutralising activity against Alpha, even lower against Delta. All controls and cases except those treated with methotrexate mounted a SARS-CoV-2 specific T-cell response. Methotrexate abrogated T-cell responses after one dose and dramatically impaired T-cell responses after two doses of BNT162b2. Third dose of vaccine improved immunogenicity in patients with low responses. CONCLUSION: Rituximab and methotrexate differentially impact the immunogenicity of BNT162b2, by impairing B-cell and T-cell responses, respectively. Delta fully escapes the humoral response of individuals treated with rituximab. These findings support efforts to improve BNT162b2 immunogenicity in immunocompromised individuals (ClinicalTrials.gov number, NCT04870411).


Asunto(s)
Vacuna BNT162 , COVID-19 , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19 , Humanos , Huésped Inmunocomprometido , Inmunogenicidad Vacunal , Metotrexato , Estudios Prospectivos , Rituximab , SARS-CoV-2
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA