Unveiling a novel NBAS mutation in common variable immunodeficiency: Expanding the genetic landscape of immunodeficiency disorders.

Common variable immunodeficiency.

Patients with common variable immunodeficiency (CVID) suffer from hypogammaglobulinemia linked to an inadequate differentiation of long-lived humoral immunity and an impaired germinal center (GC) response in most cases. We sought to further characterize the transcriptome and phenotype of T follicular helper (TFH) cells of patients with complicated CVID (CVIDc) as key players in the GC reaction. Sorted TFH cells from CVIDc lymph nodes and non-CVID immunocompetent tonsils were analyzed by bulk RNA sequencing. Altered protein expression was verified by comparison with non-CVID tonsils and lymph nodes using cytometry by time-of-flight analysis. Tissue localization of cells was determined by multifluorescence imaging. Transcriptome analysis of sorted TFH cells revealed an enrichment of cytotoxicity-associated gene sets in patients with CVIDc. Extended immune phenotyping identified different cytotoxic CD4 memory populations expressing T-bet, EOMES (eomesodermin), class I-restricted T-cell-associated molecule, perforin, and granzymes. One cluster coexpressing markers of TFH differentiation C-X-C chemokine receptor type 5, inducible costimulator, and programmed cell death protein 1 was expanded in CVIDc lymph nodes. Histologic sections confirmed the increase in Granzyme-B+EOMES+CD4 cells within GCs of patients' lymph nodes. Only few of these cells circulate in peripheral blood. Our study reports for the first time that the type 1 polarization in lymph nodes of patients with CVIDc is associated with an expansion of a distinct cytotoxic CD4 TFH-cell cluster within GCs, which is only poorly reflected in peripheral blood. Because a detrimental role of these cells has been implied in the context of autoimmunity and chronic infection, further investigations are required to explore their role in the GC failure and immune dysregulation in patients with CVID.

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency, characterised by impaired antibody production, immune dysregulation, and a broad spectrum of clinical manifestations. Gastrointestinal involvement is frequent, affecting up to 20% of patients and significantly contributing to morbidity and mortality. Among infectious triggers, norovirus plays a particularly important role, as persistent infection may drive chronic inflammation and contribute to the development of CVID-associated enteropathy, a severe non-infectious complication marked by chronic diarrhoea, malabsorption, and weight loss. The pathogenesis is multifactorial, involving impaired humoural immunity, absent mucosal IgA, and aberrant T- and B-cell interactions, resulting in defective viral clearance and sustained mucosal injury. Although viral eradication has been shown to induce clinical and histological improvement, no standardized therapeutic strategy currently exists. Intravenous or subcutaneous immunoglobulin replacement fails to adequately protect against gastrointestinal infections, and off-label antivirals such as ribavirin, nitazoxanide, or interferon alpha have yielded inconsistent results. Oral administered immunoglobulin preparations have shown variable efficacy in case reports, reflecting differences in viral genotypes, host susceptibility, and donor antibody repertoires. In this review, we summarise current knowledge on the epidemiology, pathogenesis, clinical features, and diagnostic considerations of CVID-associated enteropathy linked to chronic norovirus infection, with a special focus on therapeutic aspects. We also present our experience with a patient successfully treated with immunoglobulin therapy administered via nasogastric tube, leading to clinical remission, nutritional recovery, and viral clearance. Recognising norovirus as a key etiological factor in CVID enteropathy emphasises the need to conduct systematic studies and evidence-based therapeutic approaches.

