Journal Of Clinical Immunology[JOURNAL]
Sun
200 papers
A Novel Pathogenic Variant in TRAC Gene Associated with SCID Phenotype: Expanding the Genetic and Clinical Spectrum.
Karaselek MA, Ozbey MY, Uygun V … +13 more , Kuccukturk S, Karabey N, Tokdemir U, Ozel G, Demircioglu ZD, Yildirim S, Sahin A, Duran T, Akkus A, Yildirim S, Guner S, Reisli İ, Keles S
J Clin Immunol · 2026 Mar · PMID 41882383 · Full text
PURPOSE: Pathogenic variants in the T-cell receptor alpha constant (TRAC) gene have been primarily associated with combined immunodeficiency (CID). To date, only five patients from three unrelated families harboring the...
PURPOSE: Pathogenic variants in the T-cell receptor alpha constant (TRAC) gene have been primarily associated with combined immunodeficiency (CID). To date, only five patients from three unrelated families harboring the same TRAC variant with a CID phenotype, and three patients carrying a distinct variant with severe combined immunodeficiency (SCID), have been described. We report a previously unreported homozygous TRAC variant causing a premature stop codon in three siblings with classical SCID phenotype. METHODS: Comprehensive immunological and molecular analyses were performed, including lymphocyte immunophenotyping, proliferation assays, qPCR for T helper (Th) subset-related gene expression, and cytokine secretion profiling. In silico analyses included conservation assessment, structural modeling using ChimeraX, and protein stability prediction via PremPS to evaluate the variant's structural and functional consequences. RESULTS: All three siblings exhibited recurrent infections, refractory diarrhea, and elevated liver enzymes, accompanied by profound T-cell lymphopenia with preserved B-cell numbers. Whole-exome sequencing revealed a homozygous TRAC variant in the affected siblings and heterozygous carriage in their parents. The variant alters a highly conserved residue, disrupting hydrogen bonding and likely destabilizing the protein structure. Functional assays demonstrated a marked reduction in recent thymic emigrants (RTEs) cell ratio absence of TCRαβ⁺ T cells, skewed Th polarization, and elevated proinflammatory cytokine levelsfindings consistent with a SCID phenotype. CONCLUSION: These findings expand the clinical and molecular spectrum of TRAC-related immunodeficiency and support its inclusion among genes primarily associated with SCID. The results further emphasize that specific mutation sites within immune-related genes critically influence disease severity and phenotype variability.
Mechanistic Insights Into Immune Cell Dysregulation Mediated by Novel Heterozygous Variants in CARD11 and MALT1.
Li R, Sun X, Bao W … +9 more , Yu H, Dan Y, Wu C, Ma Y, Yin H, Lin W, Lu L, Fu Q, Yang C
J Clin Immunol · 2026 Mar · PMID 41882201 · Full text
Dysregulation of the CARD11-BCL10-MALT1 (CBM) complex is associated with a group of inborn errors of immunity termed “CBM-opathies,” which encompass a spectrum of clinical manifestations including combined immunodeficien...
Dysregulation of the CARD11-BCL10-MALT1 (CBM) complex is associated with a group of inborn errors of immunity termed “CBM-opathies,” which encompass a spectrum of clinical manifestations including combined immunodeficiency, autoimmune inflammation, atopic disorders, and lymphoproliferation. In this study, we identified novel compound heterozygous variants in the CBM complex in a patient with a family history of immune dysfunction. The patient inherited the variants CARD11 p.K215N and MALT1 p.K543R/p.M732T from asymptomatic carrier parents. Phenotypically, the patient exhibited a developmental arrest of B lymphocytes at the transitional/naïve B cell stage, accompanied by activation of virus-response pathways. Impaired development of T follicular helper cells was linked to defective germinal center formation and agammaglobulinemia. Furthermore, the patient showed expansion of T peripheral helper cells and a deficiency in regulatory T cells, both associated with autoimmunity and colitis. In vitro studies confirmed an imbalance in Tph/Tfh cell differentiation. Single-cell RNA sequencing further revealed a deficiency in B cell development and an enriched population of pro-inflammatory CD3dimCD4−CD8−CD247+ T cells, functionally enriched in the MAPK signaling pathway. Mechanistically, the MALT1 K543R and M732T variants attenuated MALT1’s enzymatic activity and compromised its protein stability, while the CARD11K215N variant disrupted CARD11-mediated promotion of BCL10 filament formation. We demonstrated that these three variants act synergistically to impair NF-κB activation. Specifically, CARD11K215N cooperates with the co-pathogenic MALT1M732T and the modifier variant MALT1K543R to destabilize the functional integrity of the CBM complex, thereby driving the patient’s phenotype. In summary, our study provides new insights into the pathogenesis of autoimmune inflammatory disorders within the spectrum of CBM-opathies and reveals a potential role for the CBM complex in regulating the balance between T peripheral helper and T follicular helper cells.
Enhancing Clinical Workflow Efficiency in Flow Cytometry Reporting with LLMs.
Tavolara TE, Meyer J, Garcia C … +2 more , Kumanovics A, Vanderboom P
J Clin Immunol · 2026 Mar · PMID 41874828 · Full text
BACKGROUND: Accurate interpretation of clinical test results is essential for diagnosing and managing complex immunological disorders. We explored the potential of large language models (LLMs) to automate interpretative...
