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Inmunodeficiencia Variable Común , Encefalitis , Enfermedad de Hashimoto , Humanos , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/diagnóstico , Encefalitis/inmunología , Encefalitis/diagnóstico , Enfermedad de Hashimoto/diagnóstico , Enfermedad de Hashimoto/inmunología , Femenino , Masculino , AdultoRESUMEN
BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by defective antibody production and impaired differentiation of B cells. B cell proliferation is an essential step for antibody synthesis. Depending on the nature of the stimulus, their response may be either T-cell-dependent or T-cell-independent. METHODS: We studied 23 CVID patients and 14 healthy donors (HD). The patients were categorized based on their percentage of memory B cells. In addition to standard immunophenotyping of circulating human B and T cell subsets, an in vitro CFSE dilution assay was used to assess the proliferative capacity of B cells and to compare the activation of the T cell-dependent and T cell-independent response among the patients. RESULTS: Patients with a reduction in memory B cells exhibited an increase in follicular T cells (Tfh) and showed low proliferation in response to PKW, CpG, and SAC stimuli (Condition II) (p= 0.0073). In contrast, patients with a normal percentage of memory B cells showed a high expression of IL-21R and low proliferation in response to CPG (Condition III); IL-21, CD40L, and anti-IgM (Condition IV) stimuli (p= 0.0163 and p = 0.0475, respectively). CONCLUSION: Defective proliferation in patients depends on the type of stimulus used and the phenotypic characteristics of the patients. Further studies are necessary to understand the disease mechanisms, which may guide us toward identifying genetic defects associated with CVID.
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Proliferación Celular , Inmunodeficiencia Variable Común , Activación de Linfocitos , Humanos , Inmunodeficiencia Variable Común/inmunología , Masculino , Femenino , Adulto , Activación de Linfocitos/inmunología , Persona de Mediana Edad , Inmunofenotipificación , Linfocitos B/inmunología , Adulto Joven , Células Cultivadas , Células B de Memoria/inmunología , Interleucinas/metabolismo , Interleucinas/inmunología , Adolescente , Memoria Inmunológica/inmunologíaRESUMEN
The interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional regulator, functioning a transcriptional corepressor by interacting with the interferon regulatory factor-2. The ubiquitous expression of IRF2BP2 by diverse cell types and tissues suggests its potential involvement in different cell signalling pathways. Variants inIRF2BP2have been recently identified to cause familial common variable immunodeficiency (CVID) characterized by immune dysregulation. This study investigated three rare novel variants inIRF2BP2, identified in patients with primary antibody deficiency and autoimmunity by whole exome-sequencing (WES). Following transient overexpression of EGFP-fused mutants in HEK293 cells and transfection in Jurkat cell lines, we used fluorescence microscopy, real-time PCR and Western blotting to analyze their effects on IRF2BP2 expression, subcellular localization, nuclear translocation of IRF2, and the transcriptional activation of NFκB1(p50). We found altered IRF2BP2 mRNA and protein expression levels in the mutants compared to the wild type after IRF2BP2 overexpression. In confocal fluorescence microscopy, variants in the C-terminal RING finger domain showed an irregular aggregate formation and distribution instead of the expected nuclear localization compared to the variants in the N-terminal zinc finger domain and their wildtype counterpart. Immunoblotting revealed an impaired IRF2 and NFκB1 (p50) nuclear localization in the mutants compared to the IRF2BP2 wildtype counterpart. LPS stimulation reduced IRF2BP2 mRNA expression in the variants compared to the wild type. Our findings significantly contribute to understanding the clinical significance of IRF2BP2 mutations in the pathogenesis of immunodeficiency and immune dysregulation. We observed impairment of the nuclear translocation of IRF2 and NFκB1 (p50) due to the upregulation of IRF2BP2, potentially affecting specific gene expressions involved in immune regulation.