Common variable immunodeficiency

The New Zealand (NZ) Common Variable Immunodeficiency Disorders (CVID) study (NZCS) is a long-term prospective cohort study, which seeks to better understand the proximal causes and sequelae of CVID. Patients were accepted to the NZCS if they had a diagnosis of CVID. After informed consent, clinical and demographic data were obtained by an interviewer-assisted questionnaire. Computerised case notes and laboratory results, linked to each patient's National Health Index (NHI) number, were also reviewed. In the current analysis, ethnic-specific data was obtained on the prevalence of CVID and its sequelae in NZ. One hundred and eight patients with a diagnosis of CVID were enrolled in the NZCS, comprising approximately 70% of patients known to have CVID in NZ. There was a much greater prevalence of bronchiectasis in Māori (79%) compared to Caucasian CVID patients (38%). Māori patients with CVID develop symptoms at a younger age and have an increased number of severe infections prior to diagnosis. Māori CVID patients with bronchiectasis had a higher prevalence of complete IgA deficiency compared to Caucasian CVID patients with bronchiectasis. In contrast to Caucasian patients with CVID, autoimmune and inflammatory sequelae were much less common in Māori. This study also demonstrated worsening diagnostic delays in patients with CVID in NZ. The Indigenous Māori of Aotearoa have a much more aggresssive early-onset, infection-only CVID variant compared to Caucasian New Zealanders.

Genetic variants in Cytotoxic T-Lymphocyte-associated protein 4 (CTLA4) and LPS responsive beige-like anchor protein (LRBA), involved in the same biological pathways, are implicated as monogenic causes of Common Variable Immunodeficiency Disorder (CVID). The pitfall in the recognition of CVID possibly related to CTLA-4 haploinsufficiency or LRBA deficiency is a clinical picture that is very heterogeneous. In the present study, we illustrate this challenge by means of clinical and immunological analysis of five patients with novel genetic variants in CTLA4 and LRBA. Whole-exome sequencing (WES) was performed to identify genetic variants in the currently known immune genes in patients. Extensive immunophenotyping, lymphocyte proliferation assays and expression of CTLA-4 and a panel of 17 co-stimulatory molecules, both in rest and upon activation, were performed to gain insight into the impact of the genetic variants on B and T cell phenotype and function. A novel heterozygous variant in CTLA4 (c.457+5G>A) was identified in three members of a single family, all presenting with different clinical manifestations. In two additional patients, two genetic variants in LRBA (c.1771T>C; c.2450-3C>A) were found, of which one is novel as well. The B cell phenotype was naïve with absence of non-switched and switched memory B cells in all patients except of the genetically affected elderly woman without any clinical manifestations. CD4 and CD8 T cell numbers and phenotype were normal. Differentiation of B cells into antibody secreting cells in vitro was reduced, especially in response to T cell-independent stimulation. The T cells showed impaired upregulation of CTLA-4 expression, which was most pronounced in CD4+CD25+FoxP3+ regulatory T cells, which helped to biologically support the genetic diagnosis. The described novel genetic variants in CTLA4 and LRBA show immunological impact and are therefore likely to underly an immune dysregulation syndrome with a highly variable clinical presentation. Apart from the immunophenotypic abnormal findings in activated T cells, the intrinsic B cell defect aids in the interpretation of novel genetic variants in these two genes in the context of a highly suspected clinical presentation.

This report presents the case of a Thai male in his twenties presenting prolonged fever, generalized lymphadenopathy and hepatosplenomegaly. Blood cultures isolated Campylobacter jejuni, while lymph node cultures isolated Histoplasma capsulatum. A gene panel for immunodeficiency revealed nuclear factor kappa B subunit 1 (NFKB1) deficiency, leading to a final diagnosis of common variable immunodeficiency (CVID) due to autosomal dominant NFKB1 deficiency. The patient was initially treated with amphotericin B (0.7 mg/kg/day) for 3 weeks, followed by itraconazole 200 mg orally twice daily, and received intravenous azithromycin 500 mg once daily for C. jejuni bacteremia for 14 days. After three months of treatment, the patient demonstrated partial clinical and radiologic improvement. Additionally, intravenous immunoglobulin was administered to treat CVID. After 12 months of itraconazole, the follow-up computed tomography showed reduced lymphadenopathy to subcentimetric nodes and resolved hepatomegaly. Patients with disseminated atypical infections should be evaluated for primary immunodeficiency disorders, even when considered healthy.

