RESUMEN

BACKGROUND: Agammaglobulinemia due to variants in IGLL1 has traditionally been considered an exceedingly rare form of severe B-cell deficiency, with only 8 documented cases in the literature. Surprisingly, the first agammaglobulinemic patient identified by newborn screening (NBS) through quantification of kappa-deleting recombination excision circles harbored variants in IGLL1. OBJECTIVE: We comprehensively reviewed clinical and immunologic findings of patients with B-cell deficiency attributed to variants in IGLL1. METHODS: NBS programs reporting the use of kappa-deleting recombination excision circle assays, the European Society for Immunodeficiencies Registry, and authors of published reports featuring patients with B-cell deficiency linked to IGLL1 variants were contacted. Only patients with (likely) pathogenic variants, reduced CD19+ counts, and no alternative diagnosis were included. RESULTS: The study included 13 patients identified through NBS, 2 clinically diagnosed patients, and 2 asymptomatic siblings. All had severely reduced CD19+ B cells (< 0.1 × 109/L) at first evaluation, yet subsequent follow-up assessments indicated residual immunoglobulin production. Specific antibody responses to vaccine antigens varied, with a predominant reduction observed during infancy. Clinical outcomes were favorable with IgG substitution. Two patients successfully discontinued substitution therapy without developing susceptibility to infections and while maintaining immunoglobulin levels. The pooled incidence of homozygous or compound heterozygous pathogenic IGLL1 variants identified by NBS in Austria, Czechia, and Switzerland was 1.3:100,000, almost double of X-linked agammaglobulinemia. CONCLUSION: B-cell deficiency resulting from IGLL1 variants appears to be more prevalent than initially believed. Despite markedly low B-cell counts, the clinical course in some patients may be milder than reported in the literature so far.

RESUMEN

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)

RESUMEN

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.

Asunto(s)

RESUMEN

Background: Inborn errors of immunity, mainly Predominantly Antibody deficiencies with normal IgG levels are unrecognized in adults with lung diseases such as bronchiectasis or recurrent pneumonia. Objective: To determine IgM, IgA, IgG2 subclass deficiencies, and Specific antibody deficiency (anti-pneumococcal polysaccharide antibodies) in adults with non-cystic fibrosis bronchiectasis or recurrent pneumonia. Methods: Cross-sectional study. Consecutive patients with non-cystic fibrosis bronchiectasis or recurrent pneumonia were recruited in Cali, Colombia. IgG, IgA, IgM, and IgE, IgG2subclass and IgG anti-pneumococcal serum levels were measured. Results: Among the 110 participants enrolled, Antibody deficiencies with normal serum IgG levels were found in 11(10%) cases. IgA deficiency (3 cases), IgM deficiency (2 cases) and IgG2 deficiency (2 cases) were the most frequent primary immunodeficiencies. In addition, IgG2+IgA deficiency, Ataxia-telangiectasia, Hyper-IgE syndrome and Specific Antibody Deficiency(anti-polysaccharides) were found in one case each. Conclusions: Predominantly antibody deficiencies with normal IgG levels are an important etiology of non-cystic fibrosis bronchiectasis and recurrent pneumonia in adults.

Antecedentes: Los Errores Innatos de la Inmunidad principalmente las Deficiencias Predominantemente de anticuerpos con niveles normales de IgG no se conocen en adultos con enfermedades pulmonares como las bronquiectasias o la neumonía recurrente. Objetivo: Determinar las deficiencias de IgM, IgA y de subclase de IgG2 y la Deficiencia Específica de Anticuerpos (anticuerpos antineumocócicos de polisacáridos) en adultos con Bronquiectasias no Fibrosis Quística (BQnoFQ) o neumonía recurrente. Métodos: Estudio observacional prospectivo. Se reclutaron 110 pacientes consecutivos con BQnoFQ o neumonía recurrente en Cali, Colombia. Se midieron los niveles séricos de IgG, IgA, IgM e IgE, subclase IgG2 y anticuerpos anti-neumococo. Resultados: Se encontraron deficiencias de anticuerpos con niveles normales de IgG en el 10% de los sujetos; Cuatro casos con IgG2 baja, incluido 1 caso de deficiencia de IgG2 + IgA, 1 caso de ataxia-telangiectasia, 3 deficiencias de IgA (IgAD), 2 deficiencias selectiva de IgM (IgMD), 1 síndrome de Hiper-IgE (HIES-AR) y 1 deficiencia específica de anticuerpos. Ocho pacientes fueron diagnosticados con enfermedades relacionadas con la hipogammaglobulinemia IgG. Conclusiones: Las deficiencias predominantemente de anticuerpos con niveles normales de IgG son una etiología importante de BQnoFQ y neumonía recurrente en adultos. Los sujetos con bronquiectasias o neumonía recurrente requieren una evaluación exhaustiva de la respuesta inmune humoral y clínica.

