Collet A, Coiffard B, Ledoult E
… +35 more, Fieschi C, Cheminant M, Serris A, Suarez F, Sanges S, Neel A, Nove-Josserand R, Stabler S, El Husseini K, Huault A, Cougoul P, Mausservey C, Cassir N, Mirgot F, Meresse B, Dendooven A, Poizot S, Le Scornet T, Bravard AS, Conrad A, Levêque M, Fadlallah J, Melenotte C, De La Roque CD, Tinevez C, Chahla WA, Dubucquoi S, Labalette M, Neven B, Malphettes M, Schleinitz N, Galicier L, Viallard JF, Gorochov G, Lefèvre G
J Clin Immunol
· 2025 Nov · PMID 41315117
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PURPOSE: Despite well-conducted replacement therapy with polyvalent immunoglobulins (IgRT), some patients with primary immunodeficiencies (PID) continue to experience recurrent or chronic infections. IgA and IgM, essenti...PURPOSE: Despite well-conducted replacement therapy with polyvalent immunoglobulins (IgRT), some patients with primary immunodeficiencies (PID) continue to experience recurrent or chronic infections. IgA and IgM, essential for mucosal and complement-mediated immunity, are absent or minimal in standard immunoglobulin products. The aim of this study is to evaluate the safety and clinical evolution profiles in PID patients with undetectable IgA/IgM levels and persistent infections despite standard IgRT, after introduction of an IgA- and IgM-enriched immunoglobulin preparation (IgGAM, Pentaglobin). METHODS: A compassionate use program (CUP) in France enrolled 20 PID patients with undetectable IgA/IgM levels, receiving IgGAM IV infusions every 7-14 days. Tolerance, infection frequency, hospitalizations, and biological markers (Ig levels, complement activation, salivary IgA) were analyzed prospectively. RESULTS: Twenty patients were included in the CUP at the time of analysis. No severe adverse event was reported. Half of the patients experienced mild to moderate hypersensitivity symptoms. Mean antibiotic courses dropped from 5.4 to 2.3/year (p = 0.0009) and mean number of hospitalizations decreased from 2.6 to 1.2/year (p = 0.01). Median serum IgA and IgM levels increased three months after IgGAM start. IgM and low levels of IgA were detected in saliva samples, suggesting at least a transient transfer of IgA/IgM from IgGAM into mucosal fluids. CONCLUSION: In patients with severe PID and undetectable IgA/IgM, IgGAM was associated with reduced infections and hospitalizations. Controlled studies are needed to confirm the benefit of IgA/M enriched immunoglobulin preparations in PID patients with persistent and/or recurrent respiratory or digestive infections.
Almohaimeed HM, Almars AI, Tounsi WA
… +6 more, Mohammedsaleh ZM, Panigrahi R, Singh I, Singh S, Dhara B, Uti DE
J Clin Immunol
· 2025 Nov · PMID 41315078
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Exosomes, as integral mediators of cellular communication, have emerged as crucial players in the pathogenesis and potential treatment of autoimmune diseases. This review explores the dual role of exosomes in mediating a...Exosomes, as integral mediators of cellular communication, have emerged as crucial players in the pathogenesis and potential treatment of autoimmune diseases. This review explores the dual role of exosomes in mediating autoantigen presentation and their impact on immune dysregulation. Exosomes, by virtue of their cargo-comprising proteins, peptides, and nucleic acids-can influence immune tolerance, potentially leading to the breakdown of self-tolerance and the perpetuation of autoimmune responses. They carry and present autoantigens directly to T cells or indirectly via antigen-presenting cells, thereby initiating and sustaining immune reactions characteristic of autoimmune disorders. Furthermore, the review delves into the therapeutic implications of targeting exosomal pathways, discussing strategies such as inhibiting exosome biogenesis, modifying exosomal content, and blocking exosome uptake by immune cells. Such interventions present promising avenues for developing novel treatments aimed at mitigating autoimmune responses. By harnessing the unique properties of exosomes, future research may pave the way for innovative therapeutic strategies that offer more precise and personalized treatment options for patients suffering from autoimmune diseases.
Ponsford MJ, Carne EM, Bramhall K
… +17 more, Ladell K, Perelygina L, Saw A, Miners K, Llewellyn-Lacey S, Kollnberger S, Tully I, Hughes S, Williams H, Kalavala M, Bigley V, Farewell D, Price DA, Walker SL, Sullivan KE, Jolles S, All Wales Syndrome Without A Name (SWAN) Clinic
J Clin Immunol
· 2025 Nov · PMID 41298860
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Autosomal recessive mutations in TAP1, TAP2, TAPBP, or B2M, are associated with major histocompatibility complex (MHC) class I deficiency. Individuals may present with granulomatous skin ulceration, but the underlying an...Autosomal recessive mutations in TAP1, TAP2, TAPBP, or B2M, are associated with major histocompatibility complex (MHC) class I deficiency. Individuals may present with granulomatous skin ulceration, but the underlying antigenic triggers remain largely unknown. We identified TAP1 deficiency in a 32-year-old female referred with a 7-year history of localized skin ulceration. Histologic immunofluorescence revealed that rubella virus (RuV) infection was a likely driver of the associated inflammation, and modest clinical improvement was observed following topical calcineurin inhibition. To better define the natural history, clinical, and immunological manifestations of this condition, we also performed a scoping literature review. We identified 45 unique individuals from 36 reports with a combined follow-up duration of 1,184 patient years. Chronic necrotizing granulomatous skin lesions and childhood-onset bronchiectasis were common. Five deaths were reported (median age 36 years), typically linked to respiratory complications. Phenotypic heterogeneity was evident, with at least four individuals reaching adulthood without clinical symptoms. Diagnostic delay frequently exceeded a decade amongst symptomatic individuals, with misdiagnosis of granulomatous disease prompting systemic immunosuppression and infection-related morbidity. The presence of an abnormal CD8 T-cell count or a history of consanguinity offered low sensitivity for MHC I deficiency (~ 50%), indicating a low threshold for further investigation is required for correct diagnosis. Graphical review of case reports identified morphologically similar lesions in other MHC I-deficient individuals. These findings suggest that the phenomenon of MHC I deficiency is underreported and that diagnosis should prompt testing for RuV.
Chen J, Huang C, Chen T
… +19 more, Feng S, Xue J, Zhou Z, Huang S, Liang T, He R, Qin B, Qin X, Mo S, Zhou C, Wu S, Wei W, Li H, Lu Z, Qin Y, Liao S, Chen L, Zhan X, Liu C
J Clin Immunol
· 2025 Nov · PMID 41291215
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BACKGROUND AND OBJECTIVES: Ankylosing spondylitis (AS) is a chronic immune-mediated inflammatory disease primarily affecting the axial skeleton. Despite significant advances, its pathogenic mechanisms remain unclear, pos...BACKGROUND AND OBJECTIVES: Ankylosing spondylitis (AS) is a chronic immune-mediated inflammatory disease primarily affecting the axial skeleton. Despite significant advances, its pathogenic mechanisms remain unclear, posing challenges to early diagnosis and effective treatment. This study aims to elucidate the pathogenic pathways of AS and explore potential therapeutic strategies. METHODS: Blood routine test results from AS and non-AS patients were collected, and t-tests and logistic regression analyses were performed on blood cell count parameters. Key findings from the blood tests were validated using GEO transcriptomic datasets. Single-cell data from GEO were then used to conduct in-depth analyses of immune cell subsets and their functions. To validate findings, single-cell sequencing was performed on bone marrow samples collected from AS and fracture control patients, followed by pathway analysis through GSEA. Finally, upstream regulatory mechanisms and potential therapeutic agents were investigated. RESULTS: This study identified a classical monocyte-macrophage-inflammatory macrophage differentiation trajectory in AS, demonstrating that monocytes/macrophages play a critical role in AS pathogenesis via the NOD-like receptor signaling pathway, primarily mediated by NLRP3. Several regulatory factors, including hsa-miR-3682-3p, AR, IRF4, MYB, RUNX1, and TAL1, were found to modulate NLRP3 expression. Additionally, various chemical compounds, anticancer drugs, and cinnamaldehyde were identified as potential therapeutic agents targeting NLRP3. CONCLUSION: In AS, the classical monocyte-macrophage-inflammatory macrophage differentiation pathway is enhanced, with monocyte/macrophage-derived NLRP3 driving disease progression via the NOD-like receptor signaling pathway. Regulatory factors and potential therapeutic agents targeting NLRP3 were identified, offering new insights into AS pathogenesis and therapeutic strategies.
Karafotias I, Martini H, Lee CV
… +8 more, Hunter TTJ, Gurugama P, Guckian M, Steven R, Jolles S, Peakman M, Fear D, Ibrahim MAA
J Clin Immunol
· 2025 Nov · PMID 41288852
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BACKGROUND: Common Variable Immunodeficiency (CVID) is a group of heterogeneous disorders with common denominators of impaired antibody production and function, and recurrent infections. Currently, prognostic biomarkers...BACKGROUND: Common Variable Immunodeficiency (CVID) is a group of heterogeneous disorders with common denominators of impaired antibody production and function, and recurrent infections. Currently, prognostic biomarkers for CVID are limited. CXCL13 is a critical regulator of germinal centre responses and antibody production, with T follicular helper (Tfh) cells as a major source, and acts as a potent B cell chemoattractant. Serum levels of CXCL13 are increased in chronic inflammatory conditions and malignancy. OBJECTIVES: We aimed to explore whether serum CXCL13 levels are altered in CVID and whether they can categorise the patients based on their clinical and immune phenotype. METHODS: We compared the serum levels of CXCL13 between CVID and healthy donors (HD) and associated them with the clinical and immune phenotype of the patients. RESULTS: The serum levels of CXCL13 were higher in CVID, especially in female patients, as compared to HD, and were positively correlated with the number of clinical complications in CVID and the total peripheral circulating Tfh cells (cTfh). CVID patients with higher levels of CXCL13 were more likely to have clinical complications and/or high frequency of CD21 B cells or low frequency of switched memory B cells. CONCLUSIONS: CXCL13 can categorise heterogeneous patients with CVID and be used as a biomarker of complex disease.
Blanco-Lobo P, Gilabert-Prieto P, de Felipe B
… +18 more, Moreno-Fuentes D, Guisado Hernández P, Ortiz-Ramírez A, Mensa-Vilaró A, Aróstegui JI, Palmou N, Velasco Gonzalez V, Deyà Martinez Á, Ramakers J, Ivorra-Cortés J, Roca C, Cordero E, Guillen I, Valerdiz Menéndez N, Lucena JM, Gaboli M, Olbrich P, Neth O
J Clin Immunol
· 2025 Nov · PMID 41288843
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Down syndrome (DS) and STAT1 gain-of-function (GOF) share clinical and molecular features, including persistent inflammation. We aimed to investigate whether the coexistence of DS and a STAT1 GOF mutation in a patient sy...Down syndrome (DS) and STAT1 gain-of-function (GOF) share clinical and molecular features, including persistent inflammation. We aimed to investigate whether the coexistence of DS and a STAT1 GOF mutation in a patient synergistically enhances interferon (IFN) signaling and exacerbates inflammatory responses, posing additional management challenges. Two patients (P1 and P2) were studied: P1, with DS and a heterozygous p.P326S STAT1 variant, and P2, with the STAT1 p.P326S variant only. Individuals with isolated DS or STAT1 GOF served as controls. IFN receptor subunits (IFNγR1/R2 and IFNαR1/R2) and responses to IFNα/γ stimulation were analyzed using flow cytometry and RT-PCR. Whole blood type I IFN signature and serum cytokines were evaluated using NanoString and Luminex assays. P1 experienced recurrent infections, chronic mucocutaneous candidiasis, interstitial pneumonitis, and pulmonary hypertension. P2 presented with esophageal candidiasis, dysphagia, and stenosis. The p.P326S variant led to increased STAT1/pSTAT1 levels in response to IFNα/γ. Both patients showed significant clinical improvement with the Janus kinase (JAK) inhibitor ruxolitinib. However, P1's key biomarkers (STAT1 levels, IFN signature, TNFα, IL-6) remained altered, indicating persistent inflammation despite clinical improvement. This first report of a STAT1 GOF variant in DS provides a unique "experiment of nature", offering insights into the interplay between trisomy 21 and STAT1-mediated immune dysregulation. Although ruxolitinib demonstrated clinical benefits, the persistent inflammation observed in P1 highlights the need for further strategies to achieve complete immune resolution. These findings emphasize the importance of comprehensive genetic and immunological assessments in individuals with DS, particularly when immune dysfunction is suspected.
Soomann M, Prader S, Agyeman PKA
… +7 more, Blanchard-Rohner G, Buettcher M, Kahlert CR, Ritz N, Theodoropoulou A, Pachlopnik Schmid J, Trück J
J Clin Immunol
· 2025 Nov · PMID 41288825
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BACKGROUND: Newborn screening (NBS) by quantification of T-cell receptor excision circles (TREC) identifies a considerable number of infants with T-cell lymphopenia (TCL) other than severe combined immunodeficiency (SCID...BACKGROUND: Newborn screening (NBS) by quantification of T-cell receptor excision circles (TREC) identifies a considerable number of infants with T-cell lymphopenia (TCL) other than severe combined immunodeficiency (SCID). While some of these children have well-defined inborn errors of immunity (IEI), many lack a clear genetic diagnosis, complicating their management and causing prognostic uncertainty. OBJECTIVE: To characterize the natural history of non-SCID TCL detected through NBS in Swiss infants between 2019 and 2023. METHODS: Clinical, genetic and laboratory data from all non-SCID TCL cases were extracted from the national NBS registry and analyzed. RESULTS: Out of 435 985 screened infants, 42 patients were identified with non-SCID, non-congenital athymia TCL, without an obvious secondary cause. A clear genetic diagnosis of IEI was established in 20 (48%) patients. Infants with confirmed IEI had significantly lower total T-cell, CD4 + T-cell and recent thymic emigrant (RTE) counts on initial lymphocyte phenotyping. In contrast, those with an unclear genetic diagnosis despite full investigations demonstrated faster normalization of total T-cell counts (hazard ratio 5.2, 95% CI 1.9 to 14.5, p = 0.001). All infants with initial CD4 + T-cell < 0.3 × 10/L showed minimal recovery of T-cell counts and remained on long-term prophylactic measures. All infants with an unclear genetic diagnosis despite investigations were able to discontinue prophylaxis at median age 6 months without experiencing opportunistic or severe infections. CONCLUSION: Infants with non-SCID TCL identified by NBS represent a heterogenous group, ranging from severe, persistent TCL to mild, transient lymphopenia. Management should be tailored based on individual immunological and genetic profiles.
Lee JK, Jang JH, Kim DR
… +6 more, Shin A, Park JH, Kim YG, Kim JW, Kim YJ, Kang ES
J Clin Immunol
· 2025 Nov · PMID 41275043
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INTRODUCTION: Inborn errors of immunity (IEIs) constitute a diverse group of more than 500 disorders resulting from pathogenic variants in over 500 causative genes, with most being monogenic diseases. The use of exome se...INTRODUCTION: Inborn errors of immunity (IEIs) constitute a diverse group of more than 500 disorders resulting from pathogenic variants in over 500 causative genes, with most being monogenic diseases. The use of exome sequencing based on next-generation sequencing technologies has significantly advanced the discovery of causative variants underlying IEIs and has achieved diagnostic yields of up to 40%. Despite these advances, a substantial proportion of patients still remain genetically undiagnosed due to limitations in detecting deep intronic or structural variants. Accordingly, we applied whole-genome sequencing to a cohort of patients suspected of IEIs in order to evaluate its diagnostic yield and capacity to identify novel structural genomic alterations. METHODS: We analyzed data from 25 probands presenting with suspected IEIs based on clinical features, who were enrolled through the National Bio-Big Data Program's whole genome sequencing (WGS) project at Samsung Medical Center, spanning July 2020 to February 2022. The study utilized a stepwise analytical protocol involving initial candidate gene panel analysis for detecting small variants, subsequent investigation of structural variants, and then a genotype-driven approach utilizing in-house bioinformatics pipelines. All identified variants were assessed for pathogenicity in accordance with the 2015 ACMG/AMP guidelines for the interpretation of sequence variants. RESULTS: Causative variants were detected in 10 (40%) probands using candidate gene panel analysis, which included BTK, CYBB, DKC1, DNAH11, DNAH5, IL2RG, NFKB2, PIK3CD and SH2D1A. Genotype-driven analysis identified pathogenic variants in two (8%) probands involving NF1 and PTPN11, while an additional five (20%) probands were found to have structural variants, including BTK, LRBA and SH2D1A. In total, genetic analysis revealed causative variants in 60% of patients. Variants of uncertain significance were identified in four cases among three probands (12%). CONCLUSION: WGS facilitated the robust identification of causative genetic variants, including complex structural changes. These results suggest that employing WGS in patients suspected of IEIs could provide additional diagnostic yield.
Palmeri S, Prigione I, Schena F
… +19 more, Jeanpierre M, Bertoni A, Penco F, Bocca P, Del Zotto G, Massucco S, Venturi C, Schenone A, Tripodi G, Recchi G, Lanciotti M, Miano M, Matucci-Cerinic C, Viglizzo G, Papa R, Rieux-Laucat F, Caorsi R, Gattorno M, Volpi S
J Clin Immunol
· 2025 Nov · PMID 41249727
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Suppressor of cytokine signaling 1 (SOCS1) haploinsufficiency is a recently described inborn error of immunity characterized by autoimmunity, inflammation, lymphoproliferation, and increased infection susceptibility. SOC...Suppressor of cytokine signaling 1 (SOCS1) haploinsufficiency is a recently described inborn error of immunity characterized by autoimmunity, inflammation, lymphoproliferation, and increased infection susceptibility. SOCS1, a negative regulator of cytokine signaling via the JAK/STAT pathway, explains the condition's broad phenotypic variability. Single nucleotide polymorphisms in SOCS1 have been linked to multiple sclerosis (MS), and SOCS1 mimetics have shown efficacy in MS animal models. However, neurological involvement has not been previously reported in patients with SOCS1 insufficiency. We describe a family with a heterozygous SOCS1 variant, highlighting neurological manifestations such as MS, autoimmune encephalitis, and recurrent complex regional pain syndrome as novel features. Next-Generation Sequencing and segregation analysis were performed on PBMCs from patients and healthy donors. Functional studies included luciferase reporter assays in HeLa cells expressing the SOCS1 mutant, flow cytometry for phenotypic analysis, and gene expression profiling of the type-I interferon (IFN) signature. Intraepidermal nerve fiber density was evaluated via immunohistochemistry on skin biopsy. Genetic analysis confirmed the variant's inheritance. Transfected cells carrying the SOCS1 variant showed increased STAT1 transcriptional activity after IFN-γ stimulation. Elevated STAT5 phosphorylation and T-cell proliferation were observed in response to IL-2. Peripheral blood revealed an elevated IFN signature during relapse. Skin biopsy showed reduced intraepidermal nerve fiber density. This report expands the clinical spectrum of SOCS1-related disorders to include neurological symptoms, emphasizing SOCS1's critical role in regulating inflammation in the central and peripheral nervous systems.
Zhu X, Fu P, Wang W
… +8 more, Ying W, Sun B, Hou J, Hui X, Sun J, Wang C, Zhou Q, Wang X
J Clin Immunol
· 2025 Nov · PMID 41249685
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PURPOSE: This study aimed to investigate the spectrum of bacterial infections in children with inborn error of immunity (IEIs). METHODS: Pediatric patients with IEIs and positive for bacteria considered to be pathogenic...PURPOSE: This study aimed to investigate the spectrum of bacterial infections in children with inborn error of immunity (IEIs). METHODS: Pediatric patients with IEIs and positive for bacteria considered to be pathogenic were included in this retrospective study. RESULTS: In this study, 1811 medical records of IEI inpatients were reviewed, and 243 IEI patients with 290 hospitalizations were enrolled. A total of 361 strains were detected, of which, 83 (22.99%) were gram-positive bacteria, and 278 (77.01%) were gram-negative bacteria. The main bacteria isolated from different IEI classifications were different. Patients with combined immunodeficiencies were more likely to have Klebsiella pneumoniae (12.68%) and Pseudomonas aeruginosa (12.68%) isolated. Patients with predominant antibody deficiencies were more prone to the isolation of Haemophilus influenzae (31.82%) and Moraxella catarrhalis (13.64%). Patients with congenital defects of phagocytes were more frequently associated with the isolation of K. pneumoniae (16.84%) and Escherichia coli (11.58%). Patients with different classifications of IEI were susceptible to specific bacteria. Salmonella was often isolated from patients with defects in intrinsic and innate immunity (4.23%), and Staphylococcus aureus was often isolated from patients with combined immunodeficiencies with syndromic features (5.52%). The percentages of methicillin-resistant S. aureus, carbapenem-resistant E. coli, K. pneumoniae, P. aeruginosa, and Acinetobacter baumannii in IEI patients were55.57%, 38.10%, 25.71%, 25.81%, and 70.59%, respectively, and these values were greater than those in non-IEI patients. CONCLUSION: Children with IEIs exhibit a unique spectrum of bacterial infections. Bacteria isolated from children with IEIs have high antimicrobial resistance.
Äärimaa E, Kesäläinen A, Askeli S
… +11 more, Toivonen A, Savonius O, Brück O, Lusila P, Vettenranta K, Heinonen S, Jahnukainen T, Koskenvuo M, Siitonen S, Lehtimäki S, Kekäläinen E
J Clin Immunol
· 2025 Nov · PMID 41249610
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Flow cytometric immunophenotyping of lymphocytes and dendritic cells, and functional lymphocyte mitogen response tests are used in the diagnostics of inborn errors of immunity (IEI), especially in pediatrics. These routi...Flow cytometric immunophenotyping of lymphocytes and dendritic cells, and functional lymphocyte mitogen response tests are used in the diagnostics of inborn errors of immunity (IEI), especially in pediatrics. These routinely used tests lack sufficient age-matched reference values in children. We established reference values for lymphocyte and dendritic cell subsets for four age groups from 68 healthy children under 12 years of age. These values were then compared to prior publicly available articles and 46 clinical samples from children with confirmed IEI diagnosis. Mitogen response results were also compared between 27 children and 177 adults. In the literature review, we found considerable variability in lymphocyte subset definitions and statistical approaches. Most IEI patients had increased transitional and naïve B, and decreased memory B cells. CHH patients had increased γδ T and DNTs. Lymphocyte stimulation via FASCIA method provides weaker stimulation results in children than in adults, which seems to result from a larger proportional count of naïve lymphocytes in children. The established reference values can be used in diagnostics of pediatric immunological conditions in laboratories that use similar analytic methods. Lower lymphocyte mitogen response results in children need to be taken into consideration when interpreting the results of lymphocyte functional tests.
Tu Y, Li C, Li T
… +8 more, Liu J, Meng L, Liu S, Li P, Wan Y, Chen A, Shi L, Wang DY
J Clin Immunol
· 2025 Nov · PMID 41240201
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BACKGROUND: Treating neutrophilic inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) remains a challenge. Managing excessive infiltration and activation of neutrophils in tissues is important for improving...BACKGROUND: Treating neutrophilic inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) remains a challenge. Managing excessive infiltration and activation of neutrophils in tissues is important for improving CRSwNP outcomes. S100A4, a calcium-binding protein, regulates cell migration, chemotaxis and tissue fibrosis. In this study, we sought to examine the role of S100A4 in neutrophilic inflammation in CRSwNP and its involvement in TLR4 signaling. METHODS: Quantitative RT-PCR and immunofluorescence were used to analyze the expression and cellular distribution of S100A4 in sinonasal mucosa. Primary human nasal epithelial cells (hNECs) were cultured and treated with S100A4 to assess cytokine and chemokine production. Additionally, we employed TLR4 inhibitor (TAK-242) to investigate whether S100A4 exert this effect via TLR4 pathway. RESULTS: We found increased levels of S100A4 mRNA and S100A4 cell number in CRSwNP patients compared with control, with the highest levels in uncontrolled and mixed eosinophilic-neutrophilic CRSwNP. Compared to eosinophils, S100A4 exhibits a stronger correlation with neutrophils. S100A4 was primarily located in inflammatory cells in lamina propria, with neutrophils forming the majority of S100A4 cells. S100A4 treatment led to upregulation of neutrophil chemokines and pro-inflammatory cytokine IL-36γ, in nasal epithelia cells. S100A4 induced effect through TLR4 pathway, and can be inhibited by clarithromycin and dexamethasone. CONCLUSION: S100A4 is elevated in neutrophilic CRSwNP and exerts its pro-inflammatory effect on nasal epithelial cells via TLR4 signaling cascade.
Stenlander C, