Serine/threonine kinase 4 (STK4) deficiency is a rare combined immunodeficiency (CID). This study aims to analyze the clinical and immunological characteristics of a child carrying novel compound heterozygous STK4 variants and to explore potential alterations in FOXO1-BACH2 signaling associated with impaired T-cell development and regulatory T cell (Treg) homeostasis. We collected the patient’s clinical data and performed genetic diagnosis using whole-exome sequencing followed by Sanger validation. T cell receptor (TCR) repertoire diversity was analyzed, and peripheral blood lymphocyte subsets and their functions were comprehensively evaluated via flow cytometry. Single-cell RNA sequencing was used to identify transcriptional alterations in major immune-cell populations. We then used Stk4 global knockout mice and an STK4-knockdown cellular model, together with Western blotting, quantitative real-time PCR, and chromatin immunoprecipitation-qPCR, to examine the potential relationship among STK4 deficiency, FOXO1-related signaling, BACH2 expression, and Treg-associated immune alterations. The patient carried compound heterozygous STK4 variants (c.733C > T, and c.771dupT) and presented with a CID phenotype, characterized by recurrent infections, naïve T-cell lymphopenia, reduced recent thymic emigrants, restricted TCR repertoire diversity, and altered Treg homeostasis. BACH2 expression was reduced in the patient and in STK4-deficient experimental models, suggesting a potential regulatory association between STK4 deficiency and BACH2 downregulation. ChIP-qPCR in total thymocytes showed FOXO1 enrichment at the Bach2 promoter region, supporting a potential FOXO1-BACH2 transcriptional relationship. This study identifies novel pathogenic STK4 variants and expands the critical and immunological spectrum of STK4 deficiency. The most prominent immunological features were impaired thymic output, naïve T-cell depletion, and restricted TCR repertoire diversity. Altered FOXO1-BACH2 signaling may contribute, at least in part, to impaired Treg homeostasis.
CARD11 is a multidomain scaffolding protein essential for antigen receptor-induced NF-κB signaling in lymphocytes. CARD11 is highly intolerant to mutations, and pathogenic variants have been implicated in various immune-related disorders. In this study, we describe a family with a novel CARD11 missense variant, associated with immunodeficiency, cytopenia, and atopy. This study aims to characterize the phenotype associated with a novel CARD11 variant and to expand the current knowledge of CARD11’s role in lymphocyte function. Trio whole-exome sequencing identified a heterozygous CARD11 c.65 T > C variant that results in p.L22S substitution. The variant was shown to have a mild dominant-negative effect in an NF-κB reporter assay performed in transiently transfected CARD11-deficient cells. Flow cytometry demonstrated decreased phosphorylation of p65S529 and S6S235/S236 in patients' T cells. In concordance with the dysregulated signaling, the patients present dampened activation and proliferation of T cells upon TCR-mediated stimuli. Moreover, transcriptomics analysis with differential expression and gene set enrichment analysis revealed dysregulation of genes involved in cell cycle regulation and inflammation. Our findings confirm that CARD11 is a central regulator of T cell signaling, and even mild loss-of-function can disrupt crucial pathways. Further studies are needed to gain a better understanding of the role of CARD11 in inborn errors of immunity and lymphocyte function.
Secondary immunodeficiency is an acquired immune deficiency caused by various factors, including cancer treatment, organ failure, chronic disease, nutritional deficiency, and physiological aging. It impairs antibody production, attenuates T-cell immune function, disrupts mucosal immunity, and increases the risk of several severe infections. This review compiles evidence on treatment approaches from 2011 to 2026, including impacts on secondary immunodeficiency, clinical reviews, disease patterns, and therapeutic interventions. Heterogeneous definitions and therapeutic challenges of immunoglobulin replacement therapy are explored. It explores the use of serum IgG testing as the primary tool for clinicians to evaluate functional antibody production. This study was conducted through systematic literature searches in PubMed, Scopus, Web of Science, and the Cochrane Library, in accordance with PRISMA 2020 guidelines. A screening process was conducted, and 100 studies across five clinical areas were identified. The three main outcomes were hypogammaglobulinemia, reduced vaccine response, and increased infections. The study found that 20–50
“Familial Mediterranean Fever (FMF) (OMIM #249,100) is the most prevalent hereditary autoinflammatory disease globally, though it remains rare outside Mediterranean populations. FMF is caused by gain-of-function mutations in the MEFV gene, which encodes the immune regulatory protein pyrin. Recent studies suggest that multiple inflammasomes, including the pyrin inflammasome, may work synergistically to enhance their activity. In this study, we focused on NLRP1, and IL-18, an interleukin found at elevated levels in FMF and MEFV variant patients. We observed that silencing or knocking out NLRP1 reduced the inflammatory profile associated with MEFV at the cellular level. NLRP1 inhibition led to decreased release of interleukins, inflammasome-related proteins, and pyroptosis in both patient-derived cells and cultured model systems under proinflammatory conditions. Given that common treatments like colchicine or anakinra can lose effectiveness over time or in certain patients, these findings offer potential avenues for new therapeutic strategies in FMF management.”