BACKGROUND: Accurate interpretation of clinical test results is essential for diagnosing and managing complex immunological disorders. We explored the potential of large language models (LLMs) to automate interpretative reports for immunodeficiency and immune competence assessment via quantitative lymphocyte profiling and B-cell subset phenotyping (QLP/BSP). METHODS: An LLM was fine-tuned using parameter-efficient techniques on a dataset consisting of immunophenotyping test results and corresponding interpretive reports. Model performance was compared against a retrieval-based method and expert pathologist reports. A novel automated evaluation framework assessed both the accuracy of cell population comments and the clinical relevance of generated interpretations. A custom application was built to simulate clinical workflows and measure the impact on pathologist efficiency and accuracy. RESULTS: Fine-tuned LLMs achieved accuracy comparable to expert pathologists in identifying and commenting on abnormal cell type counts and frequencies, in comparison the retrieval-based method exhibited substantial error rates. There was no significant difference between the rate at which abnormalities for cell subtypes were commented on between the LLMs and pathologists. More importantly, LLMs significantly reduced the time required for a single pathologist to finalize reports with a mean reduction in time of 29%. CONCLUSION: Our results suggest that LLMs hold promise for enhancing efficiency and consistency in the clinical laboratory setting. By automating aspects of interpretive reporting, LLMs can potentially reduce pathologist workload and improve the turnaround time for critical diagnostic information, while requiring expert pathologist oversight.
GATA2 Deficiency Syndrome: A Case Series and Literature Review.
Dong Z, Lai J, Li J … +5 more , Du Y, Lin L, Chen R, Gong M, Zhuansun Y
J Clin Immunol · 2026 Mar · PMID 41870648 · Full text
GATA2 functions as a critical zinc finger transcription factor and plays indispensable roles in hematopoiesis, immune regulation, and lymphatic vascular development. GATA2 deficiency underlies a diverse phenotypic spectr...
GATA2 functions as a critical zinc finger transcription factor and plays indispensable roles in hematopoiesis, immune regulation, and lymphatic vascular development. GATA2 deficiency underlies a diverse phenotypic spectrum, encompassing primary lymphedema, myelodysplasia, acute myeloid leukemia, immune dysfunction, and sensorineural deafness. This report describes three sporadic cases of GATA2 deficiency syndrome and summarizes their clinical features in the context of previously published literature. All three patients carried germline pathogenic GATA2 variants: NM_001145661.1 c.818dupG (p. Pro274Thrfs; case 1) and NM_032638.5 c.1084 C > T (p. Arg362*; cases 2 and 3). The clinical presentations included recurrent pulmonary infections, leukopenia, and thrombocytopenia (case 1) and congenital neurogenic deafness (cases 2 and 3).
Excluded GM-specific IgG Subclass Genes in Health and Disease - Inborn Errors of Immunity.
Oxelius VA
J Clin Immunol · 2026 Mar · PMID 41863686 · Full text
PURPOSE: IgG subclass genes from chromosome 14q32.3 are assessed serologically by GM allotypes, genetic markers of the Fc part of the immunoglobulin constant heavy G chains, (IGHG(Fcγ)(GM) genes. Alternative GM allotypes...
PURPOSE: IgG subclass genes from chromosome 14q32.3 are assessed serologically by GM allotypes, genetic markers of the Fc part of the immunoglobulin constant heavy G chains, (IGHG(Fcγ)(GM) genes. Alternative GM allotypes of IgG3, IgG1 and IgG2, respectively, define 6 unique, precise GM-specific IgG subclass genes, inherited the Mendelian way with allelic exclusion, and linkage disequilibrium of IgG3-IgG1. Increased number of homozygous GM-specific IgG subclass genotypes with total loss of alternative IgG subclass molecules, inborn errors of immunity (IEI), are found in severe immunological diseases. METHODS: A novel ELISA using GM-specific myeloma proteins and GM-specific monoclonals, identifies 6 alternative GM-specific IgG subclass genes and molecules IgG3*b & IgG3*g, IgG1*f & IgG1*a and IgG2*n & IgG2*-n, with different structures and functions. 4 different IgG3-IgG1-IgG2 haplotypes encode 10 individual IGHG diplotypes from 10 innate lymphoid combined B cells in 587 healthy. RESULTS: The alternative GM-specific IgG subclass genes have different structures and functions and respond differently in immunotherapy to antigen stimulation with virus, bacteria and allergens. In this report we focus on excluded GM-IgG subclass genes, inborn errors of immunity (IEI) dominating in severe immunological diseases, severe infections, primary immunodeficiencies (PIDs), JCA, asthma, diabetes type 1 and malignancy. By intravenous immunoglobulins (IVIG) the excluded IgG subclass molecules are supplied and may prevent primary virus attacks and exacerbations in autoimmune disorders. IgG subclass genes orchestrate additional immune factors of inflammation. CONCLUSION: Excluded GM-specific IgG subclass genes, IEI explore diagnosis, pathogenesis, prognosis and different phenotypes in immunological diseases, with IVIG as treatment.
Fostamatinib Dual Immunomodulation in Post-Haploidentical HSCT Autoimmune Cytopenia and Autoimmune Hepatitis: A Case Report and Review of Literature.