The purpose of this review is to describe the most recent findings regarding lymphoma and lymphoproliferative disorders (LPDs) in common variable immune deficiency (CVID) patients, presenting epidemiological data regarding the burden of disease, exploring the underlying immunological mechanisms, and offering insights into the role of genetics and possible treatment options. There have been reports of predisposition to lymphoproliferation in both monogenic forms of CVID and CVID with no identifiable genetic cause. Germline but also somatic mutations have been claimed as possible contributors to lymphomagenesis in CVID. Lower B cell counts, hyper-IgM phenotype, reduction in CD4+T cells and an exaggerated CD8+T cell response, as well preexisting immune dysregulation manifestations, have also been identified as possible predisposing factors for the development of lymphoma and LPDs in CVID patients. Lymphoma and LPDs represent a significant portion of CVID noninfectious clinical manifestations, both as presenting symptoms and long-term complications. There is a complex interplay between genetic background, humoral and cellular immunity defects, as well as infections, chronic inflammation and immune dysregulation. Diagnosis may be challenging from both a clinical and a histopathological perspective. The toll of mortality is significant, making a high degree of surveillance for hematological malignancy necessary. No consensus on specific treatment guidelines is available; viable options include standard chemo-immunotherapy and hematopoietic stem cell transplantation (HSCT), when comorbidities are permissive. From a pathophysiological standpoint, a possible application of target therapies such as immune checkpoint inhibitors has been hypothesized, though no clinical trials are available yet for the treatment of lymphoma in CVID patients.

Abstract Background and Aims Granulomatous interstitial nephritis (GIN) is a rare form of tubulointerstitial nephritis being generally associated to infection, drugs or immune mediated disease. Sarcoidosis is the most frequent disease responsible for GIN, but conversely granulomatous inflammation can also be associated with immunodeficiency. Common variable immunodeficiency (CVID) is an inborn error of immunity characterized by impaired B cell differentiation with defective immunoglobulin production. It is the most prevalent form of significant antibody deficiency affecting both children and adults and can present later in life. Besides recurrent infections, immune dysregulation seen in CVID can lead to autoimmunity, presenting with cytopenia and granulomatous infiltrations of several organs, namely the lungs, liver and lymphoid organs. Kidney involvement is rare in CVID and GIN has been reported in less than 5 cases worldwide to our knowledge. Case report We report the case of a 58-year-old man with a past medical history of type 2 diabetes mellitus, hypertension and of two major skin infections (arm infection with compartment syndrome in childhood and Fournier gangrene at adult age). He presented with anorexia, asthenia, nausea and weight loss (12 Kg in the previous 3 months). Physical examination was unremarkable. Laboratory workup identified leucopenia, lymphopenia, rapidly progressive renal insufficiency (Scr 0.98 mg/dL to 3.5 mg/dL in 2 months), with bland urinary sediment, and urinary protein-to-creatinine ratio of 512.4 mg/g. Additionally, we identified hypercalcemia 11 mg/dL (normal PTH), normal erythrocyte sedimentation rate and increased angiotensin converting enzyme level (ACE 282 U/L). Auto-antibodies screening and complement were normal. Virology (including viral load of EBV and CMV) and tuberculosis quantiferon were also negative. Protein electrophoresis revealed hypoproteinemia with normal albumin and hypogammaglobulinemia and monoclonal gammopathy was excluded. IgG (374 mg/dL) and IgM (17 mg/dL) were below normal range, with normal IgA level. IgG 1 and IgG 2 sub-classes were also markedly decreased as also specific antibodies titters for pneumococcus. Vaccine response was not tested because of the urgent need to begin immunosuppressive treatment. Peripheral blood lymphocyte immunophenotyping showed a slight decrease in B cell proportion (CD19: 4.2%), and analysis of other B and T cell subpopulations in the peripheral blood was not possible due to the urgent need of treatment. Imagiology workup with CT scan revealed multiple adenopathies, lung parenchyma with septal diffuse and irregular thickening and hepatosplenomegaly. Renal biopsy was performed and revealed tubulointerstitial nephritis with noncaseous granulomas. Lung function was normal and broncofibroscopy with biopsy revealed also noncaseous granulomas and excluded infection or neoplasm. There was absence of B cells in the in the bronchoalveolar lavage. Following multidisciplinary discussion with immunoallergology and pneumology, CVID was considered and presented with related complications as granulomatous–lymphocytic infiltration, in the lungs and kidneys, cytopenias, hepatosplenomegaly and persistent diffuse adenopathies, making sarcoidosis diagnosis less probable. Considering immunodeficiency, intravenous immunoglobulin (IVIg) was added to glucocorticoid (GC) therapy (prednisolone 1 mg/kg) with significant pulmonary improvement, decrease in adenopathy size, renal function recovery (Scr 1.2 mg/dL without proteinuria 1 month later) and normalization of ACE and calcium. Conclusion Although GIN is usually associated with sarcoidosis, finding primary hypogammaglobulinemia with defective specific antibody production should raise the suspicion of an underlining immunodeficiency. Although GC are used as first line treatment for both, IVIg replacement treatment is essential to avoid potential severe infections. As such and as our case underlines, evaluation of immunoglobulin serum levels is of paramount importance before considering immunosuppressive treatment, especially in granulomatous disease.