Inborn errors of immunity (IEI) comprise a heterogeneous group of inherited disorders associated with substantial morbidity and mortality, yet long-term outcome data from middle-income countries remain limited. We conducted a retrospective cohort study of 123 children diagnosed with IEI at a tertiary referral center in Thailand between 1991 and 2022 to characterize clinical features, treatment, and survival. Patients were retrospectively classified according to the 2022 International Union of Immunological Societies classification. Kaplan–Meier and Cox proportional hazards analyses were performed to evaluate survival and factors associated with mortality. Predominantly antibody deficiencies were the most common IEI category (40.7
Cartilage-Hair Hypoplasia (CHH), a rare ribosomopathy characterized by immune deficiency, carries a markedly increased risk of early-onset malignancy, particularly lymphoma. However, the molecular drivers of malignant transformation in CHH, and the contribution of viruses to this process, remain poorly defined. We performed targeted virome sequencing of 41 DNA viruses on FFPE tumor samples (primarily lymphomas) from 15 CHH patients and three malignancy-matched controls per patient. Subsequent analyses comprised Epstein-Barr Virus (EBV) quantification via qPCR, intra-host minor variant (MV) profiling, and high-resolution mapping of viral integration sites using ViroJoin. EBV was the only pathogen consistently detected across all CHH tumors, with viral loads exceeding those of controls by more than 400-fold. Aggregate analysis of all full-length EBV genomes revealed minimal intra-host diversity and sparse structural variations, of which inversions were the most common. Strikingly, we detected a non-random pattern of EBV integration into the host genome, with junctions frequently clustering near viral promoters, particularly within LMP1. Integrations localized preferentially to host genes, occurring 1.3-fold more frequently within genes and 8.2-fold closer to them than expected by chance. Our findings identify a distinct genomic signature associated with EBV-positive lymphomas, characterized by non-random EBV integrations into the host genome. We propose that these ectopic viral sequences may act as cis-regulatory elements, potentially dysregulating host gene expression and contributing to malignant transformation and disease severity. These results underscore the importance of virome surveillance for early risk stratification in high-risk populations.
Inborn errors of immunity (IEI) are a group of complex diseases characterized by reduced immunity and increased susceptibility to external pathogens, autoinflammation, autoimmune conditions, and/or malignancy. The IKAROS zinc-finger (IKZF) family is a group of C2H2 zinc-finger transcription factors that includes IKAROS (IKZF1), HELIOS (IKZF2), AIOLOS (IKZF3), EOS (IKZF4), and PEGASUS (IKZF5). Variants in IKZF have been reported to cause human IEI except IKZF4. This research aimed to identify the pathogenicity and underlying mechanisms of IKZF4 as a novel candidate gene for IEI. Here, we used whole-exome sequencing to identify candidate variants of IEI. Western blotting, quantitative polymerase chain reaction, immune staining, co-immunoprecipitation, flow cytometry, Luminex assays, and single-cell RNA sequencing were used to explore the phenotypes and functional effects in cell and mouse models. An 11-month-old patient presented with repeated fever and convulsions accompanied by persistently reduced immunoglobulin levels and abnormal immune indices, which supported the diagnosis of IEI. A de novo c.1472delG variant (GRCh37/hg19, NM_022465.3) in IKZF4 was selected as the candidate variant for IEI. The c.1472delG variant caused reduced EOS expression and truncated protein (predicted molecular weight 57 kDa), defective pericentromeric heterochromatin targeting, and impaired protein interactions of EOS. A mouse model harboring the corresponding variant in Ikzf4 (Ikzf4+/c.1475delG) showed a proinflammatory switch in regulatory T cells, accompanied by reduced levels of immunoglobulins and a decreased ratio of marginal zone B cells after lipopolysaccharide stimulation, which were potentially caused by the down-regulated transcriptional regulation of EOS on the nuclear factor kappa-B pathway. This research identified IKZF4 as a novel candidate gene for IEI, advancing our knowledge of the IKZF family and the complexity of human IEI.