Asunto(s)

Asunto(s)

Asunto(s)

RESUMEN

AIM: To evaluate and describe lymphocyte populations' and B cell subsets' frequencies in patients presenting with Predominantly antibody deficiencies (PAD) and diagnosed with bronchiectasis or recurrent pneumonia seen in Cali (Colombian Southwest region). MATERIALS AND METHODS: 16 subjects with PAD, 20 subjects with pulmonary complications (bronchiectasis or recurrent pneumonia) and 20 healthy donors (HD). Controls and probands between 14 and 64 years old, regardless of gender were included. Lymphocyte populations (T, B and NK cells) and B cell subsets were evaluated in peripheral blood mononuclear cells using flow cytometry, T/B/NK reagent and the pre-germinal center antibody panel proposed by the EUROflow consortium were used. EUROclass and the classification proposed by Driessen et al. were implemented. RESULTS: CVID patients exhibited increase absolute numbers of CD8+ T cells and reduce NK cells as compare with HD, other PAD cases or pulmonary complications. PAD B cell subsets were disturbed when compared to the age range-matched healthy donors. Among B cell subsets, the memory B cell compartment was the most affected, especially switched memory B cells. Four participants were classified as B- and two CVID as smB-Trnorm and smB-21low groups according to EUROclass classification. The most frequent patterns proposed by Driessen et al. were B cell production and germinal center defect. CONCLUSIONS: B cell subsets, especially memory B cells, are disturbed in PAD patients from Southwestern Colombia. To the best of our knowledge this is the most comprehensive study of B cell subsets in Colombian adults.

Asunto(s)

RESUMEN

Abstract Background: Inborn errors of immunity, mainly Predominantly Antibody deficiencies with normal IgG levels are unrecognized in adults with lung diseases such as bronchiectasis or recurrent pneumonia. Objective: To determine IgM, IgA, IgG2 subclass deficiencies, and Specific antibody deficiency (anti-pneumococcal polysaccharide antibodies) in adults with non-cystic fibrosis bronchiectasis or recurrent pneumonia. Methods: Cross-sectional study. Consecutive patients with non-cystic fibrosis bronchiectasis or recurrent pneumonia were recruited in Cali, Colombia. IgG, IgA, IgM, and IgE, IgG2subclass and IgG anti-pneumococcal serum levels were measured. Results: Among the 110 participants enrolled, Antibody deficiencies with normal serum IgG levels were found in 11(10%) cases. IgA deficiency (3 cases), IgM deficiency (2 cases) and IgG2 deficiency (2 cases) were the most frequent primary immunodeficiencies. In addition, IgG2+IgA deficiency, Ataxia-telangiectasia, Hyper-IgE syndrome and Specific Antibody Deficiency(anti-polysaccharides) were found in one case each. Conclusions: Predominantly antibody deficiencies with normal IgG levels are an important etiology of non-cystic fibrosis bronchiectasis and recurrent pneumonia in adults.

