Lung disease in primary antibody deficiency.

This Review summarises current knowledge on the pulmonary manifestations of primary antibody deficiency (PAD) syndromes in adults. We describe the major PAD syndromes, with a particular focus on common variable immunodeficiency (CVID). Respiratory infection is a common presenting feature of PAD syndromes. Respiratory complications are frequent and responsible for much of the morbidity and mortality associated with these syndromes. Respiratory complications include acute infections, the sequelae of infection (eg, bronchiectasis), non-infectious immune-mediated manifestations (notably the development of granulomatous-lymphocytic interstitial lung disease in CVID), and an increased risk of lymphoma. Although minor abnormalities are detectable in the lungs of most patients with CVID by CT scanning, not all patients develop lung complications. Mechanisms associated with the maintenance of lung health versus lung disease, and the development of bronchiectasis versus immune-mediated complications, are now being dissected. We review the investigation, treatment, and management strategies for PAD syndromes, and include key research questions relating to both infectious and non-infectious complications of PAD in the lung

Predictive Factors for and Complications of Bronchiectasis in Common Variable Immunodeficiency Disorders

Bronchiectasis is a frequent complication of common variable immunodeficiency disorders (CVID). In a cohort of patients with CVID, we sought to identify predictors of bronchiectasis. Secondly, we sought to describe the impact of bronchiectasis on lung function, infection risk, and quality of life. We conducted an observational cohort study of 110 patients with CVID and an available pulmonary computed tomography scan. The prevalence of bronchiectasis was 53%, with most of these patients (54%) having mild disease. Patients with bronchiectasis had lower median serum immunoglobulin (Ig) concentrations, especially long-term IgM (0 vs 0.25 g/l; p < 0.01) and pre-treatment IgG (1.3 vs 3.7 g/l; p < 0.01). CVID patients with bronchiectasis had worse forced expiratory volume in one second (2.10 vs 2.99 l; p < 0.01) and an annual decline in forced expiratory volume in one second of 25 ml/year (vs 8 ml/year in patients without bronchiectasis; p = 0.01). Patients with bronchiectasis also reported more annual respiratory tract infections (1.77 vs 1.25 infections/year, p = 0.04) and a poorer quality of life (26 vs 14 points in the St George's Respiratory Questionnaire; p = 0.02). Low serum immunoglobulin M concentration identifies patients at risk for bronchiectasis in CVID and may play a role in pathogenesis. Bronchiectasis is relevant because it is associated with frequent respiratory tract infections, poorer lung function, a greater rate of lung function decline, and a lower quality of life

Bowel Histology of CVID Patients Reveals Distinct Patterns of Mucosal Inflammation

Diarrhea is the commonest gastrointestinal symptom in patients with common variable immunodeficiency (CVID). Different pathologies in patients’ bowel biopsies have been described and links with infections have been demonstrated. The aim of this study was to analyze the bowel histology of CVID patients in the Royal-Free-Hospital (RFH) London CVID cohort. Ninety-five bowel histology samples from 44 adult CVID patients were reviewed and grouped by histological patterns. Reasons for endoscopy and possible causative infections were recorded. Lymphocyte phenotyping results were compared between patients with different histological features. There was no distinctive feature that occurred in most diarrhea patients. Out of 44 patients (95 biopsies), 38 lacked plasma cells. In 14 of 21 patients with nodular lymphoid hyperplasia (NLH), this was the only visible pathology. In two patients, an infection with Giardia lamblia was associated with NLH. An IBD-like picture was seen in two patients. A coeliac-like picture was found in six patients, four of these had norovirus. NLH as well as inflammation often occurred as single features. There was no difference in blood lymphocyte phenotyping results comparing groups of histological features. We suggest that bowel histology in CVID patients with abdominal symptoms falls into three major histological patterns: (i) a coeliac-like histology, (ii) IBD-like changes, and (iii) NLH. Most patients, but remarkably not all, lacked plasma cells. CVID patients with diarrhea may have an altered bowel histology due to poorly understood and likely diverse immune-mediated mechanisms, occasionally driven by infections

Common variable immunodeficiency, impaired neurological development and reduced numbers of T regulatory cells in a 10-year-old boy with a STAT1 gain-of-function mutation