Tessitore A, Curci D, Sonzogni A … +5 more , Franzin M, Schillani G, Flamigni A, Paternuosto G, Maximova N
J Clin Immunol · 2026 Mar · PMID 41863683 · Full text
PURPOSE: To describe the effectiveness and safety of fostamatinib off-label use in a pediatric patient with autoimmune cytopenia and autoimmune hepatitis following allogeneic hematopoietic stem cell transplantation (HSCT...
PURPOSE: To describe the effectiveness and safety of fostamatinib off-label use in a pediatric patient with autoimmune cytopenia and autoimmune hepatitis following allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: We report the detailed changes in clinical, histopathological, and cytokine profiling in a pediatric HSCT recipient during treatment with fostamatinib. RESULTS: Fostamatinib administration was well-tolerated with no adverse events observed, leading to sustained hematological recovery and a significant improvement in liver enzyme levels. Histological features confirmed the complete remission of autoimmune hepatitis. Cytokine profiling demonstrated substantial normalization of pro-inflammatory markers, downregulated at onset. CONCLUSION: Fostamatinib demonstrated a dual benefit in resolving autoimmune cytopenia and immune-mediated liver inflammation, supporting its potential as a therapeutic option for immune dysregulation following allogeneic HSCT.
Posttransplant B cell Development and Function in Patients with B cell Positive SCID Caused by Pathogenic Variants in IL2RG and JAK3.
Jacobsen EM, Khazaleh A, Felgentreff K … +11 more , Furlan I, Wustrau K, Sirin M, Cario H, Mayer B, Pannicke U, Schwarz K, Debatin KM, Friedrich W, Schulz AS, Hoenig M
J Clin Immunol · 2026 Mar · PMID 41863562 · Full text
Genetic defects in IL2RG or JAK3 can cause the phenotype of severe combined immunodeficiency (SCID) with absent T- and non-functional B-lymphocytes (T-B+ SCID). B cell function and the need for immunoglobulin replacement...
Genetic defects in IL2RG or JAK3 can cause the phenotype of severe combined immunodeficiency (SCID) with absent T- and non-functional B-lymphocytes (T-B+ SCID). B cell function and the need for immunoglobulin replacement therapy after hematopoietic stem cell transplantation (HSCT) depends on the engraftment of donor B-lymphocytes. In a retrospective study we describe B-lymphocyte reconstitution after HSCT with the aim to identify B cell subpopulations as an early predictor for the maturation and function of B cells after HSCT. All patients included underwent HSCT in a single institution between 1980 and 2017. First, we studied B cell maturation in cryopreserved blood samples of 12 patients with B+ SCID (IL2RG-deficiency) after haploidentical HSCT presenting with mixed B cell chimerism. Recipient and donor B cell subpopulations were identified by HLA-staining using flow cytometry. In a consecutive step we compared B cell subpopulations irrespective of chimerism between patients with or without post-transplant B cell function. Samples for this study were obtained between day + 90 to + 250 after HSCT from 25 post-transplant long-term survivors with B-positive SCID (9 with genetic variants in JAK3, 16 in IL2RG), 9/25 were dependent and 16/25 independent of immunoglobulin (Ig) -substitution.We demonstrate that a proportion of less than 2% of donor B cells can be sufficient for posttransplant B cell function and that a proportion of more than 4.7% of switched memory (IgM-) B cells in the memory B cell population (CD19 + CD27+) between days + 90 and + 250 after HSCT correlates with normal B cell function and independence from immunoglobulin substitution.
Syndromic Inborn Errors of Immunity in TREC-Newborn Screening: 5-year Experience from the German Screening Program.
Graafen L, Speckmann C, Bakhtiar S … +30 more , Bernuth HV, Lehmberg K, Bader P, Baumann U, Beier R, Borte S, Brockow I, Davies EG, Hartmann M, Holzer U, Klemann C, Kreins AY, Krüger R, Kontny U, Laws HJ, Meinhardt A, Morbach H, Naumann-Bartsch N, Rothoeft T, Schneider DT, Willasch A, Worth A, Seidel MG, Albert MH, Ehl S, Hauck F, Hönig M, Schulz A, Schuetz C, Ghosh S
J Clin Immunol · 2026 Mar · PMID 41831046 · Full text
TREC-NBS identifies patients with inborn errors of immunity (IEI) and syndromic features, but uncertainty remains regarding their immunological management. To address this, syndromic patients detected by TREC-NBS in Germ...
TREC-NBS identifies patients with inborn errors of immunity (IEI) and syndromic features, but uncertainty remains regarding their immunological management. To address this, syndromic patients detected by TREC-NBS in Germany between August 2019 and April 2024 were systematically analyzed, including phenotype, treatment, and outcomes. National registries were screened, and data were completed by the treating centres. A total of 77 syndromic patients were identified, with 22 different gene defects found in 72 individuals (93.5%). Primary thymic deficiency was present in 64% (49/77), most commonly due to 22q11.2 deletion syndrome (62%). Common clinical features included congenital heart disease (57%), facial/skeletal abnormalities (53%), and neurological symptoms (36%). Definitive treatments were provided promptly in eligible patients, including 6 thymus transplants and 6 hematopoietic stem cell transplants (HSCT). A watch-and-wait approach was applied to the remaining patients, with 34% (22/65) receiving prophylactic treatment. Recovery of CD3 + T-cell counts was limited to a minority. Overall survival was 89%, with a median follow-up of 32 months (range 0.5-60). To conclude, this is the first comprehensive study of syndromic IEI patients identified through TREC-NBS. The findings show that the German healthcare system enables both early prophylactic care and timely access to definitive therapies. Moving forward, interdisciplinary collaboration will be key to developing evidence-based management guidelines for this challenging patient group.