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Autoinmunidad , Inmunodeficiencia Variable Común , Humanos , Células HEK293 , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/inmunología , Autoinmunidad/genética , Células Jurkat , Factor 2 Regulador del Interferón/genética , Factor 2 Regulador del Interferón/metabolismo , Factor 2 Regulador del Interferón/inmunología , Masculino , Femenino , Mutación , Subunidad p50 de NF-kappa B/genética , Subunidad p50 de NF-kappa B/metabolismo , Secuenciación del Exoma , Proteínas Co-Represoras/genética , Proteínas de Unión al ADN , Factores de TranscripciónRESUMEN
Vaccine challenge responses are an integral component in the diagnostic evaluation of patients with primary antibody deficiency, including Common Variable Immunodeficiency Disorders (CVID). There are no studies of vaccine challenge responses in primary hypogammaglobulinemia patients not accepted for subcutaneous/intravenous immunoglobulin (SCIG/IVIG) replacement compared to those accepted for such treatment. Vaccine challenge responses in patients enrolled in two long-term prospective cohorts, the New Zealand Hypogammaglobulinemia Study (NZHS) and the New Zealand CVID study (NZCS), were compared in this analysis. Almost all patients in the more severely affected SCIG/IVIG treatment group achieved protective antibody levels to tetanus toxoid and H. influenzae type B (HIB). Although there was a highly significant statistical difference in vaccine responses to HIB, tetanus and diphtheria toxoids, there was substantial overlap in both groups. In contrast, there was no significant difference in Pneumococcal Polysaccharide antibody responses to Pneumovax® (PPV23). This analysis illustrates the limitations of evaluating vaccine challenge responses in patients with primary hypogammaglobulinemia to establish the diagnosis of CVID and in making decisions to treat with SCIG/IVIG. The conclusion from this study is that patients with symptoms attributable to primary hypogammaglobulinemia with reduced IgG should not be denied SCIG/IVIG if they have normal vaccine responses.
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Inmunodeficiencia Variable Común , Vacunas contra Haemophilus , Vacunas Neumococicas , Humanos , Inmunodeficiencia Variable Común/inmunología , Femenino , Masculino , Vacunas Neumococicas/inmunología , Vacunas Neumococicas/uso terapéutico , Persona de Mediana Edad , Adulto , Vacunas contra Haemophilus/inmunología , Vacunas contra Haemophilus/uso terapéutico , Vacunas contra Haemophilus/administración & dosificación , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Agammaglobulinemia/inmunología , Agammaglobulinemia/diagnóstico , Inmunoglobulinas Intravenosas/uso terapéutico , Estudios Prospectivos , Toxoide Tetánico/inmunología , Anciano , Adulto Joven , Adolescente , Nueva Zelanda , Niño , Haemophilus influenzae tipo b/inmunologíaRESUMEN
Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency disorder with different phenotypes and aetiologies. It is characterised by hypogammaglobulinaemia, defects in specific antibody response, erroneous activation and proliferation of T cells, leading to increased risk of recurrent infections. In CVID, "Variable" refers to the heterogeneity of clinical presentations, which include recurrent infections, autoimmunity, enteropathy, and increased risk of malignancies. This wide spectrum of disease manifestations and being a diagnosis of exclusion poses a diagnostic challenge. It is pertinent to mention that CVID along with associated complications is the commonest symptomatic primary antibody deficiency but is scarcely mentioned in local literature. The main aim of presenting this case is to impress upon the importance of systematic immunological workup in cases of suspected immunodeficiency to prevent morbidity and mortality.
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Inmunodeficiencia Variable Común , Países en Desarrollo , Humanos , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/complicaciones , Masculino , Femenino , AdultoRESUMEN
BACKGROUND: Common variable immunodeficiency (CVID) is considered the most symptomatic type of inborn errors of immunity in humans. Along with infectious complications, which have numerous consequences, noninfectious complications are a major challenge among CVID patients. METHODS: All CVID patients registered in the national database were included in this retrospective cohort study. Patients were divided into 2 groups based on the presence of B-cell lymphopenia. Demographic characteristics, laboratory findings, noninfectious organ involvement, autoimmunity, and lymphoproliferative diseases were evaluated. RESULTS: Among 387 enrolled patients, 66.4% were diagnosed with noninfectious complications and 33.6% with isolated infectious presentations. Enteropathy, autoimmunity, and lymphoproliferative disorders were reported in 35.1%, 24.3%, and 21.4% of patients, respectively. Some complications, including autoimmunity and hepatosplenomegaly, were reported to be significantly more frequent among patients with B-cell lymphopenia. As for organ involvement, the dermatologic, endocrine, and musculoskeletal systems were predominantly affected in CVID patients with B-cell lymphopenia. Among autoimmune manifestations, the frequency of rheumatologic, hematologic, and gastrointestinal autoimmunity was reported to be higher than that of other types of autoimmunity not associated with B cell-lymphopenia. Furthermore, hematological cancers, particularly lymphoma, were the most common type of malignancy. The mortality rate was 24.5%, and respiratory failure and malignancies were the most common causes of death, with no significant differences between the 2 groups. CONCLUSIONS: Considering that some of the noninfectious complications might be associated with B-cell lymphopenia, regular patient monitoring and follow-up with proper medication (in addition to immunoglobulin replacement therapy) are highly recommended to prevent sequelae and increase patient quality of life.
