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Identification of CVID Patients With Defects in Immune Repertoire Formation or Specification.

ABSTRACT: Common variable immune deficiency disorder (CVID) is the most clinically relevant cause of antibody failure. It is a highly heterogeneous disease with different underlying etiologies. CVID has been associated with a quantitative B cell defect, however, little is known about the quality of B cells present. Here, we studied the naïve and antigen selected B-cell receptor (BCR) repertoire in 33 CVID patients using next generation sequencing, to investigate B cells quality. Analysis for each individual patient revealed whether they have a defect in immune repertoire formation [V(D)J recombination] or specification (somatic hypermutation, subclass distribution, or selection). The naïve BCR repertoire was normal in most of the patients, although alterations in repertoire diversity and the junctions were found in a limited number of patients indicating possible defects in early B-cell development or V(D)J recombination in these patients. In contrast, major differences were found in the antigen selected BCR repertoire. Here, most patients (15/17) showed a reduced frequency of somatic hypermutation (SHM), changes in subclass distribution and/or minor alterations in antigen selection. Together these data show that in our CVID cohort only a small number of patients have a defect in formation of the naïve BCR repertoire, whereas the clear majority of patients have disturbances in their antigen selected repertoire, suggesting a defect in repertoire specification in the germinal centers of these patients. This highlights that CVID patients not only have a quantitative B cell defect, but that also the quality of, especially post germinal center B cells, is impaired.

SUBMITTER: van Schouwenburg PA

PROVIDER: S-EPMC6265514 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Identification of CVID Patients With Defects in Immune Repertoire Formation or Specification.

van Schouwenburg Pauline A PA IJspeert Hanna H Pico-Knijnenburg Ingrid I Dalm Virgil A S H VASH van Hagen P Martin PM van Zessen David D Stubbs Andrew P AP Patel Smita Y SY van der Burg Mirjam M

Frontiers in immunology 20181123

Common variable immune deficiency disorder (CVID) is the most clinically relevant cause of antibody failure. It is a highly heterogeneous disease with different underlying etiologies. CVID has been associated with a quantitative B cell defect, however, little is known about the quality of B cells present. Here, we studied the naïve and antigen selected B-cell receptor (BCR) repertoire in 33 CVID patients using next generation sequencing, to investigate B cells quality. Analysis for each individu ...[more]

PMID: 30532750

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Project description:Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by recurrent bacterial infections and defined by reduced levels of IgG, IgA, and/or IgM, insufficient response to polysaccharide vaccination, and an abnormal B-cell immunophenotype with a significantly reduced fraction of isotype-switched memory B cells. In addition to this infectious phenotype, at least one third of the patients experience autoimmune, autoinflammatory, granulomatous, and/or malignant complications. The very heterogeneous presentation strongly suggests a collection of different disease entities with somewhat different pathogeneses and most likely diverse genetic etiologies. Major progress has been made during recent years with the advent and introduction of next-generation sequencing, initially for research purposes, but more recently in clinical practice. In the present study, we performed whole exome sequencing on 20 CVID patients with autoimmunity, autoinflammation, and/or malignancy from the Danish CVID cohort with the aim to identify gene variants with a certain, possible, or potential disease-causing role in CVID. Through bioinformatics analyses, we identified variants with possible/probable disease-causing potential in nine of the patients. Of these, three patients had four variants in three different genes classified as likely pathogenic (NFKB1, TNFAIP3, and TTC37), whereas in six patients, we identified seven variants of possible pathogenic potential classified as variants of unknown significance (STAT3, IL17F, IRAK4, DDX41, NLRC3, TNFRSF1A, and PLCG2). In the remaining 11 patients, we did not identify possible genetic causes. Genetic findings were correlated to clinical disease presentation, clinical immunological phenotype, and disease complications. We suggest that the variants identified in the present work should lay the ground for future studies to functionally validate their disease-causing potential and to investigate at the mechanistic and molecular level their precise role in CVID pathogenesis. Overall, we believe that the present work contributes important new insights into the genetic basis of CVID and particular in the subset of CVID patients with a complex phenotype involving not only infection, but also autoimmunity, autoinflammation, and malignancy.

