Gut IgA functionally interacts with systemic IgG to enhance antipneumococcal vaccine responses.

The gut microbiota enhances systemic immunoglobulin G (IgG) responses to vaccines, but it is unknown whether this effect involves IgA, which coats intestinal microbes. That IgA may amplify postimmune IgG production is suggested by the impaired IgG response to pneumococcal vaccines in some IgA-deficient patients. Here, we found that antipneumococcal but not total IgG production was impaired in mice with IgA deficiency.

Saliva antibody profiles are associated with reaction threshold and severity of peanut allergic reactions.

Background: Reaction threshold and severity in food allergy are difficult to predict, and noninvasive predictors are lacking.

Objective: We sought to determine the relationships between pre-challenge levels of peanut (PN)-specific antibodies in saliva and reaction threshold, severity, and organ-specific symptoms during PN allergic reactions.

Methods: We measured PN-specific antibody levels in saliva collected from 127 children with suspected PN allergy before double-blind, placebo-controlled PN challenges in which reaction threshold, severity, and symptoms were rigorously characterized.

ICOS agonist vopratelimab modulates follicular helper T cells and improves B cell function in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is an immune defect characterized by hypogammaglobulinemia and impaired development of B cells into plasma cells. As follicular helper T cells (T) play a central role in humoral immunity, we examined T cells in CVID, and investigated whether an inducible T cell co-stimulator (ICOS) agonist, vopratelimab, could modulate T, B cell interactions and enhance immunoglobulin production. CVID subjects had decreased T and increased T subsets; this was associated with increased transitional B cells and decreased IgG B and IgDIgMCD27 memory B cells.

Circulating bioactive bacterial DNA is associated with immune activation and complications in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is characterized by profound primary antibody defects and frequent infections, yet autoimmune/inflammatory complications of unclear origin occur in 50% of individuals and lead to increased mortality. Here, we show that circulating bacterial 16S rDNA belonging to gut commensals was significantly increased in CVID serum (P < 0.0001), especially in patients with inflammatory manifestations (P = 0.

Corrigendum: TACI Isoforms Regulate Ligand Binding and Receptor Function.

[This corrects the article DOI: 10.3389/fimmu.2018.

Serum B-Cell Maturation Antigen (BCMA) Levels Differentiate Primary Antibody Deficiencies.

Background: Primary antibody deficiencies (PADs) are the most prevalent primary immunodeficiencies. More severe forms of PADs-common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA)-require immunoglobulin replacement therapy (IRT) and may have serious complications. Differentiating severe PAD from milder hypogammaglobulinemia not requiring IRT can involve prolonged evaluations and treatment discontinuation.

BAFF-driven B cell hyperplasia underlies lung disease in common variable immunodeficiency.

Background: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency and is frequently complicated by interstitial lung disease (ILD) for which etiology is unknown and therapy inadequate.

Methods: Medical record review implicated B cell dysregulation in CVID ILD progression. This was further studied in blood and lung samples using culture, cytometry, ELISA, and histology.

Differentiation of Common Variable Immunodeficiency From IgG Deficiency.

Background: Common variable immunodeficiency (CVID) and IgG deficiency are 2 of the more prevalent primary humoral immune defects. The former is defined by consensus with criteria for quantitative and qualitative antibody defects, whereas the latter is used to describe patients with reduced IgG, who commonly have recurrent sinopulmonary infections but do not fulfill CVID criteria. However, these patients are often given this diagnosis.

Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies.

We report the molecular, cellular, and clinical features of 5 patients from 3 kindreds with biallelic mutations in the autosomal LIG1 gene encoding DNA ligase 1. The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating γδT cells, and erythrocyte macrocytosis. Clinical severity ranged from a mild antibody deficiency to a combined immunodeficiency requiring hematopoietic stem cell transplantation.

TACI Isoforms Regulate Ligand Binding and Receptor Function.

TACI signals activate B cell proliferation, isotype switch and antibody production in both normal immunity and autoimmune states. In contrast to murine TACI, the human TACI gene undergoes alternative splicing to produce short and long isoforms (TACI-S and TACI-L). In previous studies, we showed that transduction of the short, but not long isoform, into murine B cells or human pre-B cells lacking TACI, caused them to become transcriptional and morphologically identical to plasma cells.

Expansion of inflammatory innate lymphoid cells in patients with common variable immune deficiency.

Background: Common variable immunodeficiency (CVID) is an antibody deficiency treated with immunoglobulin; however, patients can have noninfectious inflammatory conditions that lead to heightened morbidity and mortality.

Objectives: Modular analyses of RNA transcripts in whole blood previously identified an upregulation of many interferon-responsive genes. In this study we sought the cell populations leading to this signature.

Differential induction of plasma cells by isoforms of human TACI.

Subjects with common variable immune deficiency may have mutations in transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI). Unlike the murine gene, human TACI undergoes alternative messenger (m)RNA splicing to produce isoforms with 1 or 2 ligand-binding domains. Because both isoforms are found in human B cells, we compared their functions in transduced murine B and human pre-B cells.

IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens.

IRAK-4 and MyD88 deficiencies impair interleukin 1 receptor and Toll-like receptor (TLR) signaling and lead to heightened susceptibility to invasive bacterial infections. Individuals with these primary immunodeficiencies have fewer immunoglobulin M (IgM)(+)IgD(+)CD27(+) B cells, a population that resembles murine splenic marginal zone B cells that mount T-independent antibody responses against bacterial antigens. However, the significance of this B-cell subset in humans is poorly understood.