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Linfocitos B , Inmunodeficiencia Variable Común , Linfopenia , Humanos , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/inmunología , Femenino , Masculino , Adulto , Estudios Retrospectivos , Linfocitos B/inmunología , Persona de Mediana Edad , Linfopenia/inmunología , Adulto Joven , Autoinmunidad , Adolescente , Anciano , NiñoRESUMEN
INTRODUCTION: Interstitial lung disease (ILD) is a prevalent complication in patients with common variable immunodeficiency (CVID) and is often related to other characteristics such as bronchiectasis and autoimmunity. Because the term ILD encompasses a variety of acute and chronic pulmonary conditions, diagnosis is usually based on imaging features. Histopathology is less available. This study was conducted with the aim of investigating the ILD in patients with CVID. MATERIALS AND METHODS: In this retrospective cross-sectional study, sixty CVID patients who referred to the pulmonology and immunodeficiency clinics of Mofid Children's Hospital between 2013 and 2022 were included. The diagnosis of ILD were based on transbronchial lung biopsy (TBB) or clinical and radiological symptoms. The prevalence of ILD in CVID patients was determined. Also, the CVID patients with and without ILD were compared in terms of demographic characteristics, clinical, laboratory and radiologic findings. RESULTS: Among all patients, ten patients had ILD (16.6%). In terms of laboratory parameters, there was a significant difference between platelets in the two groups of CVID patients with and without ILD, and the level of platelets was higher in the group of patients with ILD. Moreover, in terms of clinical symptoms, pneumonia, diarrhea and hepatomegaly were significantly different between the two groups and were statistically higher in the group of patients with ILD (P < 0.05). Autoimmunity and malignancy were not significantly different in two groups. There was a significant difference in, hyperinflation between the two groups of CVID patients with and without ILD, and the frequency of, hyperinflation was higher in the patients without ILD (P = 0.040). CONCLUSION: Understanding the pathogenesis of ILD plays an essential role in revealing non-infectious pulmonary complications that occur in CVID patients. Increasing efforts to understand ILD not only shed light on its hidden pathogenesis and clinical features, but also enhance our understanding of CVID in a broader sense.
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Inmunodeficiencia Variable Común , Enfermedades Pulmonares Intersticiales , Humanos , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/epidemiología , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/inmunología , Enfermedades Pulmonares Intersticiales/epidemiología , Femenino , Masculino , Estudios Transversales , Estudios Retrospectivos , Irán/epidemiología , Adulto , Adolescente , Niño , Adulto Joven , Prevalencia , Pulmón/patología , Pulmón/diagnóstico por imagen , Persona de Mediana EdadAsunto(s)
Inmunodeficiencia Variable Común , Fiebre , Hepatopatías , Hígado , Esplenomegalia , Anciano , Humanos , Masculino , Antibacterianos/uso terapéutico , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/etiología , Médula Ósea/patología , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/terapia , Diagnóstico Diferencial , Enfermedades del Sistema Digestivo/diagnóstico , Enfermedades del Sistema Digestivo/diagnóstico por imagen , Enfermedades del Sistema Digestivo/tratamiento farmacológico , Enfermedades del Sistema Digestivo/etiología , Progresión de la Enfermedad , Fiebre/etiología , Granuloma/diagnóstico por imagen , Granuloma/tratamiento farmacológico , Granuloma/etiología , Hígado/patología , Hígado/diagnóstico por imagen , Hepatopatías/diagnóstico por imagen , Hepatopatías/tratamiento farmacológico , Hepatopatías/etiología , Neoplasias Hepáticas/patología , Imagen por Resonancia Magnética , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Nódulos Pulmonares Múltiples/tratamiento farmacológico , Nódulos Pulmonares Múltiples/etiología , Recurrencia , Fiebre Recurrente/diagnóstico , Fiebre Recurrente/tratamiento farmacológico , Fiebre Recurrente/etiología , Esplenomegalia/diagnóstico por imagen , Esplenomegalia/tratamiento farmacológico , Esplenomegalia/etiología , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: Common Variable Immunodeficiency (CVID) is characterized by hypogammaglobulinemia and failure of specific antibody production due to B-cell defects. However, studies have documented various T-cell abnormalities, potentially linked to viral complications. The frequency of Cytomegalovirus (CMV) replication in CVID cohorts is poorly studied. To address this gap in knowledge, we set up an observational study with the objectives of identifying CVID patients with active viraemia (CMV, Epstein-Barr virus (EBV)), evaluating potential correlations with immunophenotypic characteristics, clinical outcome, and the dynamic progression of clinical phenotypes over time. METHODS: 31 CVID patients were retrospectively analysed according to viraemia, clinical and immunologic characteristics. 21 patients with non CVID humoral immunodeficiency were also evaluated as control. RESULTS: Active viral replication of CMV and/or EBV was observed in 25% of all patients. CMV replication was detected only in CVID patients (16%). CVID patients with active viral replication showed reduced HLA-DR+ NK counts when compared with CMV-DNA negative CVID patients. Viraemic patients had lower counts of LIN-DNAMbright and LIN-CD16+ inflammatory lymphoid precursors which correlated with NK-cell subsets. Analysis of the dynamic progression of CVID clinical phenotypes over time, showed that the initial infectious phenotype progressed to complicated phenotypes with time. All CMV viraemic patients had complicated disease. CONCLUSION: Taken together, an impaired production of inflammatory precursors and NK activation is present in CVID patients with active viraemia. Since "Complicated" CVID occurs as a function of disease duration, there is need for an accurate evaluation of this aspect to improve classification and clinical management of CVID patients.