Project description:Common variable immunodeficiency (CVID) is one of the most frequently diagnosed primary antibody deficiencies (PADs), a group of disorders characterized by a decrease in one or more immunoglobulin (sub)classes and/or impaired antibody responses caused by inborn defects in B cells in the absence of other major immune defects. CVID patients suffer from recurrent infections and disease-related, non-infectious, complications such as autoimmune manifestations, lymphoproliferation, and malignancies. A timely diagnosis is essential for optimal follow-up and treatment. However, CVID is by definition a diagnosis of exclusion, thereby covering a heterogeneous patient population and making it difficult to establish a definite diagnosis. To aid the diagnosis of CVID patients, and distinguish them from other PADs, we developed an automated machine learning pipeline which performs automated diagnosis based on flow cytometric immunophenotyping. Using this pipeline, we analyzed the immunophenotypic profile in a pediatric and adult cohort of 28 patients with CVID, 23 patients with idiopathic primary hypogammaglobulinemia, 21 patients with IgG subclass deficiency, six patients with isolated IgA deficiency, one patient with isolated IgM deficiency, and 100 unrelated healthy controls. Flow cytometry analysis is traditionally done by manual identification of the cell populations of interest. Yet, this approach has severe limitations including subjectivity of the manual gating and bias toward known populations. To overcome these limitations, we here propose an automated computational flow cytometry pipeline that successfully distinguishes CVID phenotypes from other PADs and healthy controls. Compared to the traditional, manual analysis, our pipeline is fully automated, performing automated quality control and data pre-processing, automated population identification (gating) and deriving features from these populations to build a machine learning classifier to distinguish CVID from other PADs and healthy controls. This results in a more reproducible flow cytometry analysis, and improves the diagnosis compared to manual analysis: our pipelines achieve on average a balanced accuracy score of 0.93 (±0.07), whereas using the manually extracted populations, an averaged balanced accuracy score of 0.72 (±0.23) is achieved.

Project description:Background: Common variable immunodeficiency disorder (CVID) is one of the most frequent inborn errors of immunity, increased occurrence of malignancies, particularly lymphomas, and gastric cancers, has long been noted among CVID patients. Multifactorial etiology, including immune dysregulation, infections, chronic inflammation, or genetic background, is suggested to contribute to tumor development. Here, we present the results of the first Czech nationwide study focused on epidemiology, immunology and genetic background in a cohort of CVID patients who also developed tumors Methods: The cohort consisted of 295 CVID patients followed for 3,070 patient/years. Standardized incidence ratio (SIR) was calculated to determine the risk of cancer, and Risk ratio (RR) was established to evaluate the significance of comorbidities. Moreover, immunophenotyping, including immunoglobulin levels and lymphocyte populations, was assessed. Finally, Whole exome sequencing (WES) was performed in all patients with lymphoma to investigate the genetic background. Results: Twenty-five malignancies were diagnosed in 22 patients in a cohort of 295 CVID patients. SIR was more than 6 times greater in comparison to the general population. The most common neoplasias were gastric cancers and lymphomas. History of Immune thrombocytopenic purpura (ITP) was established as a potential risk factor, with over 3 times higher risk of cancer development. The B cell count at diagnosis of lymphoma was reduced in the lymphoma group; moreover, post-treatment B and T cell lymphopenia, associated with poorer outcome, was found in a majority of the patients. Intriguingly, no NK cell depression was observed after the chemotherapy. WES revealed heterogeneous genetic background among CVID patients with tumors, identifying gene variants associated with primary immunodeficiencies (such as CTLA4, PIK3CD, PMS2) and/or increased cancer susceptibility (including BRCA1, RABEP1, EP300, KDM5A). Conclusions: The incidence of malignancy in our CVID cohort was found to be more than 6 times greater compared to the general population. Gastric cancers and lymphomas were the most frequently diagnosed tumors. ITP was identified as a risk factor for malignancy in CVID patients. WES analysis confirmed a wide genetic heterogeneity among CVID patients. The identified causative or modifying gene variants pointed to errors in mechanisms contributing to both immunodeficiency and malignancy.

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Identification of CVID Patients With Defects in Immune Repertoire Formation or Specification.

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Identification of CVID Patients With Defects in Immune Repertoire Formation or Specification.

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