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.
Inborn errors of immunity (IEI) contribute substantially to morbidity in the Middle East and North Africa (MENA), particularly in the United Arab Emirates (UAE), where high consanguinity increases the prevalence of autosomal-recessive and complex genetic disorders. Regional IEI genomic data remain limited, and population-specific variants are underrepresented in global databases, limiting diagnostic accuracy and precision-medicine implementation. We retrospectively reviewed 2,500 patients assigned immunodeficiency-related ICD codes over ten years at two tertiary centers in Al Ain, UAE. Based on the availability of genetic testing reports for inborn errors of immunity, 232 patients ( 9
Cytotoxic T‑lymphocyte antigen‑4 (CTLA4) is a key immune checkpoint molecule, and its haploinsufficiency can lead to a highly heterogeneous immune dysregulation syndrome; however, its association with pure red cell aplasia (PRCA) remains to be systematically characterized. Here we report two adult‑onset siblings carrying an identical novel germline missense mutation in CTLA4 (c.394G>A; p.Glu132Lys), both presenting with PRCA as the initial and core manifestation, with involvement of the stomach, spleen, thyroid, and other organs. Although their genetic backgrounds are similar, the disease trajectories of the two patients exhibited noteworthy differences: the proband (elder sister) had persistent Epstein–Barr virus (EBV) infection, responded initially to long‑term cyclosporine combined with androgen therapy, then gradually developed splenomegaly, and eventually relapsed with EBV‑associated poorly differentiated gastric adenocarcinoma; the younger sister, in contrast, was EBV‑negative, but concurrently developed T‑cell large granular lymphocytic leukemia (T‑LGLL), atrophic gastritis, and splenomegaly, and her PRCA responded to cyclosporine treatment. The phenotypic divergence between the two cases (solid tumor vs. hematologic malignancy) highlights the complexity and heterogeneity of tumorigenesis in the context of immune dysregulation. Based on these observations, we propose a speculative but testable working framework that regards immune dysregulation as the common pathophysiological foundation, and suggests that different types of “second‑hit” events—such as chronic viral‑driven immune inflammation or autoreactive T‑cell clonal expansion resulting from thymic selection abnormalities—may steer the disease toward distinct neoplastic endpoints. This is the first report to describe the comorbidity of T‑LGLL in a germline CTLA4 mutation carrier. These findings expand the disease spectrum of CTLA4 haploinsufficiency and provide a reference for risk stratification and individualized management of such patients.
While genomic testing is integral to the management of pediatric inborn errors of immunity (IEI), few studies have examined strategies to support its optimal integration into routine healthcare. Thus, this study aimed to: (i) describe a pediatric IEI cohort and genomic testing practices, and (ii) assess the impact of implementing a multidisciplinary genomic model of care (MoC) on service outcomes. A comprehensive chart audit was conducted for patients (≤ 18years) who received IEI genomic testing in Queensland, Australia, from 2017 to 2025. Descriptive analyses captured demographics, clinical characteristics, genomic testing and results, and management outcomes. Inferential analyses assessed changes in genomic practices pre-MoC (< 2021) and post-MoC (≥ 2021). 322 patients met eligibility criteria (n = 481 genomic tests). Diagnostic yield (mean:26.7
ZNFX1 interferes with early viral replication after exposure to type I interferon, and interacts with mitochondrial antiviral sensors (MAVS) leading to a balanced expression of interferon-stimulated genes (ISGs). ZNFX1 deficiency mimics systemic autoinflammatory diseases and accurate identification may prevent early mortality. We compare a homozygous ZNFX1 frameshift mutation patient to subjects with known interferonopathies. We explore the association between this mutation, unregulated ISGs, and macrophage activation syndrome (MAS). Study participants included our index patient, other patients with well-characterized interferonopathies, and healthy participants. We performed western blotting for ZNFX1 and whole Blood mRNA-seq, RT-qPCR, ELISA, and Olink Proteomics analysis to assess cytokine production and the underlying immune dysregulation. Our patient had elevated expression of interferon-inducible genes compared to healthy controls, but levels were comparable to subjects with known interferonopathies. Gene sequencing revealed a novel homozygous ZNFX1 frameshift variant resulting in a truncated protein. Transcriptomic analysis pointed to the top 3 cytokine upstream regulators, tumor necrosis factor (TNF), IL-1β, and interferon-gamma. ZNFX1 deficient patients appear to have a clinical profile that differs from classical type I interferonopathies, including features such as thrombotic microangiopathy (TMA) and a higher frequency of MAS. ZNFX1 deficiency is an immune dysregulation disorder characterized by a robust type I interferon signature combined with elevated inflammatory cytokines, leading to severe early-onset multisystem inflammatory disease. Characterizing the immune profile allows targeted short-term treatments that may prolong life.
