Search

Background: Cytotoxic T-lymphocyte-associated protein 4 deficiency (CTLA4-D) is an inborn error of immunity (IEI) caused by heterozygous mutations, and characterized by immune cell infiltration into the gut and other organs, leading to intestinal disease, immune dysregulation and autoimmunity. While regulatory T-cell dysfunction remains central to CTLA4-D immunopathogenesis, mechanisms driving disease severity and intestinal pathology are unknown but likely involve intestinal dysbiosis. We determined whether the intestinal microbiome and metabolome could distinguish individuals with severe CTLA4-D and identify biomarkers of disease severity. Results: The genera Veillonella and Streptococcus emerged as biomarkers that distinguished CTLA4-D from healthy cohorts from both the National Institutes of Health (NIH) Clinical Center, USA (NIH; CTLA-D, n = 32; healthy controls, n = 16), and a geographically distinct cohort from the Center for Chronic Immunodeficiency (CCI) of the Medical Center - University of Freiburg, Germany (CCI; CTLA4-D, n = 25; healthy controls, n = 24). Since IEIs in general may be associated with perturbations of the microbiota, a disease control cohort of individuals with common variable immunodeficiency (CVID, n = 20) was included to evaluate for a CTLA4-D-specific microbial signature. Despite common IEI-associated microbiome changes, the two bacterial genera retained their specificity as biomarkers for CTLA4-D. We further identified intestinal microbiome and metabolomic signatures that distinguished patients with CTLA4-D having severe vs. mild disease. Microbiome changes were associated with distinct stool metabolomic profiles and predicted changes in metabolic pathways. These differences were impacted by the presence of gastrointestinal manifestations and were partially reversed by treatment with abatacept and/or sirolimus. Conclusions: Loss of intestinal microbial diversity and dysbiosis causing metabolomic changes was observed in CTLA4-D. Albeit some of these features were shared with CVID, the distinct changes associated with CTLA4-D highlight the fact that IEI-associated microbiome changes likely reflect the underlying immune dysregulation. Identified candidate intestinal microbial and metabolic biomarkers distinguishing individuals with CTLA4-D based on severity should be studied prospectively to determine their predictive value, and investigated as potential therapeutic ta. 5D3rs3jgvo7MqmP_TFVE2K Video Abstract [ABSTRACT FROM AUTHOR]

Introduction: Immunoglobulin replacement therapy (IgRT), either intravenous (IVIg) or subcutaneous (SCIg), is crucial for managing primary immune deficiencies (PIDs) with hypogammaglobulinemia by reducing infection rates and mortality. During the COVID-19 pandemic, a global shortage of SCIg prompted our unit to reduce SCIg doses or maintain the same dose intravenously. This study evaluates the impact of a standardized SCIg dose reduction on infection rates and clinical outcomes in patients with humoral PID and with a low burden of infections. Methods: Adult PID patients on SCIg for at least 6 months, with IgG trough levels ≥ 700 mg/dL (or ≥ 900 mg/dL under specific conditions), and no significant infections in the past 6 months were eligible. A dose reduction of 15 mg/kg/week (60 mg/kg/month) for every 150 mg/dL above 700 mg/dL (or 900 mg/dL) was proposed. Clinical and laboratory data, and infectious events at 6- and 12-month follow-ups, were analyzed. Results: Thirty-one patients with PID were included: common variable immunodeficiency (54.83%), IgG subclass deficiency (9.67%), and other PIDs (35.48%). The average SCIg dose was initially reduced from 7.82 g/week to 5.72 g/week and adjusted to 6.94 g/week at 12 months. There was no significant change in severe or mild infections before and at 6- and 12-months post-dose adjustment. The dose reduction saved an average of 5,550 euros per patient annually, totaling 172,050 euros annually for our cohort. Discussion: Optimizing SCIg doses in selected well-controlled humoral PIDs is feasible without increasing infection rates, conserving this plasma-derived product during shortages. Larger prospective studies are needed to confirm this strategy's utility and its application to other Ig formulations. [ABSTRACT FROM AUTHOR]

Copyright of Zeitschrift für Rheumatologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