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Inmunodeficiencia Variable Común , Infecciones por Citomegalovirus , Citomegalovirus , Herpesvirus Humano 4 , Replicación Viral , Humanos , Inmunodeficiencia Variable Común/inmunología , Inmunodeficiencia Variable Común/complicaciones , Masculino , Femenino , Infecciones por Citomegalovirus/inmunología , Citomegalovirus/inmunología , Citomegalovirus/fisiología , Adulto , Persona de Mediana Edad , Herpesvirus Humano 4/fisiología , Herpesvirus Humano 4/inmunología , Estudios Retrospectivos , Células Asesinas Naturales/inmunología , Adulto Joven , Viremia/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Inmunofenotipificación , Anciano , AdolescenteRESUMEN
Background: The respiratory tract microbiome is essential for human health and well-being and is determined by genetic, lifestyle, and environmental factors. Patients with Common Variable Immunodeficiency (CVID) suffer from respiratory and intestinal tract infections, leading to chronic diseases and increased mortality rates. While CVID patients' gut microbiota have been analyzed, data on the respiratory microbiome ecosystem are limited. Objective: This study aims to analyze the bacterial composition of the oropharynx of adults with CVID and its link with clinical and immunological features and risk for respiratory acute infections. Methods: Oropharyngeal samples from 72 CVID adults and 26 controls were collected in a 12-month prospective study. The samples were analyzed by metagenomic bacterial 16S ribosomal RNA sequencing and processed using the Quantitative Insights Into Microbial Ecology (QIME) pipeline. Differentially abundant species were identified and used to build a dysbiosis index. A machine learning model trained on microbial abundance data was used to test the power of microbiome alterations to distinguish between healthy individuals and CVID patients. Results: Compared to controls, the oropharyngeal microbiome of CVID patients showed lower alpha- and beta-diversity, with a relatively increased abundance of the order Lactobacillales, including the family Streptococcaceae. Intra-CVID analysis identified age >45 years, COPD, lack of IgA, and low residual IgM as associated with a reduced alpha diversity. Expansion of Haemophilus and Streptococcus genera was observed in patients with undetectable IgA and COPD, independent from recent antibiotic use. Patients receiving azithromycin as antibiotic prophylaxis had a higher dysbiosis score. Expansion of Haemophilus and Anoxybacillus was associated with acute respiratory infections within six months. Conclusions: CVID patients showed a perturbed oropharynx microbiota enriched with potentially pathogenic bacteria and decreased protective species. Low residual levels of IgA/IgM, chronic lung damage, anti antibiotic prophylaxis contributed to respiratory dysbiosis.