The need to establish inborn errors of immunity (IEI) database arose from the recognition that IEI existed in Malaysia, beginning in 1977, followed by more reports a decade later. As awareness grew, it became necessary to develop a database to systematically capture IEI data to support planning, monitoring, and improvement of patient care in this emerging area of clinical medicine in Malaysia. Patients were managed at participating hospitals under the care of clinical immunologists. Each patient underwent a comprehensive clinical assessment, including evaluation of relevant clinical features and immunological laboratory investigations at selected centres. In 2007, a database, the Malaysian Primary Immunodeficiency Network (MyPIN) Registry, was established to collate and store this information. Of 423 cases referred to immunologist-led clinics, 300 were identified as IEI, giving an estimated prevalence of 0.95 per 100,000 population. Defects in cellular immunity, including combined immunodeficiencies and well-defined combined immunodeficiency syndromes, were the most frequent (44.7
Down syndrome (DS), caused by trisomy 21, is characterized by complex immune dysregulation that increases susceptibility to infections and alters vaccine responsiveness. Gene dosage effects involving interferon receptor loci on chromosome 21 contribute to chronic type I interferon hyperactivation, sustained JAK-STAT signaling, and persistent expression of interferon-stimulated genes. This baseline inflammatory state is accompanied by quantitative and functional defects in both innate and adaptive immunity, including impaired neutrophil chemotaxis, pro-inflammatory monocyte polarization, reduced naïve T- and B-cell compartments, restricted antigen receptor diversity, diminished class-switched memory B cells, and features of accelerated immunosenescence. Clinically, these immune alterations are associated with an increased risk of severe respiratory viral infections, such as respiratory syncytial virus, influenza, and SARS-CoV-2, as well as reduced magnitude and durability of vaccine-induced immunity. Cohort studies in both pediatric and adult populations have reported higher rates of hospitalization and mortality, along with lower peak antibody titers and more rapid waning of immunity following vaccination. This review integrates molecular, cellular, and clinical evidence to define the interferon-driven immune phenotype in DS and its implications for susceptibility to infection and vaccination response. A mechanistic understanding of this immune landscape provides a framework for developing tailored preventive strategies and optimizing vaccination approaches in this vulnerable population.
Hepatic actinomycosis is a rare granulomatous disease caused by an opportunistic Gram-positive bacillus of the genus Actinomyces. We report an unusual association between hepatic actinomycosis and IgG-4 related disease. A 70-year-old man was admitted to the University Hospital of Reunion Island for asthenia and abdominal pain. Laboratory tests showed hepatic cholestasis and inflammatory reaction without cytolysis. The computer tomography scanner (CT scan) revealed a large hepatic mass in segment IV. IgG4 related disease (IgG4-RD) was diagnosed following liver biopsy. Despite the use of corticosteroids, the lesions progressed. A new biopsy was performed and a PCR test returned positive for Actinomyces spp. We observed patient improvement after 4 months of treatment with amoxicillin and discontinuation of corticosteroids. Clinical presentation, imaging characteristics, and diagnostic challenges are strikingly similar between hepatic actinomycosis and IgG4-related disease. However, distinguishing between these two disorders is essential – as the treatment of one may worsen the course of the other. Knowing and understanding the interactions between these two disorders can only be achieved through an integrated and collaborative approach involving various disciplines.