Prognostic Factors for Sideroblastic Anemia with B-cell Immunodeficiency, Periodic Fevers, and Developmental Delay Due to TRNT1 Gene Mutations: A Case Report and Systematic Review.
Su TH, Lee NC, Wang LC … +2 more , Chiang BL, Yu HH
J Clin Immunol · 2026 Mar · PMID 41795040 · Full text
Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD), a rare multisystemic syndrome, occurs due to loss-of-function mutations in the tRNA nucleotidyl transferase 1 (TRNT1) ge...
Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD), a rare multisystemic syndrome, occurs due to loss-of-function mutations in the tRNA nucleotidyl transferase 1 (TRNT1) gene. This study reports the case of a 21-month-old female patient with SIFD and compound heterozygous mutations c.824T > A, p.Leu275X (a novel variant) and c.1246 A > G, p.Lys416Glu in TRNT1 gene. The patient had presented with recurrent fever since 10 days of age, along with vasculitis, systemic inflammation with elevated proinflammatory cytokines, decreased B-cell count, and failure to thrive. Furthermore, she did not respond to intravenous immunoglobulin (IVIG) treatment, but her condition stabilized with etanercept (a tumor necrosis factor [TNF] inhibitor) and corticosteroids therapy. In addition, this study includes a systematic review of the clinical presentations, genetic mutations, treatments, and outcomes of 75 patients with SIFD. The estimated 2-, 5-, and 10-year Kaplan–Meier survival probabilities for all patients were 88.45%, 76.67%, 68.84% for all patients; 82.40%, 58.86% and 44.85% for patients with onset age of ≤ 3 months; 70%, 40% and 26.68% for patients with seizures; 88.05%, 66.62% and 59.22% for patients with decreased B cell number; 50% and 33.33% for patients who received hematopoietic stem cell transplantation (HSCT), respectively (log-rank P < 0.05). We concluded that younger age of onset of ≤ 3 months, seizures, and decreased B-cell count are significant poor prognostic factors for survival. Anti-TNF therapy early in life may stabilize patients with autoinflammatory phenotypes; however, the role of HSCT remains controversial.
Characterisation of a Leaky Splice-Site Mutation Associated with Phenotypic Diversity in Two Unrelated Patients with ARPC1B Deficiency.
Quach A, King J, Putty T … +3 more , Gold M, Quinn P, Ferrante A
J Clin Immunol · 2026 Mar · PMID 41793545 · Full text
Autosomal-recessive pathogenic variants in Actin-related protein 2/3 complex subunit 1B (ARPC1B) result in an inborn error of immunity associated with eczema, thrombocytopenia, leukocytoclastic vasculitis and colitis. AR...
Autosomal-recessive pathogenic variants in Actin-related protein 2/3 complex subunit 1B (ARPC1B) result in an inborn error of immunity associated with eczema, thrombocytopenia, leukocytoclastic vasculitis and colitis. ARPC1B deficiency leads to impaired actin filament branching, affecting cytoskeletal processes in leukocytes, including migration, adhesion, endocytosis, and phagocytosis. This report presents two index cases from different families, who despite sharing an identical germline homozygous ARPC1B splice-site variant, ARPC1Bc.64+2T> A, had distinct clinical phenotypes including age of onset of symptoms and clinical manifestations. In addition, differences were observed in their immunological profiles including neutrophil chemotaxis, upregulation of complement receptor expression as well as B cell maturation and responses to EBV transformation. Further molecular investigation suggests the downstream cryptic splice-site activated by the mutation permits ‘leaky splicing’, enabling trace expression of wildtype ARPC1B. This supports a less severe deficiency in ARPC1B activity, rendering a less severe phenotype in one case compared with the other due to differential transcriptional activity of wildtype ARPC1B.
The Experience of a Tertiary Reference Center in Central Anatolia with Children Carrying ZAP-70 Variants, Including Two Novel Variants.
Göktaş S, Kalaycik Sengul O, Erdem Ş … +21 more , Eke Güngör H, Babayeva R, Bilgic-Eltan S, Güzel T, Dörterler K, Rohlfs M, Özcan A, Yilmaz E, Karakukcu M, Akar HH, Karakoc-Aydiner E, Özen A, Elmas M, Patiroğlu T, Doğan ME, Baş H, Taylor N, Baris S, Klein C, Eken A, Ünal E
J Clin Immunol · 2026 Mar · PMID 41790376 · Full text
PURPOSE: Zeta-chain-associated protein kinase 70 (ZAP-70) deficiency, a rare form of combined immunodeficiency (CID), is caused by homozygous or compound heterozygous variants in the ZAP70 gene. ZAP-70, a tyrosine kinase...