A retrospective cohort study of non-melanoma skin cancer in patients with common variable immunodeficiency

Gastric cancer has emerged as a prominent cause of mortality in individuals with primary antibody deficiencies (PAD), especially common variable immunodeficiency (CVID), however its pathogenesis remains still poorly understood. Helicobacter (H.) pylori contributes to gastric cancerrisk in PAD, warranting early detection and eradication strategies. Prevention measures and screening programmes are still debated. This review provides an overview of recent advances in the field and discusses future perspectives. Over the last years, several papers have focused on the epidemiology, pathology, and treatment related to the high incidence and mortality of gastric cancer in PAD. Histological findings support the role of H. pylori as a key contributor, warranting early detection and eradication strategies. Immune dysregulation and genetic susceptibility have also been shown to contribute to the increased risk. H. pylori screening and treatment, along with endoscopic surveillance to identify premalignant and early malignant lesions, are widely recommended. In recent years, a decline in gastric cancer mortality has been observed in patients with CVID, paralleling trends in the general population, reflecting improved H. pylori management and enhanced surveillance. Gastric cancer surveillance is a priority in PAD. Further research should clarify pathogenesis, identify reliable biomarkers for risk stratification, and to define optimal surveillance strategies, ultimately improving early diagnosis and survival.

ABSTRACTObjectiveChronic rhinosinusitis (CRS) is prevalent and causes a great negative impact on quality of life. Primary antibody deficiency (PAD) is highly prevalent with CRS compared to the background population. There are efficient treatment options to consider when CRS is a symptom of PAD. The condition seems to be underdiagnosed.DesignA prospective cohort study investigating adults with CRS for PAD.ResultsOne hundred and thirty‐eight patients were included in the study. Mean age was 49 years. Twenty‐nine (21%) had hypogammaglobulinemia. Nine of 83 (11%) patients had insufficient response to pneumovax polysaccharide vaccine, but insufficient clinical history for diagnosis of Specific Antibody Deficiency (SPAD). Four patients met the clinical criteria for PAD; one had Common Variable Immune Deficiency (CVID), one had IgA deficiency, and two had IgG subclass deficiency. No clinical characteristic was predictive of PAD, and severity of CRS was not indicative of hypogammaglobulinemia or insufficient vaccine response.ConclusionImmunoglobulin testing should be a routine part of the diagnostic work‐up in chronic rhinosinusitis before considering biologics, as primary antibody deficiency is an under‐recognised but treatable cause of refractory disease.