Thymic epithelial tumors (TETs) are associated with Good Syndrome (GS), a secondary immunodeficiency characterized by hypogammaglobulinemia, B-cell lymphopenia, and recurrent infections. This study investigated the immunological profile of TET patients to identify immune alterations associated with GS, independently of autoimmune diseases (AD) and disease stage. Seventy patients with TETs were stratified according to GS status (GS+/GS−), AD status (AD+/AD−), and disease stage (advanced disease, IVA/B, or no evidence of disease, NED). Serum immunoglobulins, peripheral immune cell subsets, and circulating cytokines, chemokines, growth factors, and metabolic markers were evaluated. Results GS+ patients showed reduced IgM and IgG levels compared with GS- patients; however, after stratification, only IgM remained reduced in GS+AD− NED patients. Peripheral B-cell lymphopenia was consistently observed in GS+ patients across both disease stages, independently of AD status. Treg frequencies increased in GS− patients with advanced disease and in GS+AD+ NED patients. Monocytopenia and an inverted CD4+/CD8+ ratio were mainly observed in GS+AD+ patients with advanced disease. Cytokine profiling identified increased levels of IL-1β, IL-10, IL-17, TNFα, IFN-γ, IL-4, IL-5, IL-6, Eotaxin, G-CSF, and IP-10 in GS+ patients. Among these, IP-10 remained consistently elevated regardless of disease stage or AD status. Peripheral B-cell lymphopenia and elevated IP-10 levels represent the most consistent immunological features associated with GS, independent of disease stage and AD status, whereas serum immunoglobulin levels appear less reliable in advanced disease. These findings support the diagnostic value of immunophenotyping, particularly B-cell quantification and IP-10 measurement, for identifying GS in patients with TETs.
TRNT1 deficiency (SIFD syndrome) is a rare inborn error of immunity characterized by sideroblastic anemia, immunodeficiency, periodic fevers, and developmental delay. We report two Romanian patients with genetically confirmed TRNT1 deficiency presenting with characteristic hematologic and immunologic abnormalities and a distinctive facial dysmorphism. One patient additionally developed severe gastrointestinal ischemia and intracranial hemorrhage in the setting of concomitant hereditary antithrombin III deficiency. These observations expand the phenotypic spectrum associated with TRNT1 deficiency and highlight the marked clinical variability of this disorder. The contribution of TRNT1-associated inflammation to the vascular phenotype remains speculative and cannot be distinguished from the effects of the concomitant thrombophilic condition.
Systemic autoimmune diseases and primary immunodeficiencies/inborn errors of immunity (PIDs/IEIs) have traditionally been viewed as opposing immunological entities. However, growing genetic, immunological, and clinical evidence challenges this dichotomy, revealing a shared spectrum of immune dysregulation, genetic vulnerability, and convergent phenotypes. Advances in next-generation sequencing have identified monogenic IEIs presenting with autoimmune manifestations indistinguishable from polygenic systemic autoimmune diseases, blurring diagnostic boundaries and carrying therapeutic implications. This review aims to explore the relationships between autoimmunity, immunodeficiency, and malignancy, emphasizing how immune dysregulation underlies susceptibility to infections, cancer, and treatment-related complications. We performed a narrative review of the literature with a focus on underlying mechanisms, clinical manifestations, and implications for diagnosis and management. Immune dysregulation underlies susceptibility to infections, cancer, and treatment-related complications. Immunosuppressive and biologic/targeted therapies remain cornerstone treatments but entail risks, including serious and opportunistic infections, organ toxicity, and malignancy, particularly when underlying PIDs/IEIs remain unrecognized. Failure to recognize underlying PID/IEI in patients with early-onset, refractory, syndromic, or otherwise atypical autoimmune disease leads to misdiagnosis and harmful therapeutic escalation, underscoring the need for prompt immunological screening. Immunological screening, including immunoglobulin profiling, lymphocyte subsets, and genetic testing, may improve diagnostic accuracy and guide treatment strategies. Malignancy represents an intersection point, with disease-specific cancer patterns reflecting distinct pathogenic mechanisms across autoimmune diseases and IEIs, highlighting the clinical relevance of disease-specific cancer risk stratification and surveillance. Integrating mechanistic insights and genetic profiling may enable a precision medicine approach that optimizes efficacy while minimizing harm across this expanding immunological continuum.
Transient neutropenia in early childhood is a relatively common condition often associated with neutrophil-specific autoantibodies; however, its connection to broader humoral immune system abnormalities remains poorly understood. The current study investigated this relationship through a retrospective cohort analysis at a pediatric tertiary center in Switzerland. In total, 92 children aged 0 to 6 years seen at our hospital between January 2014 and December 2023 were included in the final cohort. Of the 68 children who underwent detailed immunological testing, 52 (77