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Inmunodeficiencia Variable Común , Disbiosis , Orofaringe , Infecciones del Sistema Respiratorio , Humanos , Inmunodeficiencia Variable Común/microbiología , Inmunodeficiencia Variable Común/inmunología , Inmunodeficiencia Variable Común/complicaciones , Orofaringe/microbiología , Masculino , Femenino , Persona de Mediana Edad , Adulto , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/inmunología , Microbiota , Estudios Prospectivos , Anciano , ARN Ribosómico 16S/genética , Enfermedad Aguda , Bacterias/clasificación , Bacterias/genética , Estudios de Casos y ControlesRESUMEN
Despite advancements in genetic and functional studies, the timely diagnosis of common variable immunodeficiency (CVID) remains a significant challenge. This exploratory study was designed to assess the diagnostic performance of a novel panel of biomarkers for CVID, incorporating the sum of κ+λ light chains, soluble B-cell maturation antigen (sBCMA) levels, switched memory B cells (smB) and the VISUAL score. Comparative analyses utilizing logistic regression were performed against established gold-standard tests, specifically antibody responses. Our research encompassed 88 subjects, comprising 27 CVID, 23 selective IgA deficiency (SIgAD), 20 secondary immunodeficiency (SID) patients and 18 healthy controls. We established the diagnostic accuracy of sBCMA and the sum κ+λ, achieving sensitivity (Se) and specificity (Spe) of 89% and 89%, and 90% and 99%, respectively. Importantly, sBCMA showed strong correlations with all evaluated biomarkers (sum κ+λ, smB cell and VISUAL), whereas the sum κ+λ was uniquely independent from smB cells or VISUAL, suggesting its additional diagnostic value. Through a multivariate tree decision model, specific antibody responses and the sum κ+λ emerged as independent, signature biomarkers for CVID, with the model showcasing an area under the curve (AUC) of 0.946, Se 0.85, and Spe 0.95. This tree-decision model promises to enhance diagnostic efficiency for CVID, underscoring the sum κ+λ as a superior CVID classifier and potential diagnostic criterion within the panel.
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Biomarcadores , Inmunodeficiencia Variable Común , Humanos , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/inmunología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Modelos Logísticos , Adulto Joven , Adolescente , Anciano , Cadenas kappa de Inmunoglobulina/sangre , Cadenas kappa de Inmunoglobulina/genética , Sensibilidad y Especificidad , Linfocitos B/inmunología , Cadenas lambda de Inmunoglobulina , Células B de Memoria/inmunologíaRESUMEN
LRBA is a cytoplasmic protein that is ubiquitously distributed. Almost all LRBA domains have a scaffolding function. In 2012, it was reported that homozygous variants in LRBA are associated with early-onset hypogammaglobulinemia. Since its discovery, more than 100 pathogenic variants have been reported. This review focuses on the variants reported in LRBA and their possible associations with clinical phenotypes. In this work LRBA deficiency cases reported more than 11 years ago have been revised. A database was constructed to analyze the type of variants, age at onset, clinical diagnosis, infections, autoimmune diseases, and cellular and immunoglobulin levels. The review of cases from 2012 to 2023 showed that LRBA deficiency was commonly diagnosed in patients with a clinical diagnosis of Common Variable Immunodeficiency, followed by enteropathy, neonatal diabetes mellitus, ALPS, and X-linked-like syndrome. Most cases show early onset of presentation at <6 years of age. Most cases lack protein expression, whereas hypogammaglobulinemia is observed in half of the cases, and IgG and IgA levels are isotypes reported at low levels. Patients with elevated IgG levels exhibited more than one autoimmune manifestation. Patients carrying pathogenic variants leading to a premature stop codon show a severe phenotype as they have an earlier onset of disease presentation, severe autoimmune manifestations, premature death, and low B cells and regulatory T cell levels. Missense variants were more common in patients with low IgG levels and cytopenia. This work lead to the conclusion that the type of variant in LRBA has association with disease severity, which leads to a premature stop codon being the ones that correlates with severe disease.
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Dominios Proteicos , Humanos , Dominios Proteicos/genética , Fenotipo , Agammaglobulinemia/genética , Agammaglobulinemia/inmunología , Agammaglobulinemia/diagnóstico , Niño , Edad de Inicio , Mutación , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/inmunología , Proteínas Adaptadoras Transductoras de SeñalesRESUMEN
The COVID-19 pandemic highlighted the importance of effective vaccination strategies in controlling the spread of infectious diseases. SARS-CoV-2 vaccine has demonstrated high efficacy in preventing COVID-19 infection in the general population. However, the efficacy of this vaccine in patients with predominantly antibody deficiencies, such as common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA), should be closely monitored. CVID and XLA are rare genetic disorders that impair the immune system's ability to produce antibodies, which are crucial for fighting infections. Patients with these disorders have a higher risk of severe disease and mortality from COVID-19 due to their compromised immune systems. In this study, we evaluated the humoral and cellular immune responses after four doses of mRNA-1273 and one BNT162b2 bivalent vaccine in a cohort of patients with CVID and XLA. The response in this population was lower than in the control group. However, the administration of the third dose improved the number of patients with seroconversion and the intensity of the humoral response, as well as the number of patients with a positive cellular response. Finally, the administration of the fourth and fifth doses improves the antibody titer and neutralization against wild type variant, but not against the prevalent XBB1.5 variant.
