cell therapies

2025-11-26 | CO:10:2 | Common variable immunodeficiency patients complicated by autoimmune and inflammatory rheumatic manifestations reveal high frequency of genetic variants potentially linked to inborn errors of immunity

Background. Common variable immunodeficiency (CVID) is the most frequent clinically symptomatic primary immunodeficiency; its clinical spectrum is highly variable, ranging from isolated recurrent infections to autoimmune (AID) and inflammatory rheumatic diseases (IRD), which may even be the unique manifestation at disease onset [1]. CVID is mainly a polygenic disease, even if recent studies employing whole-genome and exome sequencing analysis have highlighted that 15–30% may display a monogenic origin [2]. Aim of the study is to describe our CVID patients (pts) cohort, highlighting AID and IRD, and to describe genetic variants possibly linked to immunodeficiency and autoimmunity and therapeutic implications. Methods. This is a monocentric observational retrospective study considering CVID pts followed since 1985 to 2024. Diagnosis was made according to European Society for Immunodeficiency criteria [3]. A next generation sequencing (NGS) analysis of genes potentially linked to hypo-agammaglobulinemia and to antibody deficiency was executed when considered clinically appropriate. Results. Eighty-three pts with a CVID diagnosis were included. CVID total cohort description and comparisons between CVID pts with and without AID are reported in Table 1. Autoimmune cytopenia was the most common autoimmune manifestation occurring in 22.9% of the pts, with immune thrombocytopenia being the most prevalent. Immunosuppressive treatment was necessary in 89.5% of the pts affected by autoimmune cytopenia; in 5 cases, due to refractory cytopenia, rituximab was employed, achieving persistent remission in 4 pts. A diagnosis of IRD was made in 12 pts; 75.0% suffered from inflammatory arthritis. In one pt with Adenosine Deaminase 2 deficiency, genetic analysis aided in employing a target therapy leading remission of the IRD (Table 2). Genetic analysis for variants potentially leading to CVID had been performed in 37.3% of pts; analysis resulted positive in 41.9% of the tested. Genetic variants potentially linked to inborn errors of immunity (IEI) were found in more than half of pts with AID, much more frequently than in other CVID pts (56.5% vs 0.0%; p:0.010). The identified genetic variants are reported in Table 3. Conclusions CVID can be complicated by a wide spectrum of clinical pictures, including AID and IRD, being in our cohort inflammatory arthritis in most of the cases, categorized as a form of Spondyloarthritis in about two thirds. Notably, CVID pts affected by AID and IRD showed a higher frequency of genetic variants potentially leading to IEI; in one case genetic testing aided in orienting IS treatment, leading to remission of the IRD. Nowadays genetic analysis has still limited implications in influencing treatments in CVID, but in the future it might help in targeting precise mechanisms in patients with AID and IRD. References Thalhammer J, Kindle G, Nieters A, et al. Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations. J Allergy Clin Immunol. 2021 Nov;148(5):1332-1341.e5. Maffucci P, Quinti I, Pulvirenti F, et al. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency. Front Immunol. 2016 Jun 2;7:220. Seidel MG, Kindle G, Gathmann B, et al. The European Society for Immunodeficiencies (ESID) registry clinical criteria for inborn errors of immunity diagnosis. Clin Exp Immunol. 2019;197(2):205-214.

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2025-10-29 | Antibody Secretion Capacity in CVID Patients: Immunoglobulin Isotypes and Antigen Specificities After T-Cell-Dependent In Vitro Stimulation.

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.

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2025-10-01 | S5801 Severe Variceal Bleeding in Common Variable Immunodeficiency-Associated Nodular Regenerative Hyperplasia

Introduction: Common variable immunodeficiency (CVID) is a heterogeneous group of primary immunodeficiency disorders characterized by impaired B-cell differentiation and hypogammaglobulinemia. Hepatic complications occur in at least 10% of CVID patients, with nodular regenerative hyperplasia (NRH) as the most common histologic subtype. NRH can lead to non-cirrhotic portal hypertension (NCPH), which in rare cases may cause life-threatening gastrointestinal bleeding. We report a case of a young patient with CVID and NRH, presenting with acute-on-chronic, refractory stomal variceal bleeding. Case Description/Methods: A 24-year-old man with CVID on monthly intravenous immunoglobulin, confirmed STAT1 gain of function mutation, CVID enteropathy, inflammatory rectal pseudopolyposis status post abdominopelvic resection with permanent colostomy one year prior, and NCPH secondary to NRH presented with acute on chronic parastomal bleeding. He underwent Sotradecol sclerotherapy and coil embolization of the stomal varices, but continued to experience oozing into his stomal bag, requiring multiple red blood transfusions. Upper endoscopy and triple-phase computed tomography enterography demonstrated very small esophageal varices and enlarged parastomal varices, without definite vascular malformation or enhancing mass within the small bowel. The patient underwent transhepatic coil embolization of stomal varices, resulting in successful resolution of the bleeding. Transjugular liver biopsy with pressure measurements revealed a gradient of 12-13 mmHg, indicating portal hypertension and biopsy demonstrated patchy sinusoidal fibrosis. Initial therapies failed to control bleeding, and the patient re-presented for stomal bleeding. Given treatment-refractory stomal varices, transjugular portosystemic shunt (TIPS) was placed, reducing the portosystemic gradient from 10 mmHg to 4 mmHg and achieved bleeding resolution. Follow-up was arranged to evaluate the use of ruxolitinib and/or bone marrow transplantation for further CVID management. Discussion: This case illustrates the first reported instance of severe, recurrent stomal variceal bleeding in a young patient due to CVID-associated NRH successfully managed with TIPS. Given the complexity of CVID with multisystem involvement, genetic profiling and immunologic therapies may offer future therapeutic potential.