Resumen Antecedentes: Los Errores Innatos de la Inmunidad principalmente las Deficiencias Predominantemente de anticuerpos con niveles normales de IgG no se conocen en adultos con enfermedades pulmonares como las bronquiectasias o la neumonía recurrente. Objetivo: Determinar las deficiencias de IgM, IgA y de subclase de IgG2 y la Deficiencia Específica de Anticuerpos (anticuerpos antineumocócicos de polisacáridos) en adultos con Bronquiectasias no Fibrosis Quística (BQnoFQ) o neumonía recurrente. Métodos: Estudio observacional prospectivo. Se reclutaron 110 pacientes consecutivos con BQnoFQ o neumonía recurrente en Cali, Colombia. Se midieron los niveles séricos de IgG, IgA, IgM e IgE, subclase IgG2 y anticuerpos anti-neumococo. Resultados: Se encontraron deficiencias de anticuerpos con niveles normales de IgG en el 10% de los sujetos; Cuatro casos con IgG2 baja, incluido 1 caso de deficiencia de IgG2 + IgA, 1 caso de ataxia-telangiectasia, 3 deficiencias de IgA (IgAD), 2 deficiencias selectiva de IgM (IgMD), 1 síndrome de Hiper-IgE (HIES-AR) y 1 deficiencia específica de anticuerpos. Ocho pacientes fueron diagnosticados con enfermedades relacionadas con la hipogammaglobulinemia IgG. Conclusiones: Las deficiencias predominantemente de anticuerpos con niveles normales de IgG son una etiología importante de BQnoFQ y neumonía recurrente en adultos. Los sujetos con bronquiectasias o neumonía recurrente requieren una evaluación exhaustiva de la respuesta inmune humoral y clínica.

RESUMEN

Predominantly antibody deficiencies (PADs) encompass a heterogeneous group of disorders characterized by low immunoglobulin serum levels in the presence or absence of peripheral B cells. Clinical presentation of affected patients may include recurrent respiratory and gastrointestinal infections, invasive infections, autoimmune manifestations, allergic reactions, lymphoproliferation, and increased susceptibility to malignant transformation. In the last decades, several genetic alterations affecting B-cell development/maturation have been identified as causative of several forms of PADs, adding important information on the genetic background of PADs, which in turn should lead to a better understanding of these disorders and precise clinical management of affected patients. This review aimed to present a comprehensive overview of the known and potentially involved molecules in the etiology of PADs to elucidate the pathogenesis of these disorders and eventually offer a better prognosis for affected patients.

Asunto(s)

RESUMEN

Predominantly antibody deficiencies (PADs) are a heterogeneous group of primary immunodeficiency disorders (PIDs), consisting of recurrent infections, autoimmunity, inflammation, and other immune complications. In the recent years, several immunological and genetic defects have been recognized in PADs. Currently, 45 distinct PAD disorders with 40 different genetic defects have been identified based on the 2019 IUIS classification. Genetic analysis is helpful for diagnosing PIDs; however, genetic studies are expensive, time-consuming, and unavailable everywhere. Flow cytometry is a highly sensitive tool for evaluating the immune system and diagnosing PADs. In addition to cell populations and subpopulations assay, flow cytometry can measure cell surface, intracellular and intranuclear proteins, biological changes associated with specific immune defects, and certain functional immune abnormalities. These capabilities help in rapid diagnostic and prognostic assessment as well as in evaluating the pathogenesis of PADs. For the first time, this review particularly provides an overview of the application of flow cytometry for diagnosis, immunophenotyping, and determining the pathogenesis of PADs.

Asunto(s)

RESUMEN

Hypogammaglobulinaemias are the most common primary immunodeficiency diseases. This group of diseases is very heterogeneous, and little is known about these diseases in children. In the Pediatric Predominantly Antibody Deficiencies (PedPAD) study, we analysed data from the European Society for Immunodeficiencies (ESID) online database to gain more insight into the characteristics of children with hypogammaglobulinaemia; 46 centres in 18 different countries agreed to participate. Data from 2076 of the 3191 children who were registered at the time of data extraction with a diagnosis of hypogammaglobulinaemia (this excludes agammaglobulinaemia and defects in class-switch recombination) were available for analysis. The data set showed several limitations. Because of country-related differences in diagnostic criteria used for the classification of different types of primary hypogammaglobulinaemia, further analysis of the data was performed in the combined data set. The most striking observation is the strong majority of male patients in the group of children with primary hypogammaglobulinaemia (n = 1292, 63%). This male predominance was observed in each of the 18 countries involved. The boys were younger at diagnosis (mean age males 5·3 years; mean age females 5·8 years). Moreover, one or more complications were more frequently reported in boys (12%) compared to girls (5%). The male predominance suggests that patients with an undetected or unknown X-linked genetic cause are included in this group of children registered as primary hypogammaglobulinaemia.

Asunto(s)