Background: Common variable immunodeficiency (CVID), the most prevalent symptomatic inborn error of immunity, involves impaired B-cell differentiation and antibody production, causing recurrent infections and the need for life-long immunoglobulin replacement therapy. Methods: This study evaluated the in vitro differentiation of memory B-cells (MBCs) into antibody-secreting cells (ASCs) in CVID patients. Peripheral blood mononuclear cells from 13 CVID patients and 10 healthy controls were stimulated using two protocols: (I) Staphylococcus aureus Cowan Strain I, Pokeweed mitogen, and CpG, or (II) a T-cell-dependent approach using CD40 ligand, interleukin-21, and CpG. B-cell subpopulations were analyzed by flow cytometry, ASC differentiation using ELISpot, and antibody levels in supernatants by ELISA. Results: Despite severely restricted in vivo antibody production, MBCs from all 13 CVID patients differentiated into IgG and IgM ASCs under adequate in vitro stimulation. Protocol II, mimicking T-cell help, was more effective than protocol I. As expected, the patients exhibited reduced class-switched MBCs ex vivo, but the MBCs differentiated and proliferated to an extent similar to those in healthy controls. IgA secretion remained significantly impaired post-stimulation. Specific IgG antibodies against tetanus toxoid and Streptococcus pneumoniae were detected in the patient supernatants, while no double-stranded DNA autoantibodies emerged after in vitro stimulation. Conclusions: These findings indicate that the MBCs of most patients retain functional B-cell differentiation and antigen-specific IgG secretion under T-cell dependent stimulation, though IgA secretion remains impaired. Tailored stimulation protocols could deepen our understanding of how to restore MBC formation in CVID patients in vivo. This methodology provides a platform to investigate antigen-specific functional memory responses like post-vaccination.

Common Variable Immunodeficiency (CVID) is the most frequently encountered symptomatic primary immunodeficiency in clinical practice, presenting with heterogeneous clinical and genetic features. While traditionally considered polygenic, recent advances in genomic technologies have revealed monogenic causes in a significant subset of patients. This study aimed to investigate the genetic background of adult patients diagnosed with CVID or CVID-like phenotypes, using clinical exome sequencing (CES), focusing on atypical and syndromic presentations. Thirty adult patients fulfilling the ESID/PAGID criteria for CVID underwent CES. Genetic analysis targeted 451 immune-related genes, with variants interpreted according to ACMG guidelines. Pathogenicity was confirmed with Sanger sequencing. We detected potentially disease-related variants (TNFRSF13B, BTK, RAG1, SAMD9, NFKB2, PRKDC, CFTR, FCN3, IFIH1, ITGA3, and TNFRSF1A) in 12 of the 30 patients (40%). TNFRSF13B was the most frequently mutated gene among these patients. Deep phenotyping analyses revealed atypical findings included a hemizygous BTK variant mimicking CVID, a homozygous RAG1 variant consistent with leaky SCID, and a heterozygous SAMD9 variant not presenting with MIRAGE phenotype, and a homozygous ITGA3 insertion region variant that suggested a mild form of ILNED syndrome. Variants in CFTR, FCN3, and TNFRSF1A further expand the phenotypic spectrum, highlighting overlap between immunodeficiency and immune dysregulation syndromes in adulthood. A substantial proportion of adult patients with CVID-like phenotypes harbor variants in genes beyond the classical CVID-associated loci. Our findings support the utility of broad genetic screening in adult-onset antibody deficiency, particularly when non-infectious complications are present. Molecular diagnosis facilitates accurate classification, guides personalized treatment, and aids in genetic counseling.