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2025-09-22 | The Presentation, Diagnosis, and Management of Autosomal Dominant Common Variable Immunodeficiency Type XII with NFKB1 Mutation and Autoimmune Neutropenia Treated with Allogenic Stem Cell Transplantation

Background and Clinical Significance: Common Variable Immunodeficiency (CVID) is a prevalent manifestation of primary immunodeficiency disorder. The current mainstay of treatment is immunoglobulin replacement therapy; however, in patients with severe complications or refractory disease, hematopoietic stem cell transplant (HSCT) is indicated. Despite this, there has been little research regarding HSCT as a treatment for CVID, with few case reports demonstrating clinical benefit. Case presentation: We present a unique case of common variable immunodeficiency Type XII (CVID12) with rare NFKB mutation and its management. A 20-year-old female with autoimmune alopecia, eczema, and a congenital atrophic right kidney presented to the emergency department with a three-month history of intermittent fever, malaise, lymphadenopathy, mouth sores, diarrhea, and odynophagia, accompanied by a 5 lb. unintentional weight loss and night sweats. Previously, she received multiple steroid prescriptions for these symptoms, providing only temporary relief with each course. Lab findings revealed severe neutropenia and imaging demonstrated hepatosplenomegaly and lymphadenopathy. Flow cytometry revealed a slightly atypical CD8-positive T-cell population and bone marrow biopsy revealed variable cellular marrow with trilineage hematopoiesis. Genetic testing confirmed the diagnosis of Autosomal Dominant Common Variable Immunodeficiency Type XII with an NFKB1 mutation. Pre-transplant treatments included monthly IVIG, weekly rituximab, and daily filgrastim, all of which failed to improve her autoimmune neutropenia and hypogammaglobulinemia and failed to reduce her symptomatic burden. Given the patient’s young age and refractory autoimmune neutropenia, it was decided to manage them definitively with hematopoietic stem cell transplantation (HSCT). She ultimately underwent allogenic stem cell transplantation (haploidentical, donor was the mother) with 3.96 × 108/kg TNC without immediate post-transplant complications. Conclusions: This article demonstrates a rare case of NFKB1-positive CVID that was successfully treated with HSCT and highlights the importance of considering transplant therapy in younger patients with clinically significant, refractory autoimmune cytopenia.

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2025-08-27 | Pediatric and Adult Inborn Errors of Immunity and COVID-19: A Comparative Study.

COVID-19 has worse clinical outcomes in inborn errors of immunity (IEI) patients. We aimed to determine COVID-19-related hospitalization/ICU admission/mortality risk in patients with IEI. We included 62 COVID-19 (29 children and 33 adults) in a referral center. F/M ratio was 0.94 with median age, 19 (8 months-64 years) years. 53.2% had primary antibody deficiency. Hospitalization rate was 11/29 in children, 21/33 in adults and 7/11 in patients with combined immunodeficiency diseases. Myalgia was more common in adults compared to children (p = 0.013). Inpatients have more cough compared to outpatients (p = 0.002). D-dimer and ferritin levels were higher in inpatients (p = 0.033 and p = 0.046, respectively). Cough (OR: 6.05; [95% CI: 1.76-20.74], p = 0.004) and immunoglobulin replacement therapy use in IEI (OR: 5.15; [95% CI: 1.46-18.11], p = 0.010) were related to hospitalization risk. Inpatients with intensive care unit (ICU) admission had higher ferritin levels (p = 0.02). 77.4% had at least one comorbidity like pulmonary (45.2%), autoimmune (38.7%), and gastrointestinal diseases (32.3%). ICU admission was high in agammaglobulinemia (40%) and immune dyseregulation (ID) (16.6%). An LRBA deficiency patient experienced MIS-C (Multisystem Inflammatory Syndrome in Children) and another died. Eight patients, four in the present center, received convalescent plasma (X-linked agammaglobulinemia [XLA] [n = 3], autosomal recessive agammaglobulinemia [n = 1], LRBA deficiency [n = 1], and CTLA4 deficiency [n = 1], CVID [n = 1], and STAT1 deficiency [n = 1]). Overall mortality was 6.5%, high in ID (16.6%), none in children. Higher D-dimer and ferritin levels is associated with a higher hospitalization ratio- twice in adults compared to children. Overall mortality (6.5%) was about six times the general population with no mortality in children. A high ICU ratio in agammaglobulinemia, suggesting the importance of mucosal IgA in COVID-19 defense. Convalescent plasma helps shorten hospitalization period in agammaglobulinemia.