CVID (common variable immunodeficiency) is associated with a variety of gastrointestinal disorders including those mimicking Crohn’s disease and ulcerative colitis. At present there is no clear trial data for the treatment of CVID enteropathy. There are no specific recommendations for treatment; however, it is commonly treated in a similar manner to inflammatory bowel disease, with corticosteroids, 5-aminosalicylates (5-ASA), azathioprine and anti-TNF therapy all being used. We describe the case of a 54-year-old with CVID-enteropathy presenting with diarrhoea and evidence of granulomatous inflammation on colonic biopsies. He was successfully treated with ustekinumab following failure/intolerance of prednisolone, 5-ASA and azathioprine. Features of CVID-enteropathy improved both clinically and histologically, with no evidence of serious treatment-related side effects. [ABSTRACT FROM AUTHOR]

Background/Objectives: Gastrointestinal diseases are a major cause of morbidity in common variable immunodeficiency disorder (CVID), clinically often mimicking other conditions including celiac disease and inflammatory bowel disease (IBD). Hence, diagnosis of CVID remains challenging. This study aims to raise awareness and highlight histopathological clues for CVID in intestinal biopsies, emphasizing diagnostic pitfalls for the pathologist/gastroenterologist. Methods: We reviewed 63 (18 duodenal, 23 ileal, 22 colonic) biopsies and case histories from seven CVID patients, obtained over a 31-year period, with attention to active inflammation, intraepithelial lymphocytes, plasma cells, lymphoid hyperplasia, crypt/villous architecture, subepithelial collagen, apoptosis, granulomas, and infections. Clinical information of 41 pathology requests was reviewed. Results: Gastrointestinal symptoms were variable. Histological features included IBD-like (3/7), celiac disease-like (2/7), graft-versus-host disease (GVHD)-like (2/7), lymphocytic sprue/colitis-like (3/7), collagenous colitis-like (2/7), and acute colitis-like (4/7) patterns, often overlapping (2/7) and/or changing over time (3/7). Lymphoid hyperplasia was seen in 3/7 patients; 1/7 had giardiasis; and 5/7 had few plasma cells, usually only in part of the gut (3/5). Clinical information of 12/41 (29%) pathology requests mentioned known/suspected CVID, despite being known in 33/41 (80%). Conclusions: Clinical/histological features of CVID in the gut are diverse, often mimicking IBD, microscopic colitis, celiac disease and/or GVHD, hence the importance of adequate clinical information. Some histological features are atypical of these established entities and may indicate CVID, as may overlapping/changing histological patterns and/or few plasma cells in part of the gut. Awareness of the heterogenous clinical presentation and histopathological indicators of CVID may improve diagnosis. [ABSTRACT FROM AUTHOR]

Reduced function or hypomorphic variants in recombination-activating genes (RAG) 1 or 2 result in a broad clinical phenotype including common variable immunodeficiency (CVID) and even adult-onset disease. Milder RAG variants are less characterized. Here we describe the longitudinal course of a milder combined RAG deficiency in 3 of 7 siblings sharing the same RAG2 mutations over a 50-year study. Whole-genome and repertoire sequencing, bacteriophage immunizations, and deep immunophenotyping were used to compare affected and unaffected family members. The clinical phenotype of three affected siblings with hypomorphic RAG deficiency ranged from combined immunodeficiency and early mortality to a late-onset CID with hyper-IgM phenotype. T cells were remarkably similar across affected siblings, yet CDR3 skewing and regulatory T cell defects were not observed. B cell analysis showed elevated unswitched CD27+ and CD21low cells as well as features of an autoreactive antibody repertoire and presence of secreted autoantibodies, yet no clinical autoimmunity was present. Most striking was an expanded polyclonal marginal zone-like B cell population (IgM+IgD+CD27+) utilizing the self-reactive unmutated VH4-34 receptor demonstrating that hypomorphic RAG deficiency can promote expansion of self-reactive B cells. This process, however, was not sufficient to trigger clinical autoimmunity. Utilizing multiple approaches, we functionally measured the specific RAG2 variant effects and assessed how selection and secondary triggers altered the BCR repertoire and immunophenotype overtime. Overall, we demonstrate a broad disease spectrum in siblings with identical hypomorphic RAG deficiency, highlighting that phenotypic divergence can result from expansion of IgM + memory B cells. [ABSTRACT FROM AUTHOR]