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Agammaglobulinemia , Anticuerpos Antivirales , Vacuna BNT162 , COVID-19 , Inmunodeficiencia Variable Común , SARS-CoV-2 , Vacunación , Humanos , Inmunodeficiencia Variable Común/inmunología , COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2/inmunología , Masculino , Adulto , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Persona de Mediana Edad , Femenino , Vacuna BNT162/inmunología , Vacuna BNT162/administración & dosificación , Agammaglobulinemia/inmunología , Inmunidad Humoral , Estudios de Seguimiento , Vacunas contra la COVID-19/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Vacuna nCoV-2019 mRNA-1273/inmunología , Inmunidad Celular , Adulto JovenRESUMEN
Background and Objectives: Predominantly antibody deficiencies (PAD) represent the most common type of primary immunodeficiencies in humans, characterized by a wide variation in disease onset, clinical manifestations, and outcome. Considering that the prevalence of PAD in Greece is unknown, and there is limited knowledge on the clinical and laboratory characteristics of affected patients, we conducted a nationwide study. Materials and Methods: 153 patients (male/female: 66/87; median age: 43.0 years; range: 7.0-77.0) diagnosed, and followed-up between August 1979 to September 2023. Furthermore, we classified our cohort into five groups according to their medical history, immunoglobulin levels, and CTLA4-mutational status: 123 had common variable immunodeficiency (CVID), 12 patients with "secondary" hypogammaglobulinemia due to a previous B-cell depletion immunotherapy for autoimmune or malignant disease several years ago (median: 9 years, range 6-14) displaying a typical CVID phenotype, 7 with combined IgA and IgG subclass deficiencies, 5 patients with CVID-like disease due to CTLA4-mediated immune dysregulation syndrome, and 6 patients with unclassified hypogammaglobulinemia. Results: We demonstrated a remarkable delay in PAD diagnosis, several years after the onset of related symptoms (median: 9.0 years, range: 0-43.0). A family history of PAD was only present in 11.8%, with the majority of patients considered sporadic cases. Most patients were diagnosed in the context of a diagnostic work-up for recurrent infections, or recurrent/resistant autoimmune cytopenias. Interestingly, 10 patients (5.6%) had no history of infection, diagnosed due to either recurrent/resistant autoimmunity, or during a work-up of their medical/family history. Remarkable findings included an increased prevalence of lymphoproliferation (60.1%), while 39 patients (25.5%) developed bronchiectasis, and 16 (10.5%) granulomatous disease. Cancer was a common complication in our cohort (25 patients, 16.3%), with B-cell malignancies representing the most common neoplasms (56.7%). Conclusion: Our findings indicate the necessity of awareness about PAD and their complications, aiming for early diagnosis and the appropriate management of affected patients.
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Antígeno CTLA-4 , Diagnóstico Tardío , Humanos , Grecia/epidemiología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Niño , Anciano , Diagnóstico Tardío/estadística & datos numéricos , Adolescente , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/epidemiología , Adulto Joven , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/epidemiología , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/inmunología , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/epidemiología , Agammaglobulinemia/inmunología , Agammaglobulinemia/complicacionesRESUMEN
Human inborn errors of immunity include rare disorders entailing functional and quantitative antibody deficiencies due to impaired B cells called the common variable immunodeficiency (CVID) phenotype. Patients with CVID face delayed diagnoses and treatments for 5 to 15 years after symptom onset because the disorders are rare (prevalence of ~1/25,000), and there is extensive heterogeneity in CVID phenotypes, ranging from infections to autoimmunity to inflammatory conditions, overlapping with other more common disorders. The prolonged diagnostic odyssey drives excessive system-wide costs before diagnosis. Because there is no single causal mechanism, there are no genetic tests to definitively diagnose CVID. Here, we present PheNet, a machine learning algorithm that identifies patients with CVID from their electronic health records (EHRs). PheNet learns phenotypic patterns from verified CVID cases and uses this knowledge to rank patients by likelihood of having CVID. PheNet could have diagnosed more than half of our patients with CVID 1 or more years earlier than they had been diagnosed. When applied to a large EHR dataset, followed by blinded chart review of the top 100 patients ranked by PheNet, we found that 74% were highly probable to have CVID. We externally validated PheNet using >6 million records from disparate medical systems in California and Tennessee. As artificial intelligence and machine learning make their way into health care, we show that algorithms such as PheNet can offer clinical benefits by expediting the diagnosis of rare diseases.