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proteins

2026-08-15 | Elevated IL-10 is Linked With the Expansion of T-bethighCD21low B Cells in Patients With Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is frequently complicated by autoimmune and inflammatory manifestations associated with profound immune dysregulation (CVIDc), including expansion of T-bethighCD21low B cells (CD21low B cells). Elevated serum IL-10 levels have repeatedly been reported in CVIDc, yet their relationship to CD21low B-cell differentiation remains unclear. In this study, we determined a significant correlation between increased serum IL-10 levels and frequency of circulating CD21low B cells, particularly marked in CVIDc patients. Transcriptomic and protein analyses identified multiple cellular sources of IL-10 in CVID, including monocytes, T cells, and a subset of CD21low B cells in peripheral blood and inflamed tissues. CD21low B cells expressed elevated levels of IL-10 receptor subunits and displayed intact IL-10-induced STAT3 signaling, indicating preserved responsiveness to IL-10. Functionally, IL-10 alone neither induced CD21low B-cell differentiation nor inhibited IFN-γ-driven polarization. However, in vitro differentiation assays showed that IL-10 can substitute for IL-21 during CD40L/T cell-dependent differentiation of CD21low-like B cells and promote their survival in vitro. These findings suggest that IL-10 may support the expansion and persistence of CD21low B cells at inflammatory sites. Collectively, our data identify IL-10 as a component of the inflammatory environment associated with CD21low B-cell expansion and suggest that IL-10 can functionally replace IL-21 during their differentiation and promote their survival in CVID-associated immune dysregulation.

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2026-06-08 | Clinical, genetic, and functional characterization of novel NFKB1 variants in Chinese patients with primary immunodeficiency.

The nuclear factor κB (NF-κB)-related disorders encompassed not only common variable immunodeficiency but also manifestations of autoinflammation, autoimmunity, and malignancies. While most cases have been reported in European populations, reports in the Chinese population are sparse. Clinical data and genetic variants from four Chinese patients with NFKB1 variants, alongside four previously reported cases, were analyzed and compared with an international cohort. Additionally, comprehensive in vitro functional assays-including immunoblotting, transcript analyses, dual-luciferase reporter, and co-immunoprecipitation assays-were conducted to explore the molecular defects of the novel variants. Our cohort included three men and one woman, all presenting with recurrent fever and hypogammaglobulinemia. Three patients experienced recurrent sinopulmonary infections, accompanied by decreased B cells and NK cells, while two patients developed pneumonia, bronchiectasis, and hepatitis. Three novel NFKB1 (NM_003998) variants were identified: c.559C > T (p. Arg187Trp), c.1509del (p. Glu504Argfs*19), and c.1753-11_1760del (p. Thr585Alafs*9). Functional analyses revealed distinct pathomechanisms: the frameshift/splicing variants drive classical haploinsufficiency via nonsense-mediated mRNA decay (NMD), triggering compensatory inflammatory hyperactivation; conversely, the p.Arg187Trp missense variant maintains protein stability and heterodimerization but strictly abolishes DNA-binding capacity. Compared to a previously reported cohort, Chinese patients were predominantly male, had a later median age of onset and diagnosis. Notably, Chinese patients exhibited a higher prevalence of hepatitis (25%) and cirrhosis (12.5%), potentially reflecting the high endemicity of hepatitis B virus in China. They also showed increased rates of viral infections, sepsis, and bronchiectasis, with more pronounced reductions in NK and B cells. In contrast, autoimmune diseases and bronchitis were less frequent than in the foreign cohort. This study represents the first and largest case series of Chinese patients with NF-κB1-related diseases, providing molecular characterization for three novel variants. In this limited case series, the observed delayed onset and frequent hepatic complications in our cohort may reflect regional factors, such as HBV endemicity, or ascertainment bias. Our findings underscore that suspected AOSD accompanied by hypogammaglobulinemia warrants immediate genetic investigation. Early diagnosis is essential to prioritize immunoglobulin replacement and prevent fatal complications from immunosuppressive therapy.

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2026-06-01 | Concurrent hereditary angioedema type I and common variable immunodeficiency presenting as suspected antibiotic hypersensitivity: Case report and literature discussion.

Hereditary angioedema (HAE) and common variable immunodeficiency (CVID) are rare disorders with heterogeneous clinical presentations that pose significant diagnostic challenges. HAE is characterized by recurrent episodes of subcutaneous or submucosal edema affecting the skin, gastrointestinal tract, or airway, whereas CVID presents with variable immune dysfunction, recurrent infections, and impaired vaccine responses. The clinical manifestations of these conditions can mimic allergic reactions, drug hypersensitivity, mast cell disorders, autoimmune diseases, and other immunodeficiencies, making careful differential diagnosis essential. Here, we present an exceptionally rare case of a patient with concurrent HAE type I and CVID, initially evaluated for suspected antibiotic hypersensitivity, highlighting the complexity of diagnosis and therapeutic decision-making. Laboratory findings confirmed both conditions, showing low C1 inhibitor levels and activity, markedly reduced serum concentrations of immunoglobulin G (including subclasses G1, G2, and G4), immunoglobulin A, and immunoglobulin M, along with a poor specific antibody response to vaccines. Skin allergy and oral provocation tests were negative, effectively ruling out antibiotic hypersensitivity. The genetic analysis identified a heterozygous pathogenic SERPING1 variant, c.498C > A (p.Asn166Lys), previously reported in 1 Romanian and 1 Czech case, confirming the diagnosis of HAE. Human leukocyte antigen (HLA) genotyping revealed HLA-B∗35:01 and B∗44:01, with homozygosity for HLA-C∗04:01, alleles previously associated with increased susceptibility to CVID. Using this case as a framework, we review the literature on coexisting HAE and CVID, examining clinical presentations, diagnostic approaches, biomarker profiles, and reported HLA associations. The review highlights the critical importance of a comprehensive and personalized therapeutic approach, combining prophylactic and on-demand treatment for HAE with individualized immunoglobulin replacement for CVID. Integrating detailed clinical assessment with immunologic and genetic testing is essential for the management of rare, complex disorders, and further studies are needed to clarify potential immunogenetic links between HAE and CVID.