PURPOSE: Zeta-chain-associated protein kinase 70 (ZAP-70) deficiency, a rare form of combined immunodeficiency (CID), is caused by homozygous or compound heterozygous variants in the ZAP70 gene. ZAP-70, a tyrosine kinase, plays a key role in T-cell receptor (TCR) signaling, which is critical for T cell activation. ZAP-70 deficiency manifests clinically in a variety of ways, including recurring respiratory infections and cutaneous manifestations. METHODS: This study describes the clinical, genetic, and immunological characteristics of four Turkish, two Syrian, and one Azerbaijani patient with ZAP-70 deficiency, including two novel variants. RESULTS: Among seven patients diagnosed with ZAP-70 deficiency, two previously unreported ZAP70 variants were identified. Functional analyses performed in four patients—including three with novel variants—demonstrated impaired TCR-induced proliferation, reduced Interleukin 2 (IL-2) production, and markedly diminished CD8⁺ T cell numbers, supporting the pathogenicity of these variants. Clinical phenotypes were heterogeneous, ranging from severe early-onset infections and cytopenias to autoimmune manifestations and atopy. Notably, even siblings carrying the same variant exhibited divergent immunological profiles and disease severity, highlighting the influence of potential genetic or environmental modifiers. Hematopoietic stem cell transplantation (HSCT) was curative in four patients, while one patient died before transplant. CONCLUSION: This report expands the genetic and phenotypic spectrum of ZAP-70 deficiency by describing two novel variants and emphasizing the value of functional analysis in variant classification and patient management.
Two Cases of CLIPPERS-like Syndrome Sharing a Hypomorphic UNC13D Variant.
Sagawa H, Hirata K, Katayama S … +17 more , Shibata H, Toyofuku E, Kaneko S, Katata Y, Takezawa Y, Uematsu M, Onishi I, Yamazaki Y, Hattori T, Yamamoto M, Shimizu M, Imai K, Yasumi T, Morio T, Yokota T, Sasahara Y, Kanegane H
J Clin Immunol · 2026 Mar · PMID 41781714 · Full text
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) syndrome is a central nervous system (CNS) inflammatory disease characterized by contrast-enhanced MRI findings of...
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) syndrome is a central nervous system (CNS) inflammatory disease characterized by contrast-enhanced MRI findings of salt-and-pepper-like lesions predominantly affecting the brainstem and cerebellum. We report two patients with CLIPPERS-like brain MRI findings who carried the same missense UNC13D variant in one allele along with deleterious variants in the opposite allele. Patient 1, a 23-year-old female, presented at 15 years of age with neurological symptoms and an MRI showing spontaneously resolving, contrast-enhancing lesions in the cerebellum. At age 16, the patient experienced an episode with systemic manifestations followed by recurrent CNS lesions that responded to steroid therapy. At age 22, the patient developed punctate to nodular contrast-enhancing lesions in the brainstem, cerebellum, and cerebrum, findings consistent with CLIPPERS. Patient 2, an 18-year-old female, presented at age 11 with ataxia and dysarthria, and an MRI showing multiple contrast-enhancing lesions in the cerebellum and brainstem, consistent with CLIPPERS MRI findings. Cerebellar biopsy revealed perivascular CD4+ T-lymphocyte infiltration, and the patient responded to steroid therapy, leading to an initial diagnosis of CLIPPERS. These patients were suspected of having inborn errors of immunity and were identified to have compound heterozygous UNC13D variants along with downregulated Munc13-4 protein. Both patients underwent allogeneic hematopoietic cell transplantation, with patient 1 remaining neurologically stable for two years post-transplantation, while patient 2 experienced a post-transplant relapse requiring steroid therapy. These cases highlight that biallelic variants in the UNC13D gene may cause CNS-predominant inflammation that mimics CLIPPERS.
Unraveling BCR Repertoire Diversity and its Impact on Glucocorticoid Therapy in Pediatric Idiopathic Nephrotic Syndrome.
Luo Y, Zou C, Yu X … +8 more , Guo C, Dai H, Huang J, Xun M, Duan C, Li S, Li Z, Yang G
J Clin Immunol · 2026 Mar · PMID 41772268 · Full text
AIM: Idiopathic nephrotic syndrome (INS) is the most common glomerular disease in children, but its underlying mechanisms remain unclear. Although glucocorticoids (GC) are the first-line treatment, approximately 10% of I...
AIM: Idiopathic nephrotic syndrome (INS) is the most common glomerular disease in children, but its underlying mechanisms remain unclear. Although glucocorticoids (GC) are the first-line treatment, approximately 10% of INS cases are steroid-resistant (SRNS), and 50% may progress to refractory nephrotic syndrome (RNS). B cells play a crucial role in INS pathogenesis, treatment, and prognosis. This study aims to explore B-cell receptor repertoire (BCRR) characteristics in INS patients to identify molecular signatures associated with disease outcomes and develop early risk prediction models for RNS and SRNS. METHODS: A case-control study was conducted using peripheral blood samples from 40 initial diagnosed INS patients and 56 age-matched healthy controls. BCRR was sequenced using dimer-avoided multiplex PCR, followed by Illumina NovaSeq sequencing. Immunoglobulin heavy chain (IGH) sequences were mapped and analyzed for diversity, clone expansion and shared clone, isotype usage, class-switch recombination (CSR), IGHV/J gene usage, CDR3 length and somatic hypermutation (SHM). Additionally, a prospective cohort study was conducted on INS patients, with BCRR measured at baseline and follow-up to track changes in response to treatment. Longitudinal analysis was performed to identify specific B-cell clones and predict treatment resistance. RESULTS: The BCRR of INS patients exhibited lower evenness compared to controls, with significant increases in the usage of IGHM/D mutated and IgE/IgG12 isotypes. Public B-cell clones, including five specific CDR3 amino acid sequences, were identified across INS patients. NRNS patients showed increased clonal expansion with specific CDR3 sequences characters on IGHV5-51_IGHJ6 sequences and shorter CDR3 lengths, suggesting strong and focused autoimmune responses. In contrast, RNS and SRNS patients exhibited enhanced IgE-mediated immune responses, characterized by increased IgE BCRR diversity, decreased evenness and increased CSR. Early prediction models were developed based on BCRR parameters, successfully distinguishing between RNS and NRNS, SRNS and SSNS patients. CONCLUSION: B-cell-mediated humoral immunity plays a pivotal role in INS pathogenesis, with distinct immune profiles associated with clinical outcomes. Non- refractory nephrotic syndrome (NRNS) patients exhibit clonal expansion with antigen-driven immune responses, whereas SRNS and RNS patients demonstrate persistent IgE-mediated responses that are resistant to GC but sensitive to second-line immunosuppressants. These findings offer new insights into the mechanisms of steroid resistance and provide a basis for early diagnosis and personalized treatment strategies in INS.