Background: Immunodeficiencies are a heterogeneous group of disorders classified etiologically as primary (congenital) or secondary (acquired). Primary immunodeficiencies (PIDs), such as common variable immunodeficiency (CVID), result from genetic mutations that impair the development and function of lymphocytes. Secondary immunodeficiencies (SIDs) arise as a consequence of chronic diseases, lymphoid malignancies, or immunosuppressive therapies. Aim of the study: The purpose of this study was to assess the serum expression profile of selected microRNAs (miRNAs) in patients with CVID and in those with chronic lymphocytic leukemia (CLL) and coexisting SID, compared to healthy individuals. Methods: Digital PCR (dPCR) was applied to quantify the serum expression levels of selected miRNAs in patients with CVID, patients with CLL and SID, and in healthy controls. Results: dPCR revealed significantly reduced levels of miR-16, miR-30c, miR-181a, miR-29a, miR-150, and miR-326 in the CVID group, potentially reflecting impaired regulatory mechanisms of the immune system. In contrast, elevated levels of miR-21, miR-125b, and miR-155 were observed in the CLL group with SID, suggesting their role in tumorigenesis and secondary immunosuppression. Correlations between miRNA levels and the expression of immune checkpoints (PD-1, CTLA-4, CD200) indicated the involvement of a complex regulatory network encompassing both humoral and cellular immune mechanisms. Conclusions: The results provide preliminary evidence that selected miRNAs could reflect disease-specific immune dysregulation patterns and may hold potential as diagnostic and prognostic biomarkers in both PIDs and SIDs.

Background: Common Variable Immunodeficiency (CVID) is the most common primary immunodeficiency in adults. Autoimmune complications occur in up to 30% of patients, including inflammatory arthritis that often resembles rheumatoid arthritis. Standard management typically involves immunoglobulin replacement , combined with disease - modifying antirheumatic drugs (DMARDs) and corticosteroids, which are effective in most cases.4,6 Case Presentation: We present a 55-year-old male with CVID who developed progressive inflammatory arthritis refractory to multiple regimens. His management was complicated by methotrexate - induced leukopenia, corticosteroid - induced osteoporosis, and limited specialty continuity. Despite therapy with immunoglobulin, DMARDs, and corticosteroids, his joint symptoms persisted and worsened. Discussion: This case underscores the challenges of treating autoimmune complications in immunodeficient patients. It highlights the importance of careful monitoring for drug toxicities, vigilance for secondary complications, and coordination across specialties. Conclusion: Inflammatory arthritis secondary to CVID is often responsive to immunoglobulin therapy and standard regimens but may prove challenging to treat when complications or contraindications limit treatment. Keywords: Common Variable Immunodeficiency, Inflammatory Arthritis, Primary Care, Case Report

Introduction: Common variable immunodeficiency (CVID) is a genetic disorder characterized by decreased immunoglobulin levels, predisposing individuals to recurrent infections. The gastrointestinal tract is a common site of involvement, with manifestations ranging from infectious colitis to, in rare cases, inflammatory polyposis. Cytomegalovirus (CMV) colitis, primarily seen in immunocompromised hosts, has rarely been associated with inflammatory polyps. We present an unusual case of a middle-aged woman with CVID who developed CMV colitis with numerous inflammatory polyps, requiring intravenous antiviral therapy after oral treatment failure. Case Description/Methods: A 45-year-old woman with CVID, interstitial lung disease, pulmonary hypertension, and chronic hypoxemic respiratory failure presented with several months of 15-20 episodes of bloody diarrhea daily and microcytic anemia. A colonoscopy at an outside facility revealed inflammatory polyps, with biopsies showing CMV inclusions. She was not treated for CMV at that time. Repeat colonoscopy months later revealed numerous inflammatory polyps throughout the colon. Pathology again showed CMV inclusions consistent with CMV colitis. She was referred to Infectious Disease and started on oral valganciclovir. After 5 days, she experienced worsening diarrhea (30-50 times/day) and weight loss. She was advised to go to the Emergency Department, where labs showed elevated ESR (57 mm/hr), C-reactive protein (2.5 mg/dL), CMV viral load (75.6 IU/mL), and CMV DNA (899 IU/mL). She was admitted and treated with 4 days of intravenous (IV) ganciclovir, resulting in significant symptom improvement. She was discharged on oral valganciclovir for 3 weeks. CMV DNA became undetectable after 1 week of treatment and has remained negative since. Discussion: In immunocompromised patients like those with CVID, CMV can cause significant GI disease, including ulceration, diarrhea, hematochezia, and, rarely, inflammatory polyps. Oral valganciclovir is the standard treatment for CMV and typically is as efficacious as IV ganciclovir. However, in patients with significant GI involvement, mucosal damage may impair absorption. This patient’s severe diarrhea, weight loss, and lack of response to oral therapy indicated a component of malabsorption. IV ganciclovir, which bypasses the gut, led to clinical improvement and viral clearance. This case underscores the importance of early recognition and appropriate parenteral treatment in immunocompromised patients with CMV colitis and suspected malabsorption.