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2026-05-27 | Common Variable Immune Deficiency and Pregnancy: Improving Outcomes Through Multidisciplinary Care.

Background: Pregnancy presents unique immunological and obstetrical challenges for women with Common Variable Immune Deficiency (CVID). No standardized guidelines currently exist to guide pregnancy management, as CVID is a rare diagnosis, with pregnancy outcomes limited to case reports and case series. Establishing a structured approach to care is important to optimize maternal and fetal outcomes. Methods: A narrative review of the literature with a structured search was performed to detail pregnancy outcomes in CVID and management strategies. A 10-year retrospective chart review of women with CVID who became pregnant while receiving care at the McGill University Health Centre between January 2015 and January 2025 was conducted to add to the existing clinical data. Results: Pregnancy outcomes were improved through pre-conception planning, regular serum Immunoglobulin G (IgG) monitoring, trimester-based immunoglobulin replacement dose adjustments, proactive management of autoimmune or infectious complications, and multidisciplinary care. Subcutaneous immunoglobulin may offer better flexibility and stability of IgG levels. Conclusions: In the available observational literature and our institutional experience, many patients with CVID have carried pregnancies to term with favorable maternal and neonatal outcomes when managed with IgRT and multidisciplinary coordination. We outline a stepwise multidisciplinary framework for clinicians caring for women with CVID who are planning or undergoing pregnancy, and we identify gaps in knowledge for future studies.

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2026-04-01 | Common Variable Immunodeficiency Presenting With Bilateral Optic Nerve Edema: Case Report

Common variable immunodeficiency is typically characterized by recurrent infections, autoimmunity, and primary antibody failure, with an increased risk for malignancy. Ophthalmic and neurologic complications are considered rare. We describe a unique case presenting with bilateral optic disc edema, which resolved with IgG replacement therapy.

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small molecules

2026-06-01 | Budesonide for Celiac-like Enteropathy in Common Variable Immunodeficiency

Introduction: Impaired immunoglobulin production is linked to Common Variable Immunodeficiency (CVID), which can be manifested as autoimmune or celiac-like enteropathy. Distinguishing between CVID-related enteropathy and true celiac disease can be difficult especially when there are no serological markers [ 1 ] [ 2 ]. Case Description: A 52-year-old man who had been previously treated for lung adenocarcinoma and had a history of CVID on immunoglobulin replacement therapy was assessed for persistent diarrhea. Lower limb edema and hypoalbuminemia were found during the initial work-up and paraneoplastic etiology was ruled out by imaging. The patient underwent upper and lower GI endoscopy which showed scalloping of the duodenal folds and histology consistent with celiac disease. After initial response to strict gluten-free diet the patient developed relapse with severe weight loss and protein loosing gastroenteropathy. Under the suspicion of CVID-related enteropathy rather than refractory celiac disease he was successfully treated with oral budesonide. Conclusion: Although celiac-like enteropathy in CVID may resemble classical celiac disease, it frequently exhibits no IgA serological response and may only partially respond to gluten-free diet. It is important to distinguish between CVID-associated enteropathy and true celiac disease especially in patients who continue to experience symptoms despite strict gluten withdrawal since they can successfully respond to immunomodulatory treatment like budesonide. Publication History Article published online: 05 June 2026 © 2026. European Society of Gastrointestinal Endoscopy. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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2026-05-01 | A63-06 Pulmonary Arterial Hypertension, Lymphocytic Interstitial Pneumonia, Common Variable Immunodeficiency, and Myopathy in a Patient With a STAT3 Gain of Function Mutation

Abstract Background Signal transducer and activator of transcription (STAT) 3 is a regulator of cellular proliferation, differentiation, and survival. STAT3 gain of function (GOF) disease is a rare disorder of immune dysregulation which is associated with endocrinopathies, lymphoproliferative disease, cytopenias, immunodeficiencies, and interstitial lung disease. STAT3 has also been well described in the pathophysiology of pulmonary arterial hypertension (PAH), where its upregulation leads to downstream upregulation of pro-proliferative and anti-apoptotic mechanisms, including the inhibition of bone morphogenic protein receptor type 2 (BMPR2). Pulmonary artery (PA) biopsies in patients with PAH have demonstrated elevated levels of STAT3 activation. Case A 48-year-old woman with a history of lymphocytic interstitial pneumonia (LIP) diagnosed by surgical lung biopsy, common variable immunodeficiency (CVID), and myopathy of unclear etiology presented to the emergency department with progressive dyspnea and multiple syncopal episodes. Echocardiogram demonstrated a dilated, dysfunctional, and hypertrophic right ventricle (RV) with peak tricuspid regurgitant jet velocity 4.2 meters/second and normal left ventricular function. Right heart catheterization was performed and revealed severe pre-capillary pulmonary hypertension with mean PA pressure 55 mm Hg, cardiac output (CO) 3.7 liters/minute, and pulmonary vascular resistance (PVR) 13.2 Woods units (WU). Vasoreactivity testing with inhaled nitric oxide was performed, and the mPA pressure fell to 31 mm Hg with CO f 3.8 liters/minute and PVR 6.6 WU. CT scan of the chest demonstrated apical predominant nodular opacities, and there was no evidence of chronic thromboembolism on ventilation/perfusion scan. Serologic testing was performed and was negative. The patient was diagnosed with idiopathic, vasoreactive PAH and treatment with calcium channel blockers was attempted but abandoned due to hypotension. The patient was treated with Macitentan and inhaled Treprostinil with significant improvement in exercise capacity and PVR. Due to her multiple immunologic conditions, she was referred for genetic testing and was found to have a gain of function mutation in STAT3. Discussion We present a patient with STAT3 GOF disease with CVID, LIP, myopathy, and PAH. While the immunologic presentations have been well described, PAH has only been described once in the literature in patients with STAT3 GOF disease, and testing for STAT3 mutations is not recommended as part of the genetic evaluation of patients with PAH. Given the physiologic plausibility by which upregulation of STAT3 leads to PAH, it seems likely that this patient’s PAH is secondary to STAT3 GOF disease, which may suggest response to therapies targeted at the JAK/STAT pathway. This abstract is funded by: None