Background: Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and recurrent infections. Significant morbidity and mortality are caused by immune dysregulation complications (CVIDid), which affect around one-third of CVID patients and have a poorly understood etiology. Here, we investigate the hypothesis that gut microbial dysbiosis contributes to the inflammation underlying CVIDid. Results: Bacterial invasion of colonic crypts was observed in CVID (3/15) and X-linked agammaglobulinemia (XLA, 1/3), but not in healthy control (HC, 0/9) biopsies. Fecal gut microbiota was characterized using 16S rRNA-targeted amplicon sequencing. Increased bacterial load, decreased alpha diversity and distinct beta diversity were observed in CVIDid (n = 42) compared to HC (n = 48), and similar results were seen in CVID with IgA deficiency (n = 40) compared to HC. CVIDid and CVID-IgA showed enrichment of the genus Enterococcus, and in vitro studies confirmed the inflammatory potential of Enterococcus gallinarum and Enterococcus hirae in patient monocytes. Conclusions: This study further supports the hypothesis that a dysregulated gut microbiota, with IgA deficiency as an important driving factor, contributes to systemic inflammation in primary antibody deficiency, and introduces enterococci as potential pathobionts in CVIDid. EQUitBFVXYmTZpXE6XWtg9 Video Abstract [ABSTRACT FROM AUTHOR]

Primary immunodeficiencies (PIDs) are rare diseases in which chronic pulmonary diseases are common. Chronic pulmonary complications affect the long-term survival of these patients. The aim of this study was to evaluate the accompanying lung diseases and respiratory functions in adult PID patients in the Turkish population. Patients' files who applied to the immunology clinic between 2015 and 2020 were evaluated retrospectively. The respiratory system was evaluated by physical examination, and if necessary, computed tomography, chest radiography, and pulmonary function test (PFT) were performed. The diagnosis of PIDs was based on the European Society of Immunodeficiency's (ESID) criteria. A total of 186 patients were included in the study. The median age of the patients was 38 years. The distribution of the diseases included in the study in order of frequency is: Common Variable Immunodeficiency (CVID) (47.8%), Severe Combined Immunodeficiency (SCID) (22.6%), Selective IgA deficiency (SIgAD) (10.8%), X-Linked Agammaglobulinemia (XLA) (10.2%), Chronic Granulomatous Disease (CGD) (8.6%). The most common findings on chest radiology were bronchiectasis (37.1%), parenchymal nodule (32.8%), ground glass opacity (31.2%), lymphadenopathy (24.7%), fibrotic changes (24.8%), reticular opacities (23.7%) and bronchial wall thickening (23.1%). PFT's results were lower in patients with CGD. Bronchiectasis (37.1%), asthma (22%), and tuberculosis (9.7%) were the most common lung complications. We think that the frequency of other lung complications, especially asthma and bronchiectasis, is higher in adult patients with PIDs, and patient management is poor as there are no guidelines for the follow-up, diagnosis, and treatment of pulmonary complications. [ABSTRACT FROM AUTHOR]

TRAF3, a versatile adaptor protein within the TRAF family, participates in various signaling pathways involving the tumor necrosis factor receptor, toll-like receptor, and retinoic acid-inducible gene I-like receptor families. In 2010, autosomal dominant TRAF3 deficiency was reported in a patient with herpes simplex virus-1 encephalitis, consistent with the role of TRAF3 in type I interferon production. Recently, a novel, completely different clinical phenotype was described in patients with TRAF3 haploinsufficiency (TRAF3Hl), characterized by recurrent bacterial infections, autoimmune features, systemic inflammation, and hypergammaglobulinemia. In this study, we conducted a TRAF3-targeted reanalysis of next-generation sequencing data from 800 patients with inborn errors of immunity. Through this reassessment and additional familial investigations, we identified three previously unidentified cases of TRAF3Hl within two different families. These individuals harbored stop-gain variants (p.Arg163* and p.Gln407*) and experienced recurrent bacterial infections with hypogammaglobulinemia. Previously, the patients had been diagnosed with common variable immunodeficiency (CVID) and were receiving immunoglobulin replacement therapy. In addition, a TRAF3 start-loss variant (c.3G > A) was identified in a fourth patient, but after familial and molecular studies, it was not considered disease-causing, excluding TRAF3Hl in this patient. This study illustrates the usefulness of targeted reanalysis of genes with reported novel phenotypes. We rescued three patients with TRAF3Hl, presenting similarities and differences with the previously reported patients. The most significant differences were hypogammaglobulinemia and a CVID-like presentation. These data expand the clinical phenotype of TRAF3Hl and pave the way for further investigation into loss-of-function variants in patients with CVID. [ABSTRACT FROM AUTHOR]