Porto-sinusoidal Vascular Disease is Associated with Gastrointestinal Disorders in Common Variable Immunodefiency.
Corvilain E, Gérard L, Fadlallah J … +9 more , Galicier L, Delaval L, Alchidiac J, Plessier A, Boutboul D, Fieschi C, Oksenhendler E, Rautou PE, Malphettes M
J Clin Immunol · 2026 Feb · PMID 41762359 · Full text
PURPOSE: We aimed to describe porto-sinusoidal vascular disease (PSVD) in a large cohort of predominantly antibody deficiency (PAD) patients and sought to identify contributing factors for PSVD development by comparing C...
PURPOSE: We aimed to describe porto-sinusoidal vascular disease (PSVD) in a large cohort of predominantly antibody deficiency (PAD) patients and sought to identify contributing factors for PSVD development by comparing CVID patients with and without PSVD. METHOD: Patients were retrospectively identified from a national database. RESULTS: Sixty-eight of 386 PAD patients, including 63 of 267 CVID patients were diagnosed with PSVD. Median time from PAD to PSVD diagnosis was 9.2 years (interquartile range, 4.6–14.5). CVID patients with late onset combined immunodeficiency and non-infectious complications were overrepresented among PSVD patients (37.5% and 87.3%, respectively). Nodular regenerative hyperplasia (NRH) was the most common finding on liver biopsy (79%), alongside with intra-sinusoidal CD8+ T-cell infiltration (65.7%). In an adjusted multivariate model, gastro-intestinal (GI) complications (adjusted odds ratio, 4.94; 95% CI, 1.91–12.79; p = 0.001) and low naive CD4+ T-cell count (p = 0.001) were strongly associated with the occurrence of PSVD in CVID patients, together with low serum IgA level (p = 0.018) and lymphoproliferation (p = 0.027). GI complications were observed in 90.5% of PSVD patients, preceding PSVD diagnosis in 84% of them by a median duration of 10.7 years. The 20-year probability to develop PSVD after CVID diagnosis was estimated at 38.7% (95% CI, 30.1–48.7) and 11.7% (95% CI, 5.0–26.0) in patients with or without GI complications, respectively (p < 0.001). The median overall survival from onset of PSVD was 8.4 years. CONCLUSION: Our data suggest that impaired intestinal barrier in a context of T-cell defect may play a key role in the development of PSVD in CVID patients. Whether complete control of GI complications would prevent the occurrence of PSVD remains to be evaluated.
Primary Immunodeficiency Diseases with BCG-Induced Diseases: A 15-Year Longitudinal Cohort Study.
Xia L, Yang Y, Li XY … +5 more , Liu P, Wang XM, Huang Z, Lu SH, Liu XH
J Clin Immunol · 2026 Feb · PMID 41748971 · Full text
BACKGROUNDS: Children with primary immunodeficiency (PID) may develop severe infections after BCG vaccination. There is limited information on the long-term prognosis and management of these BCG-induced diseases. METHODS...
BACKGROUNDS: Children with primary immunodeficiency (PID) may develop severe infections after BCG vaccination. There is limited information on the long-term prognosis and management of these BCG-induced diseases. METHODS: Data were gathered from a cohort study on BCG-induced diseases at the Shanghai Public Health Clinical Center, spanning from January 2007 to August 2022. The study enrolled patients with confirmed PIDs, and information was obtained via personal interviews with patients or their guardians, as well as from their medical records. This allowed us to gather clinical and genetic details, treatment history, and the outcomes of their PIDs. We evaluated antimycobacterial outcomes and analyzed the impact of HSCT and IFN-γ therapy on the risk of death. RESULTS: Out of 422 patients with BCG-induced diseases, 109 patients with confirmed PID were included in the analysis. Of these, 88.1% had developed distant or disseminated BCG infection, and the median duration of illness documented in the study was 57 months (IQR 31–79). The three most common PIDs in this cohort were MSMD (47/109, 43.1%), CGD (28/109, 25.7%), and CID (19/109 or 17.4%). The estimated five-year and ten-year survival rates were 80.3% (95%CI, 72.1%-88.5%) and 69.3% (95%CI, 56.8%-81.8%). Patients who received hematopoietic stem cell transplantation therapy (HSCT) had a significantly higher success rate with antimycobacterial treatment (75.8% vs. 0%). The survival benefit of HSCT varies across immunodeficiency types but is clearly beneficial for CID (p < 0.001). IFN-γ therapy presented no significant effect on the survival of CGD and MSMD. The initial STRONGkids nutritional score (HR = 2.27 per point, 95%CI 1.65–3.13) and gender (HR for male = 4.89, CI 1.36–17.57) are significant predictors of survival. Mutations in 6 genes (IL12RB1, CYBB, IFNGR1, IL2RG, STAT1, and RAG1) account for 66% of BCG-associated immunodeficiency mutations. CONCLUSIONS: PID complicated by BCG infection may cause persistent and severe conditions. Patients with severe nutritional risk in the early stages of infection have a higher risk of death and should prioritize HSCT.