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2026-05-01 | NFKB1 Truncating Variants Associated with Significant Autoimmunity and Lymphoproliferation in Common Variable Immunodeficiency

Heterozygous NFKB1 variants have been increasingly identified in patients with common variable immunodeficiency. These patients, however, often experience substantial immune dysregulation beyond humoral deficiency. NFKB1 encodes p105, which undergoes proteolytic cleavage to release p50, the transcriptionally active subunit of canonical NF-κB. While several in vitro transfection systems have demonstrated loss-of-function of these variants regarding canonical NF-κB reporter activity, the immune-related phenotypes of these patients differ from those with well-characterized defects leading to impaired canonical NF-κB activation (i.e., IKBKG or NFKBIA variants). Notably, the C-terminal part of p105 contains ankyrin repeats, which can repress downstream signaling by retaining NF-κB dimers in the cytosol. We therefore hypothesize that loss of p105 inhibitory function may contribute to the immune dysregulation observed in some affected patients. In this study, we evaluated 8 patients from 8 unrelated kindreds presenting with early-onset common variable immunodeficiency, complicated by diverse and severe immune dysregulations, including multiple autoimmunity and lymphoproliferation (NCT00001355). In addition to immunoglobulin replacement therapy for hypogammaglobulinemia, all required multiple immunomodulatory therapies. One patient ultimately underwent allogeneic hematopoietic stem cell transplantation for disease control. All patients harbored private germline heterozygous NFKB1 truncating variants (nonsense, n = 2; frameshift, n = 5; splice, n = 1) located in the N-terminal p50 part of the protein, prior to the ankyrin repeats. Beyond the well-recognized B cell failure in these patients, peripheral blood mononuclear cells showed lower basal IκBα level and enhanced IκBα degradation following ex vitro stimulation, indicating activation of canonical NF-κB signaling. Their T cells showed increased phospho-AKT upon stimulation. Together, these findings suggest a potential loss of p105 inhibitory function in these patients. Further elucidation of the mechanisms underlying profound immune dysregulation is crucial because these patients may benefit from the PI3Kδ inhibitor leniolisib, given the observed PI3K signaling activation. A prospective clinical trial is currently recruiting such participants to investigate this targeted therapy (NCT06549114).

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2026-04-19 | From CVID to PIRD: Genetic Testing Leading to Signal Transducer and Activator of Transcription 3 Gain-of-Function Diagnosis and Directed Therapy.

Genetic testing to evaluate for monogenic inborn errors of immunity is considered the standard of care in newly diagnosed common variable immunodeficiency (CVID) patients; however, not all patients receive it for a variety of clinical and access reasons. Similarly, patients with a longstanding diagnosis of CVID diagnosed before the wide availability of genetic testing may not be considered for genetic testing as readily as those with new diagnoses. Here we present a case illustrating diagnostic and management dilemmas in a patient with a longstanding diagnosis of CVID who ultimately was found to have a STAT3 gain-of-function (GOF) variant more than 10 years after his initial CVID diagnosis. Genetic testing was prompted not only by the unusual infection history (lymphadenitis due to nontuberculous mycobacteria) but also by worsening clinical status and the presence of noninfectious features, including enteropathy, chronic cough, lymphoproliferation, and autoimmune cytopenias. The genetic diagnosis led to more precise treatments and allowed for diagnosis and improved management strategies for several affected family members. The pathophysiology, clinical presentation, and management options for STAT3 GOF are reviewed.

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2026-03-05 | Immune-related enteropathy.

Immune-related enteropathies (IREs) represent a heterogeneous group of disorders characterised by immune-mediated small bowel injury. While coeliac disease is the most common cause, widespread use of small bowel endoscopy has expanded the recognition of rarer causes. This review aims to summarise recent advances in diagnosis, classification and management of IRE. Significant overlap exists between coeliac disease, autoimmune enteropathy, collagenous sprue, drug-induced enteropathies, common variable immunodeficiency (CVID) associated enteropathy and other IRE. A recent meta-analysis supports a no-biopsy approach in selected adults with significantly elevated IgA tissue transglutaminase levels and suspected coeliac disease. Refractory coeliac disease type II is now recognised as a low-grade intraepithelial T-cell lymphoma with a high risk of progression to enteropathy-associated T-cell lymphoma (EATL). Drug-induced enteropathies, particularly olmesartan-associated enteropathy, are increasingly detected and may mimic autoimmune enteropathy histologically. Novel therapeutic approaches, including cladribine, JAK inhibitors and biologics, have shown promise in refractory disease, although evidence is limited to small studies. IREs present substantial diagnostic and therapeutic challenges due to overlapping characteristics and variable disease course. A structured approach integrating clinical, serological and histopathological data is essential for accurate diagnosis. Early recognition and tailored management are crucial to prevent long-term complications.