Common variable immune deficiency (CVID) with the frequency of 1 in 25000 is the "COMMON" form among the primary immunodeficiency diseases. It has a phenotype encompassing symptoms involving the lungs, gastrointestinal (GI) tract often, and joints. Symptoms are due to autoimmune and inflammatory reactions. These are seen from childhood to adult life with variable progression. Diagnostic criteria are defined now and include ruling out acquired hypogammaglobulinemia and agammaglobulinemia and include genetic testing. A higher incidence of cancer of the lymphoid or GI tract is reported. Treatment is the replacement of immunoglobulins. We report a patient with CVID with isolated GI symptoms. CVID is a less suspected, less recognized disease in India. Isolated GI symptoms in the form of diarrhea with no sinopulmonary and other organ involvement are even more, less common. [ABSTRACT FROM AUTHOR]

The pathogenesis of cervical extension of the thymus has been postulated to be incomplete descent of the thymus in the midline of the neck, which is considered normal in children. The thymus normally extends to the neck in approximately two-thirds of children. Ectopic thymus mainly occurs in 1%–13% of the younger population. In this study, we report two cases of asymptomatic neck swelling, one due to cervical extension of the thymus and the other due to a right submandibular ectopic thymus. None of the patients required any intervention. Recurrent suprasternal swelling in children that becomes more pronounced during coughing/crying or Valsalva maneuvers can be more accurately diagnosed using neck ultrasonography and/or magnetic resonance imaging. [ABSTRACT FROM AUTHOR]

The article discusses a case series of post-Rituximab (RTX) enteropathy in patients with common variable immunodeficiency disease (CVID) at a tertiary care center. Patients presented with diarrhea, weight loss, and hypogammaglobulinemia after RTX therapy, resembling primary CVID enteropathy. The study highlights the association between RTX therapy and loss of plasma cells in the small bowel, leading to severe malabsorption and malnutrition. Clinicians should consider a CVID-like enteropathy in patients with prior RTX use presenting with gastrointestinal symptoms. [Extracted from the article]

Background: Common variable immunodeficiency (CVID) predisposes patients to inflammatory bowel disease (IBD). There are limited studies characterizing adults with concomitant CVID and IBD (CVID-IBD)., Methods: Demographics, clinical courses, endoscopic findings, and disease-specific therapies were obtained in adults ≥18 years with CVID-IBD over a 5-year period., Results: We identified 11 patients with CVID-IBD, 6 with Crohn's disease (CD), and 5 with ulcerative colitis (UC). The presenting symptoms in 10 (91%) were abdominal pain and diarrhea. A majority of patients were diagnosed with IBD before CVID. Patients with CVID-IBD were diagnosed with CVID at an older age compared to patients with CVID only. The most prevalent endoscopic finding in CD was either erythema or erosions in the ileum, whereas in UC, it was pancolitis. One patient with CD and 1 with UC required treatment with immunomodulators to achieve remission. Three patients with CD and 2 with UC required treatment with biologics to achieve remission. Eight received intravenous immunoglobulin (IVIG) for CVID. Four patients with CD and 1 with UC were diagnosed with either leukemia or lymphoma, and the most common malignancy was chronic lymphocytic leukemia ( n  = 3)., Conclusions: This is one of few studies evaluating demographic, clinical, endoscopic, histologic features, and therapeutic management in patients with CVID-IBD. Further studies are required to elucidate long-term differences in the clinical course and treatment of patients with CVID-IBD., Competing Interests: The authors have no conflicts of interest with the exception of the following: M.R. holds the position of editor-in-chief for Crohn’s & Colitis 360 and has been recused from reviewing or making decisions for the manuscript. E.M. is on the editorial board for Crohn’s & Colitis 360 and has been recused from reviewing or making decisions for the manuscript. The authors have no financial disclosures., (© The Author(s) 2025. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation.)