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Inmunodeficiencia Variable Común , Registros Electrónicos de Salud , Humanos , Inmunodeficiencia Variable Común/diagnóstico , Aprendizaje Automático , Algoritmos , Masculino , Femenino , Fenotipo , Adulto , Enfermedades no Diagnosticadas/diagnósticoRESUMEN
BACKGROUND: Autoimmune cytopenias (AICs) regularly occur in profoundly IgG-deficient patients with common variable immunodeficiency (CVID). The isotypes, antigenic targets, and origin(s) of their disease-causing autoantibodies are unclear. OBJECTIVE: We sought to determine reactivity, clonality, and provenance of AIC-associated IgM autoantibodies in patients with CVID. METHODS: We used glycan arrays, patient erythrocytes, and platelets to determine targets of CVID IgM autoantibodies. Glycan-binding profiles were used to identify autoreactive clones across B-cell subsets, specifically circulating marginal zone (MZ) B cells, for sorting and IGH sequencing. The locations, transcriptomes, and responses of tonsillar MZ B cells to different TH- cell subsets were determined by confocal microscopy, RNA-sequencing, and cocultures, respectively. RESULTS: Autoreactive IgM coated erythrocytes and platelets from many CVID patients with AICs (CVID+AIC). On glycan arrays, CVID+AIC plasma IgM narrowly recognized erythrocytic i antigens and platelet i-related antigens and failed to bind hundreds of pathogen- and tumor-associated carbohydrates. Polyclonal i antigen-recognizing B-cell receptors were highly enriched among CVID+AIC circulating MZ B cells. Within tonsillar tissues, MZ B cells secreted copious IgM when activated by the combination of IL-10 and IL-21 or when cultured with IL-10/IL-21-secreting FOXP3-CD25hi T follicular helper (Tfh) cells. In lymph nodes from immunocompetent controls, MZ B cells, plentiful FOXP3+ regulatory T cells, and rare FOXP3-CD25+ cells that represented likely CD25hi Tfh cells all localized outside of germinal centers. In CVID+AIC lymph nodes, cellular positions were similar but CD25hi Tfh cells greatly outnumbered regulatory cells. CONCLUSIONS: Our findings indicate that glycan-reactive IgM autoantibodies produced outside of germinal centers may contribute to the autoimmune pathogenesis of CVID.
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Autoanticuerpos , Plaquetas , Inmunodeficiencia Variable Común , Eritrocitos , Inmunoglobulina M , Polisacáridos , Humanos , Inmunoglobulina M/inmunología , Inmunoglobulina M/sangre , Eritrocitos/inmunología , Inmunodeficiencia Variable Común/inmunología , Polisacáridos/inmunología , Plaquetas/inmunología , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Masculino , Femenino , Subgrupos de Linfocitos B/inmunología , AdultoRESUMEN
Background: The main treatment of common variable immunodeficiency (CVID) is to maintain immunoglobulin G (IgG) levels within the target range. However, trough IgG levels differ among patients with similar body mass index (BMI) and those receiving the same dose of immunoglobulin replacement therapy (IGRT). A crucial factor that underlies these differences is the presence of extensive bronchiectasis, which is associated with the immunoglobulin salvage pathway. Objective: We compared trough IgG levels in patients with CVID and with and in those without bronchiectasis who had received the same dose of IGRT for 2 years to determine the association of IgG level with infection frequency. Method: This retrospective cohort study included 61 patients with CVID, of whom 21 had bronchiectasis. We reviewed the electronic records for demographic variables, baseline immunoglobulin levels, mean trough IgG levels over 2 years, efficacy levels (trough IgG level - baseline IgG level), the time interval from treatment initiation to achieving the target trough IgG level (700 mg/dL), and the number of infections. Results: The median age of the patients was 39 years (IQR, 27-51), and 29 were women (47.5%). There were no significant differences between the groups in terms of age, age at diagnosis, delay in diagnosis, sex, BMI, IGRT type (subcutaneous or intravenous), and baseline immunoglobulin levels. Trough IgG and efficacy levels were lower (P < 0.001 and P = 0.016, respectively), the time required to achieve the target IgG level was longer in patients with bronchiectasis than in those without bronchiectasis, and this time interval was significantly associated with the infection frequency. Trough IgG and albumin levels were correlated (p = 0.007), with minor differences between the groups (p = 0.04). Conclusion: Bronchiectasis was significantly associated with a longer time to achieve the target IgG levels. These long-term differences between the patients with and those without bronchiectasis have significant clinical implications.
Asunto(s)
Bronquiectasia , Inmunodeficiencia Variable Común , Inmunoglobulina G , Humanos , Bronquiectasia/inmunología , Femenino , Masculino , Inmunodeficiencia Variable Común/terapia , Inmunodeficiencia Variable Común/inmunología , Persona de Mediana Edad , Adulto , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Estudios Retrospectivos , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunoglobulinas Intravenosas/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento , Inmunización PasivaRESUMEN
Patients with predominantly antibody deficiencies (PADs) display hypogammaglobulinemia with a high prevalence of infections, along with autoimmune manifestations, benign and malignant lymphoproliferation and granulomatous disease. It is noteworthy that PAD patients, even those with defects in the same causative genes, display a variable clinical phenotype, suggesting that additional genetic polymorphisms, located in either immune-related or non-immune-related genes, may affect their clinical and laboratory phenotype. In this context, we analyzed 80 PAD patients, including 70 with common variable immunodeficiency (CVID) for SERPINA1 defects, in order to investigate the possible contribution to PAD clinical phenotype. Ten CVID patients carried heterozygous pathogenic SERPINA1 defects with normal alpha-1 antitrypsin levels. Interestingly, the presence of the Z allele (rs28929474), which was found in three patients, was significantly associated with liver disease; hepatic complications were also observed in patients carrying the p.Leu23Gln (rs1379209512) and the p.Phe76del (rs775982338) alleles. Conversely, no correlation of SERPINA1 defective variants with respiratory complications was observed, although patients with pathogenic variants exhibit a reduced probability of developing autoimmune diseases. Therefore, we recommend SERPINA1 genetic analysis in PAD in order to identify patients with a higher risk for liver disease.
Asunto(s)
Inmunodeficiencia Variable Común , Heterocigoto , alfa 1-Antitripsina , Humanos , alfa 1-Antitripsina/genética , Masculino , Femenino , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/inmunología , Adulto , Persona de Mediana Edad , Fenotipo , Alelos , Adolescente , Niño , Adulto Joven , Anciano , Agammaglobulinemia/genética , Agammaglobulinemia/inmunología , Predisposición Genética a la EnfermedadRESUMEN
Equine common variable immunodeficiency (CVID) is a rare, late-onset, nonfamilial humoral deficiency characterized by B-cell depletion and/or dysfunction resulting in inadequate antibody production and predisposition to recurrent infections. Serum immunoglobulin concentration and peripheral blood lymphocyte immunophenotyping are required to diagnose and characterize CVID in horses. Early recognition of the disease by the equine practitioner is paramount to managing the quality of life for these patients, for whom specific treatment is not yet available and long-term prognosis remains poor. An approach to the diagnosis, identification of complicating factors, and management of horses with CVID are discussed.
Asunto(s)
Inmunodeficiencia Variable Común , Enfermedades de los Caballos , Animales , Caballos , Inmunodeficiencia Variable Común/veterinaria , Inmunodeficiencia Variable Común/diagnóstico , Enfermedades de los Caballos/diagnóstico , Fiebre/veterinariaRESUMEN
PURPOSE: A large proportion of Common variable immunodeficiency (CVID) patients has duodenal inflammation with increased intraepithelial lymphocytes (IEL) of unknown aetiology. The histologic similarities to celiac disease, lead to confusion regarding treatment (gluten-free diet) of these patients. We aimed to elucidate the role of epigenetic DNA methylation in the aetiology of duodenal inflammation in CVID and differentiate it from true celiac disease. METHODS: DNA was isolated from snap-frozen pieces of duodenal biopsies and analysed for differences in genome-wide epigenetic DNA methylation between CVID patients with increased IEL (CVID_IEL; n = 5) without IEL (CVID_N; n = 3), celiac disease (n = 3) and healthy controls (n = 3). RESULTS: The DNA methylation data of 5-methylcytosine in CpG sites separated CVID and celiac diseases from healthy controls. Differential methylation in promoters of genes were identified as potential novel mediators in CVID and celiac disease. There was limited overlap of methylation associated genes between CVID_IEL and Celiac disease. High frequency of differentially methylated CpG sites was detected in over 100 genes nearby transcription start site (TSS) in both CVID_IEL and celiac disease, compared to healthy controls. Differential methylation of genes involved in regulation of TNF/cytokine production were enriched in CVID_IEL, compared to healthy controls. CONCLUSION: This is the first study to reveal a role of epigenetic DNA methylation in the etiology of duodenal inflammation of CVID patients, distinguishing CVID_IEL from celiac disease. We identified potential biomarkers and therapeutic targets within gene promotors and in high-frequency differentially methylated CpG regions proximal to TSS in both CVID_IEL and celiac disease.