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antibodies

2026-09-24 | The immunogenic cross-talk in pediatric MASLD: does subclinical immune dysfunction accelerate early hepatic destruction?

The pathogenesis of pediatric Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is increasingly recognized as an immunometabolic process driven by chronic low-grade inflammation (metainflammation). While nutritional surplus and visceral adiposity are established primary drivers, the contribution of underlying subclinical host immune variations remains largely unexplored. This mini-review investigates the intersection between childhood obesity and subclinical humoral immune dysfunctions, specifically variants of Common Variable Immunodeficiency (CVID). We propose that subtle defects in adaptive immunity-such as partial secretory IgA or IgG subclass deficiencies-compromise mucosal barrier integrity, triggering a breakdown of the gut-liver axis. This barrier failure allows an influx of pathogen-associated molecular patterns (PAMPs) into the portal circulation, overwhelming hepatic immune tolerance. Within the liver, this persistent microbial exposure primes Toll-like receptor pathways and activates the NLRP3 inflammasome within Kupffer cells, accelerating hepatocyte pyroptosis and tissue damage. Concurrently, the T-cell dysregulation characteristic of CVID variants interacts with hepatic lipotoxicity, changing the disease phenotype from simple steatosis to aggressive tissue remodeling. Identifying these subclinical immunodeficiencies in progressive pediatric MASLD is essential for developing personalized, targeted immunometabolic therapies for at-risk youth.

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2026-09-02 | Evaluation of Regulatory B10 Cells in Common Variable Immunodeficiency Patients with and without Autoimmunity

Common variable immunodeficiency disease (CVID) is the most prevalent symptomatic inborn errors of immunity, determined by defective B cell function, impaired antibody production, and susceptibility to frequent respiratory infections, enteropathy, autoimmunity, and malignancy. Due to the importance of autoimmunity in CVID and the probable role of regulatory B lymphocytes, we aimed to determine the frequency of B10 cells in CVID patients with and without autoimmunity. A total of 24 CVID patients and 12 healthy controls were enrolled in the study. Patients were divided into two equal groups, with and without autoimmunity. Peripheral blood cells were stained with monoclonal antibodies (mAbs) to identify CD24hiCD38hi B cells, CD27int CD38+ (plasmablasts), and CD24hiCD27+ B cells by flow cytometry. The percentages of B10, CD24hiCD27+ and CD27int CD38+ cells were significantly lower in total CVID patients, CVID patients with autoimmunity and CVID patients without autoimmunity compared to healthy controls (mean±standard deviation (SD) percentage of B10 cells: 6.36±9.21(total CVID), 2.81±5.00 (CVID with autoimmunity), and 3.25±3.5 (CVID without autoimmunity) vs. 13.02±12.45 (healthy controls); CD24hiCD27+ cells: 2.39±3.89, 3±5.20 and 1.78±1.94 vs. 20.38±14.27; CD27int CD38+ cells: 6.80±18.49, 7.40±20.24 and 6.20±17.45 vs. 11.84±5.71). CVID patients without autoimmunity had a higher percentage of CD24hiCD38hi cells than CVID patients with autoimmunity (4.73±4.14 vs. 2.62±5.02). The defect of regulatory B cells plays a significant role in the pathogenesis of autoimmunity in CVID. Further multicenter studies with higher sample sizes are suggested to determine the role of Breg cells in the clinical course of autoimmunity.

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2026-08-28 | Beyond B cells: T and Innate Immune Mechanisms of Autoimmunity in Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency, affecting approximately 1 in 25 000-50 000 individuals. Although classically characterized by hypogammaglobulinemia and recurrent bacterial infections, over 50% of patients develop non-infectious complications that constitute the major determinants of morbidity and mortality. The coexistence of immunodeficiency and immune dysregulation challenges the traditional B-cell-centric model of CVID pathogenesis. In this narrative review, we synthesize current evidence demonstrating that autoimmune manifestations in CVID arise from complex, multilayered immune dysfunction extending far beyond the B-cell compartment. Key abnormalities include Th1-skewed CD4⁺ T-cell responses with persistent IFN-γ production, numerical and functional defects in regulatory T cells, disruption of follicular T-cell subset balance favoring autoreactive germinal center responses, and progressive CD8⁺ T-cell exhaustion. At the innate immune level, NK-cell lymphopenia, constitutive monocyte activation, dendritic cell deficiency, neutrophil dysregulation, and proinflammatory innate lymphoid cell activity collectively contribute to the breakdown of self-tolerance. These immune perturbations are further amplified by systemic cytokine dysregulation. Pathogenic variants identified in patients with CVID-like disorders may further underlie autoimmune pathology and immune dysregulation, particularly those affecting T-cell co-stimulation, immune checkpoint signaling, NF-κB, and PI3K pathways. Collectively, CVID-associated autoimmunity represents a paradigm of systems-level immune dysregulation, underscoring the need for comprehensive immune phenotyping, genotype-informed stratification, and precision immunomodulatory strategies targeting the full spectrum of immune abnormalities involved.

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2026-08-27 | IVIG-associated anterior uveitis resolving after switch to subcutaneous immunoglobulin.