Pulmonary radiologic findings in common variable immunodeficiency: clinical and immunological correlations.

Background: It remains unclear whether interstitial lung disease (ILD) in common variable immunodeficiency (CVID) is a consequence of chronic infection or a manifestation of dysregulated lymphoid proliferation found in those with this condition.

Objective: To increase understanding of CVID-associated lung disease by comparing clinical and immunologic associations in those with bronchiectasis, ILD, or no lung disease observed on chest computerized tomography (CT).

Methods: Retrospective review of electronic medical records of 61 patients with CVID was used to identify clinical and laboratory correlates of bronchiectasis, ground glass opacity, and pulmonary nodules on CT scan.

TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes.

Background: Mutations in the gene coding for the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) are found in 8% to 10% of subjects with common variable immunodeficiency (CVID). Although heterozygous mutations may coincide with immunodeficiency in a few families, most mutation-bearing relatives are not hypogammaglobulinemic. Thus, the role of TACI mutations in producing the immune defect remains unclear.

TLR-mediated B cell defects and IFN-α in common variable immunodeficiency.

Common variable immune deficiency (CVID) B cells have impaired responses to TLR7 and TLR9 agonists including poor cell proliferation, loss of cytokine production, and failure to produce IgG or IgA. We show that TLR7- or 9-activated B cells from CVID subjects with >0.5% peripheral isotype-switched CD27(+) B cells (group 2) have increased mature Cγ1 and Cγ2 heavy-chain mRNA transcripts compared to subjects who have <0.

Transmembrane activator and CAML interactor (TACI) haploinsufficiency results in B-cell dysfunction in patients with Smith-Magenis syndrome.

Background: Heterozygous deleterious mutations in the gene encoding the tumor necrosis factor receptor superfamily member 13b (TNFRSF13B), or transmembrane activator and CAML interactor (TACI), have been associated with the development of common variable immunodeficiency. Smith-Magenis syndrome (SMS) is a genetic disorder characterized by developmental delay, behavioral disturbances, craniofacial anomalies, and recurrent respiratory tract infections. Eighty percent of subjects have a chromosome 17p11.

Toll-like receptor 7 and 9 defects in common variable immunodeficiency.

Background: Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia, reduced numbers of peripheral blood isotype-switched memory B cells, and loss of plasma cells.

Objective: Because Toll-like receptor (TLR) activation of B cells can initiate and potentially sustain normal B cell functions, we examined functional outcomes of TLR7 and TLR9 signaling in CVID B cells.

Methods: TLR7-mediated, TLR7/8-mediated, and TLR9-mediated cell proliferation, isotype switch, and immunoglobulin production by control and CVID B cells or isolated naive and memory B cell subsets were examined.

Memory B cells in common variable immunodeficiency: clinical associations and sex differences.

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired antibody responses, recurrent infections, inflammatory, autoimmune and malignancy-related conditions. We evaluated the relationship between memory B cell phenotype, sex, age at diagnosis, immunologic and clinical conditions in 105 CVID subjects from one medical center. Reduced numbers of switched memory B cells (cutoff View Article and Find Full Text PDF

Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: clinical and immunologic outcomes in heterozygotes.

Background: Mutations in the gene coding for transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) have been identified in common variable immunodeficiency (CVID). Mutations coincided with immunodeficiency in families, suggesting dominant inheritance.

Objective: Because most subjects with CVID have no immunodeficient family members and heterozygous mutations predominate, the role of TACI mutations in sporadic CVID is unclear.

High serum levels of BAFF, APRIL, and TACI in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is characterized by low levels of immune globulins and lack of antibody. Mutations in transmembrane activator and calcium-modulating cyclophilin ligand (TACI), are found in 8-10%, associated with autoimmunity and splenomegaly. Some patients with mutations had increased serum levels of TACI.

TLR9 activation is defective in common variable immune deficiency.

Common variable immune deficiency (CVID) is a primary immune deficiency characterized by low levels of serum immune globulins, lack of Ab, and reduced numbers of CD27+ memory B cells. Although T, B, and dendritic cell defects have been described, for the great majority, genetic causes have not been identified. In these experiments, we investigated B cell and plasmacytoid dendritic cell activation induced via TLR9, an intracellular recognition receptor that detects DNA-containing CpG motifs from viruses and bacteria.

Immune competence and switched memory B cells in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is presumed to be a heterogenous group of disorders with potentially separate etiologies. Memory B cell subsets, characterized by CD27 expression, have been suggested as a means to subclassify CVID patients. 53 patients were subdivided based on percentages of switched memory B cells (CD27+IgM-IgD-): 33 were placed in Group I (<0.

Deficient IL-12 and dendritic cell function in common variable immune deficiency.

Patients with common variable immune deficiency have reduced serum IgG, IgA, and/or IgM, defective antibody production, and many have cellular abnormalities, including proliferative defects, accelerated T cell apoptosis, and insufficient production of IL-2 and IL-10. Excess monocyte intracellular IL-12 leading to a polarized Th-1-type response which could prevent antibody production has been suggested. Here we found that dendritic cells (DCs) of CVID subjects have a significantly reduced capacity to secrete IL-12, as compared to DCs of normal subjects when cultured with physiologic simulators: LPS (P = 0.