Fatal Systemic Granulomatous Disease Associated with Vaccine-Derived Rubella Virus in AIOLOS-Associated Immunodeficiency.
Zhou L, Kuehn HS, Gager D … +13 more , Silva AAG, Perelygina LM, Hao L, Chen MH, Niemela JE, Stoddard JL, Helm M, Wanat K, Sullivan K, Foulke G, Leung TH, Rosenzweig SD, Rosenbach M
J Clin Immunol · 2026 Feb · PMID 41746515 · Full text
We present a case of disseminated granulomatous disease associated with live attenuated vaccine-derived rubella virus (VDRV) in an immunodeficient patient who subsequently developed fatal multi-organ failure, including n...
We present a case of disseminated granulomatous disease associated with live attenuated vaccine-derived rubella virus (VDRV) in an immunodeficient patient who subsequently developed fatal multi-organ failure, including neurological deficits, with VDRV detected in the cerebrospinal fluid. Posthumous genetic analysis found a heterozygous missense mutation in IKZF3, a gene where haploinsufficiency is linked to immunodeficiency and immune dysregulation. Functional studies demonstrated that this mutation decreases AIOLOS protein stability and half-life, and family members carrying the same mutation exhibited decreased AIOLOS levels. This report underscores the importance of considering persistent rubella virus (RuV) infection in patients with cutaneous granulomatous lesions and highlights the need for comprehensive evaluation to uncover potential underlying immunodeficiencies, which could inform and optimize individualized treatment strategies.
A Cohort Study of 38 Classic Wiskott-Aldrich Syndrome Cases with Six Novel Mutations.
Razaghian A, Badalzadeh M, Hamidieh AA … +22 more , Shokouhi Shoormasti R, Behniafard N, Houshmand M, Moradi L, Alavi S, Behfar M, Movahedi M, Gharagozlou M, Rostami T, Moussavi F, Fallahpour M, Shariat M, Parvaneh N, Shafiei A, Ahanchian H, Babaei D, Bemanian MH, Radmehr R, Khademi R, Shamlou S, Fazlollahi MR, Pourpak Z
J Clin Immunol · 2026 Feb · PMID 41718912 · Full text
PURPOSE: Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by eczema, microthrombocytopenia, and recurrent infections. This study evaluates the frequency of clinical manifestations and overall...
PURPOSE: Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by eczema, microthrombocytopenia, and recurrent infections. This study evaluates the frequency of clinical manifestations and overall outcomes in WAS patients, comparing those who received hematopoietic stem cell transplantation (HSCT) with those who did not. METHODS: Thirty-eight boys with a definite diagnosis of WAS were retrospectively evaluated in the Immunology, Asthma, and Allergy Research Institute registry in Tehran from 2006 to 2023. RESULTS: The median ages at symptom onset, diagnosis, and delay to diagnosis were 3.5, 7.5, and 4.5 months, respectively. The clinical presentations include allergies in 38 (100%), infection in 37 (97.4%), hemorrhage in 36 (94.7%), autoimmunity in 14 (36.8%), and malignancies or myelodysplasia syndrome in 3 (7.9%) patients. Although microthrombocytopenia is a hallmark of WAS, 34.4% of our cases had normal platelet size. The WAS gene analysis in 36 of 38 patients identified six novel mutations. Sixteen patients underwent HSCT. Disease-free survival was reported in 10 (62.5%) of them, whereas 6 (37.5%) of them were deceased. The mortality rate in non-transplant patients was 15/22 (68.2%). CONCLUSION: Most WAS patients experienced atopy, recurrent infections, and bleeding. Moreover, autoimmunity and malignancies have increased relative to the general population. Moreover, the mortality rate is high, especially among those who did not receive HSCT. Keeping in mind that thrombocytopenia alongside eczema and/or infection in a male infant can be the presentation of this fatal disease. Early diagnosis and treatment could be lifesaving and prevent severe morbidities.
TFRC Germline Variants and Inborn Error of Immunity: Mechanistic Insights into Iron-Immune Crosstalk.
Aljohani AH
J Clin Immunol · 2026 Feb · PMID 41714512 · Full text
Mutations in TFRC, which encodes transferrin receptor 1 (TfR1/CD71), have emerged as a rare but significant cause of inborn error of immunity (IEI). TfR1 is a crucial membrane glycoprotein responsible for receptor-mediat...