Recently, gain-of-function (GOF) mutations in the gene encoding signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis (CMC). This case report describes a 10-year-old boy presenting with signs of common variable immunodeficiency (CVID), failure to thrive, impaired neurological development, and a history of recurrent mucocutaneous Candida infections. Sequencing of the STAT1 gene identified a heterozygous missense mutation in exon 7 encoding the STAT1 coiled-coil domain (c.514T > C, p.Phe172Leu). In addition to hypogammaglobulinemia with B-cell deficiency, and a low percentage of Th17 cells, immunological analysis of the patient revealed a marked depletion of forkhead-box P3+-expressing regulatory T cells (Tregs). In vitro stimulation of T cells from the patient with interferon-α (IFNα) and/or IFNɣ resulted in a significantly increased expression of STAT1-regulated target genes such as MIG1, IRF1, MX1, MCP1/CCL2, IFI-56K, and CXCL10 as compared to IFN-treated cells from a healthy control, while no IFNα/ɣ-mediated up-regulation of the FOXP3 gene was found. These data demonstrate that the STAT1 GOF mutation F172L, which results in impaired stability of the antiparallel STAT1 dimer conformation, is associated with inhibited Treg cell development and neurological symptoms

BAFFR activates PI3K/AKT signaling in human naive but not in switched memory B cells through direct interactions with B cell antigen receptors.

Binding of BAFF to BAFFR activates in mature B cells PI3K/AKT signaling regulating protein synthesis, metabolic fitness, and survival. In humans, naive and memory B cells express the same levels of BAFFR, but only memory B cells seem to survive without BAFF. Here, we show that BAFF activates PI3K/AKT only in naive B cells and changes the expression of genes regulating migration, proliferation, growth, and survival. BAFF-induced PI3K/AKT activation requires direct interactions between BAFFR and the B cell antigen receptor (BCR) components CD79A and CD79B and is enhanced by the AKT coactivator TCL1A. Compared to memory B cells, naive B cells express more surface BCRs, which interact better with BAFFR than IgG or IgA, thus allowing stronger responses to BAFF. As ablation of BAFFR in naive and memory B cells causes cell death independent of BAFF-induced signaling, BAFFR seems to act also as an intrinsic factor for B cell survival

NFKB1 regulates human NK cell maturation and effector functions

12siopenopenLougaris, Vassilios; Patrizi, Ornella; Baronio, Manuela; Tabellini, Giovanna; Tampella, Giacomo; Damiati, Eufemia; Frede, Natalie; van der Meer, Jos W.M.; Fliegauf, Manfred; Grimbacher, Bodo; Parolini, Silvia; Plebani, AlessandroLougaris, Vassilios; Patrizi, Ornella; Baronio, Manuela; Tabellini, Giovanna; Tampella, Giacomo; Damiati, Eufemia; Frede, Natalie; van der Meer, Jos W. M.; Fliegauf, Manfred; Grimbacher, Bodo; Parolini, Silvia; Plebani, Alessandr

Altered Microbiota, Impaired Quality of Life, Malabsorption, Infection, and Inflammation in CVID Patients With Diarrhoea

© Copyright © 2020 van Schewick, Nöltner, Abel, Burns, Workman, Symes, Guzman, Proietti, Bulashevska, Moreira, Soetedjo, Lowe and Grimbacher. Background: Diarrhoea is the commonest gastrointestinal symptom in patients with common variable immunodeficiency (CVID). Objective: The aim of this study was to describe the prevalence and clinical presentation of chronic and recurrent diarrhoea in the Royal-Free-Hospital (RFH) London CVID cohort, including symptoms, infections, level of inflammation, and microbial diversity. Methods: A cross-sectional study of adult CVID patients (139 out of 172 diagnosed with CVID completed the screening questionnaire). Those with diarrhoea ≥6 days/month had stool and blood samples analysed and completed the short Inflammatory Bowel Disease Questionnaire (sIBDQ). BMI, spleen-size, lymphocytes and gut-microbial diversity were compared. Due to logistical and clinical restraints, not all patients could be analysed on all measures. Results: 46/139 (33.1%) patients had current significant diarrhoea. In patients with past or present diarrhoea, BMI was lower (median 23.7 vs. 26, p = 0.005), malabsorption more common (57.97 vs. 35.71%, p = 0.011). CD4+ lymphocytes were higher in patients with diarrhoea (p = 0.028; n = 138), but CD4+ naïve lymphocytes were significantly higher in non-diarrhoea patients (p = 0.009, N = 28). Nine patients had confirmed or probable current gastrointestinal infections. Calprotectin was >60 μg/g in 13/29 with significant diarrhoea including 9 without infection. SIBDQ revealed a low median score of 4.74. Microbial alpha diversity was significantly lower in CVID patients compared to healthy household controls. There was no significant difference in alpha diversity in relation to antibiotic intake during the 6 weeks prior to providing samples. Conclusion: Patients with CVID and significant diarrhoea had infections, raised calprotectin, malabsorption, a lower BMI, an impaired quality of life (comparable to active IBD), and they differed from non-diarrhoea patients in their lymphocyte phenotyping. Furthermore, microbial diversity was altered. These findings strongly imply that there may be an inflammatory nature and a systemic predisposition to diarrhoea in CVID, which necessitates further investigation