Introduction: Immunoglobulin (Ig) therapy, based on the administration of human plasma-derived Ig, is used to treat various autoimmune diseases and immunodeficiencies, like the common variable immunodeficiency (CVID), which is characterized by lymphocytic abnormalities and defective antibody production, with resulting opportunistic infections and, in some cases, autoimmune disorders. Case Description: A 50-year-old female with CKD G3a presented with increasing proteinuria (UPCR 1.5 g/g). Eighteen years earlier, she underwent an autologous hematopoietic stem cell transplantation (HSCT) to treat severe refractory systemic lupus erythematosus, with no evidence of lupus activity thereafter. Six years following HSCT she was diagnosed with CVID and started weekly immunoglobulin replacement therapy (IRT). Kidney biopsy showed frequent glomerular capillary wall duplication and mesangial expansion with hypercellularity, focal segmental glomerulosclerosis, and mild tubulointerstitial scarring. Immunofluorescence revealed 3+ granular mesangial and glomerular capillary wall staining for IgG, kappa and lambda light chains. Staining for IgG subclasses was positive for IgG1 (2+) and IgG2 (1+) [Fig.1]. Electron microscopy demonstrated extensive glomerular basement membranes remodeling, and subendothelial, intramembranous and mesangial electron-dense deposits [Fig.2]. Discussion: The biopsy showed chronic microangiopathic features, compatible with the prior history of HSCT, and findings consistent with immune-complex glomerulonephritis, which is rarely reported in the setting of CVID. Of interest, the patient had B cell depletion and received IRT. Thus, the circulating Ig were primarily of exogenous origin, and were conceivably the main component of the observed glomerular immune deposits. Further studies will be necessary to understand the potential pathogenic role of long-term Ig therapy in the development of glomerular diseases.

Common variable immunodeficiency (CVID) is an inborn error of immunity characterized by a defect in terminal B cell differentiation, resulting in hypogammaglobulinemia and impaired production of specific antibodies. Stimulation via Toll-like receptors (TLRs) has been shown to promote the differentiation and functional maturation of late-stage B cells. To assess aberrations in TLR2 signaling among patients with CVID and to explore their associations with clinical manifestations and immunological parameters. Sixteen CVID patients and 16 healthy controls were recruited for this individual-matched case-control study. Genetic variants in patients had been previously identified through whole-exome sequencing. TLR2 and TLR4 downstream gene expression were analyzed using qRT-PCR, while cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA). Statistical associations between clinical features and laboratory parameters were analyzed using SPSS software. Downstream gene expression following TLR2 stimulation was significantly reduced in 25% of CVID patients, while the TLR4 signaling pathway remained largely unaffected. Patients exhibiting TLR2 overexpression demonstrated a later disease onset, presenting with autoimmunity, lymphoproliferation, and atopic manifestations. A consistent immunologic feature among patients with defective TLR2 signaling was the reduction in marginal zone and switched memory B cell populations. Furthermore, Levels of IL-6 and IL-1β following agonist stimulation were significantly lower in CVID patients compared to healthy controls. This study demonstrates that functional impairment of TLR2 signaling influences the clinical presentation, immunologic profile, and cytokine production in patients with CVID. These findings suggest a potential underlying etiology in a subset of patients with unidentified monogenic defects.