Mutations in TFRC, which encodes transferrin receptor 1 (TfR1/CD71), have emerged as a rare but significant cause of inborn error of immunity (IEI). TfR1 is a crucial membrane glycoprotein responsible for receptor-mediated iron uptake, playing fundamental roles in erythropoiesis and immune function, and linking impaired iron homeostasis to profound immune dysfunction. Notably, TFRC deficiency provides a biologically instructive human model demonstrating that iron uptake via TfR1 is a non-redundant metabolic and signaling checkpoint required for antigen receptor–driven immune activation, clonal expansion, and immune homeostasis. This review summarizes the molecular mechanisms of TfR1, including its interactions with transferrin, and explores how pathogenic TFRC mutations impair iron uptake, affect immune cells, lymphocyte activation, and clonal diversity. We also examine TfR1 in the context of immunodeficiency, linking its roles in iron metabolism and immune regulation to clinical outcomes. By integrating current knowledge on TfR1 biology, molecular mechanisms with patients’ clinical presentation, observations, variants, and therapeutic approaches, this review highlights knowledge gaps and unresolved questions, providing a framework for future research toward elucidating TfR1 mechanisms, improving patient diagnosis, and ultimately enabling the development of targeted therapies for TfR1-mediated immunodeficiency.
Good's Syndrome Mirrors a Combined Immunodeficiency with Anti-Cytokine Antibodies in the Total Absence of B Cells.
Kabir A, Gilbert L, Almasizadeh D … +5 more , Alizadehfar R, Polito V, Langlais D, Michel RP, Tsoukas CM
J Clin Immunol · 2026 Feb · PMID 41701387 · Full text
Good’s Syndrome, an adult-onset immune deficiency, has been traditionally grouped with humoral immune deficiencies such as Common Variable Immune Deficiency (CVID) and X-linked agammaglobulinemia (XLA) despite the unique...
Good’s Syndrome, an adult-onset immune deficiency, has been traditionally grouped with humoral immune deficiencies such as Common Variable Immune Deficiency (CVID) and X-linked agammaglobulinemia (XLA) despite the unique presence of the thymic neoplasm, late age of onset, frequent opportunistic infections and multiple cytopenias. Low prevalence and sporadic reporting have limited investigative efforts. We conducted a prospective, multimodal, study to establish the GS phenotype in the absence of severe infections. A previously characterized cohort of GS patients was compared to healthy individuals and those diagnosed with CVID or XLA using serology, immunophenotyping and histopathology. We also attempted to establish an inborn cause of the immune deficiency with HLA typing and Whole Exome Sequencing. GS patients exhibited severe hypogammaglobulinemia, a complete absence of B-cells in the peripheral blood and in biopsied primary and secondary lymphoid tissues. Total lymphocytes and CD4 T-cell counts were markedly reduced in GS but with intact T-cell proliferative capacity to in vitro mitogen and lectin stimulation. Autoantibody profiling identified high titers of antibodies in GS patient plasma to several cytokines, notably anti-interferons, which persisted for several years. These antibodies overlapped with those observed in thymoma patients without GS. We demonstrate that GS involves profound B-cell-loss, extending beyond blood to the lymphoid tissue, however plasma cells and circulating anti-cytokine antibodies can persist for years. In the absence of a unifying monogenic defect, the findings are suggestive of a thymoma-associated breakdown in central tolerance driving the immune dysregulation and deficiency seen in GS.
Spectrum of Primary Immune Regulatory Disorders in Children in a Highly Consanguineous Population: Report from a National Registry.
Alajmi A, Alsharidah S, Khalifa N … +4 more , Elhussein A, Al-Khabaz A, Alaqeel A, Al-Herz W
J Clin Immunol · 2026 Feb · PMID 41688586 · Full text
BACKGROUND: Primary Immune Regulatory Disorders (PIRDs) are caused by genetic defects resulting in diverse clinical manifestations. We aimed to present the spectrum of PIRDs in children in Kuwait. METHODS: The data was o...
BACKGROUND: Primary Immune Regulatory Disorders (PIRDs) are caused by genetic defects resulting in diverse clinical manifestations. We aimed to present the spectrum of PIRDs in children in Kuwait. METHODS: The data was obtained from the Kuwait National Primary Immunodeficiency Disorders Registry (KNPIDR), and the patients were followed prospectively. RESULTS: 59 patients with PIRDs, constituting 14% of all patients registered in the KNPIDR, were included in this study. Most of the patients belonged to familial hemophagocytic lymphohistiocytosis syndromes (42.4%), followed by regulatory T cell defects subcategories (15.3%). The median ages at the onset of symptoms and diagnosis were 4 and 18 months, respectively. Parental consanguinity was documented in 88.1% of cases while family history of PIRDs in 45.7%. The most common clinical features were lymphoproliferation, hematologic manifestations, and infections, affecting 71.2%, 67.8%, and 47.5%, respectively. Genetic diagnosis was reached in 84.9% of the tested patients and the most common genes affected were STXBP2 followed by PRF1 and LYST. Most patients (88.8%) had autosomal recessive disease. 35.6% of the patients underwent hematopoietic stem cell transplantation and a similar percentage received immunosuppressive and/or immunomodulating therapies. There was a total of 21 deaths (35.6%) with a median age at death of 36 months while the median time from diagnosis to death was 5 months. CONCLUSIONS: PIRDs are heterogenous group of disorders with complex disease phenotypes. Genetic testing should be done as soon as possible when these diseases are suspected since early diagnosis is crucial for proper therapeutic interventions.
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