Intravenous immunoglobulin (IVIG) therapy can occasionally induce unexpected inflammatory complications. A case report and literature review. We report a patient with hypogammaglobulinemia and systemic autoimmunity who developed reproducible unilateral anterior uveitis following IVIG administration across multiple formulations. Discontinuation of IVIG resolved the ocular inflammation but caused underlying disease exacerbation. Transition to facilitated subcutaneous immunoglobulin (SCIG) achieved stable serum IgG levels and maintained complete ocular and systemic remission over a four-year follow-up period. This case demonstrates peak-driven immune activation as a plausible mechanism for IVIG-induced uveitis and highlights SCIG as a safe, effective therapeutic alternative that bypasses rapid peak IgG dynamics while preserving immune protection.

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2026-08-10 | Dissecting the molecular heterogeneity of common variable immunodeficiency using an integrative multi-omics approach

Common variable immunodeficiency (CVID), the most common clinically significant inborn error of immunity (IEI), is characterized by hypogammaglobulinemia and impaired antibody responses to infections and vaccination. Although monogenic defects have been identified in a subset of patients, the molecular basis of CVID remains unresolved in most cases, reflecting substantial clinical and biological heterogeneity and contributions from polygenic, epigenetic, and environmental factors. In this narrative review, we summarize recent advances in genomics, epigenomics, transcriptomics, proteomics, microbiomics, metabolomics, and multi-omic integration based on published literature identified through searches of major biomedical databases. These approaches have uncovered dysregulated immune signaling pathways, impaired B-cell differentiation programs, inflammatory molecular endotypes, altered immune tolerance mechanisms, and host–microbiome–metabolite interactions contributing to disease heterogeneity. Emerging multi-omic studies further demonstrate mechanistic links among microbial translocation, metabolic re-programming, inflammatory signaling, and immune dysfunction in CVID. Integrative multi-omic approaches enable improved disease stratification, refined molecular classification of CVID phenotypes, enhanced diagnostic resolution, and identification of biomarkers and therapeutic targets, particularly in genetically unresolved patients. Emerging evidence also supports precision medicine strategies by linking molecular endotypes with pathway-directed therapeutic interventions. Continued advances in integrated multi-omic approaches are expected to improve molecular diagnosis and facilitate more personalized management of CVID.

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2026-05-08 | Delayed humoral kinetics but stabilization of IgG responses in common variable immunodeficiency after SARS-CoV-2 mRNA booster vaccination

Abstract Purpose Patients with common variable immunodeficiency (CVID) frequently exhibit impaired antibody responses to vaccination, yet the dynamics of humoral and cellular immunity following mRNA immunisation remain incompletely defined. This study aimed to characterise the temporal evolution of anti-SARS-CoV-2 antibody and T cell responses across successive vaccine doses in a well-characterised CVID cohort, and to identify key determinants of vaccine responsiveness in this population. Methods We performed a longitudinal and cross-sectional analysis of serum and peripheral blood mononuclear cell (PBMC) samples collected from 88 CVID patients after two, three, or four doses of mRNA vaccine (Moderna/mRNA-1273 or Pfizer-BioNTech/BNT162b2). Anti-receptor-binding domain (RBD) IgG titers were quantified in relation to vaccine dose, time since last vaccination, and clinical characteristics. Vaccine-specific CD4 + and CD8 + T cell responses were assessed ex vivo using an activation-induced marker (AIM) assay by flow cytometry. Results The proportion of patients with detectable anti-RBD IgG increased from 35% after two doses to more than 80% after four doses. Boosting-dependent increases in IgG titers were observed exclusively in samples collected more than three months after the last dose, and antibody levels correlated positively with time since vaccination, consistent with delayed but progressive humoral kinetics that stabilised after the third dose. In contrast, spike-specific CD4 + and CD8 + T cell responses were rapidly induced and remained stable across all timepoints. Conclusion Vaccine-induced immunity in CVID is characterised by delayed humoral responses alongside preserved cellular immunity. Early post-vaccination serology may systematically underestimate vaccine responsiveness, and booster vaccination supports stabilisation of antibody responses in this population.

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2026-01-25 | Global research landscape of inborn errors of immunity: a bibliometric analysis (1991-2025).

Inborn errors of immunity (IEI), though individually rare, collectively represent a significant disease burden. From 1980 to 2024, classified IEI disorders expanded from dozens to 559 entities, reflecting advances ranging from immunoglobulin replacement to gene therapy. This bibliometric analysis-a comprehensive mapping of the global IEI landscape-analyzed 7,455 publications (1991-2025) from Web of Science Core Collection using Bibliometrix, VOSviewer, and CiteSpace. Key findings: (1) Annual publication growth: 10.27% (H-index = 173); (2) US dominance: 36.3% publications, 115,221 citations, and TLS = 105,825; (3) Research priorities: Immunodeficiency mechanisms, clinical diagnostics, and key diseases (SCID, CVID, APDS); (4) Therapeutic frontiers: HSCT, gene therapy, targeted signaling inhibitors. (5) Critical gaps: Newborn screening implementation, quality-of-life metrics. This study provide a comprehensive, multidimensional visualization of the IEI research landscape over 35 years. Although the field maintains a high H-index and broad scope, the pace of research growth appears to have stabilized in the past five years. It is important to note that the observed flattening in total citation counts during this period may be influenced by citation windows and pandemic-related confounding, and should not be interpreted as definitive evidence of field maturity or stagnation. Nonetheless, this observed pattern highlights that that sustaining historical growth rates may require transformative technological advances-particularly in gene editing-to catalyze the next wave of progress in IEI research.

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2025-09-30 | CVID Enteropathy Is Difficult To Treat and Shows a Heterogeneous Histopathology.

Enteropathy is a non-infectious complication in Common Variable Immune Deficiency (CVID) associated with increased morbidity and mortality. We characterized this group of CVID enteropathy (CVID-E) patients and investigated the effectiveness of immunosuppressive treatments on its clinical course. We identified patients with CVID-E in two academic teaching hospitals and obtained informed consents. Using electronic patient health care records, we retrospectively collected clinical information in the national Primary immunodeficiency disorder database until 01-2023. We included 39 patients with CVID-E. Bronchiectasis (69.2%) and lymphoproliferation (46.1%) were the most frequent co-occurring symptoms. The most common endoscopy findings concerned inflammation (72.2%) and erythema (69.4%); The most prevalent histopathologic findings were IBD-like inflammation (55.6%), indiscriminate chronic inflammation (47.2%) and indiscriminate active inflammation (38.9%). We assessed 88 events of treatment response in the 25 treated patients. Overall treatment response was poor, however there were 31 events of remission observed, ranging from partial to sustained remission. Of these 26 were the result of tumor necrosis factor inhibitors (TNFi) or thiopurines, either as monotherapy or in combination with other immunosuppressive treatment. 10 patients achieved complete remission. In this study, we describe a cohort of CVID-E patients including related comorbidity, clinical course and response to therapy. CVID-E patients frequently develop other, sometimes severe comorbidities. Our study confirms the alleged heterogeneity regarding endoscopic and histopathological findings, and in one third of patients even multiple distinct abnormalities co-occurred in the same biopsy. We found azathioprine and/or TNFi to be the most effective current treatment.

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2025-09-10 | When Less Could be More: Successful Treatment of Granulomatous Lymphocytic Interstitial Lung Disease with Azathioprine.

Interstitial lung disease is a major complication in patients with common variable immunodeficiency. There are some publications that try to shed light on the pathophysiology of this non-infectious complication, most of them highlight the role of follicular T cells and CD21low B cells. Moreover, there are no guidelines based on randomized controlled studies on the treatment of patients with interstitial lung disease and the published case series or small uncontrolled studies describe a wide range of response rates to treatment. In this scenario, the decisions are based on expert opinion rather than on robust scientific evidence. This could lead to potential biases associated with expert opinion based on a small number of patients. We present the case of an adult patient with common variable immunodeficiency and interstitial lung disease. He did not receive rituximab due to an adverse reaction and underwent treatment with azathioprine, achieving prolonged remission after treatment discontinuation. If T-cell involvement could be the main underlying cause of this complication, treatment targeting T-cells may possibly be an effective therapeutic option. Our case, complemented with a physiopathology review, suggests a beneficial effect of azathioprine that warrants further research. It is important to keep in mind that patients with common variable immunodeficiency are a heterogeneous group, so no single treatment will be the best for all of them. It is necessary to review the rationale for the increasing use of anti-CD20 drugs in non-infectious complications in patients with common variable immunodeficiency. Such use is based on expert recommendations and not on randomized, controlled studies with quantitative endpoints. There are no guidelines based on randomized controlled studies on the treatment of patients with common variable immunodeficiency and interstitial lung disease.The use of rituximab in the treatment of various non-infectious manifestations in patients with common variable immunodeficiency, including interstitial lung disease, could be the result of potential biases associated with expert opinion based on a small number of patients.T-cell involvement could be the main underlying cause of this complication so treatment targeting T-cells may possibly be an effective therapeutic option.

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2025-05-30 | Granulomatous lymphocytic interstitial lung disease in common variable immune deficiency: an in-depth clinical, immunological, functional and radiological exploration with a focus on its management, challenged by chronic CMV infection.

Common variable immune deficiency (CVID) is the most prevalent inborn error of immunity (IEI), marked by diverse clinical-immunological phenotypes and significant immune-dysregulation, including granulomatous lymphocytic interstitial lung disease (GLILD). GLILD is a severe manifestation of CVID, contributing to reduced life expectancy and a challenging diagnosis due to its insidious and non-specific clinical course. Current management strategies for GLILD rely on expert opinion due to a lack of randomized controlled trials (RCTs). This study aims to provide a comprehensive immunophenotypical characterization of CVID patients with and without GLILD, investigate predictive biomarkers for GLILD development, and explore therapeutic strategies, particularly during concomitant SARS-CoV-2 and chronic cytomegalovirus (CMV) infections. Primary data were collected from a cohort of 25 patients with CVID who underwent high-resolution computed tomography (HRCT), immunophenotyping, and serum immunoglobulin analysis at diagnosis and after immunoglobulin replacement therapy. Existing literature on CVID and GLILD biomarkers, immunological profiles, and therapeutic interventions informed comparative analyses. Patients with GLILD exhibited distinct immunophenotypical features, including reduced regulatory T-cells, CD8+ naïve, central memory T-cells, and B-cell subsets (memory and switched memory), alongside increased CD21low B-cells and naïve B-cells, indicative of chronic inflammation-driven immune activation. IgA and IgG4 concentrations were significantly lower in patients with GLILD at diagnosis. Immunosuppressive therapy, predominantly mycophenolate mofetil (MMF), demonstrated favorable clinical and functional outcomes, though radiological progression persisted in some cases. CMV infection in patients with GLILD on immunosuppressants resulted in favorable outcomes, underscoring the importance of personalized treatment strategies. This study highlights novel immunological markers and clinical-radiological patterns as potential predictors for GLILD, advocating for their integration into diagnostic and monitoring frameworks to reduce reliance on invasive histopathology. Future research should focus on validating biomarkers and conducting RCTs to establish evidence-based guidelines for GLILD management.

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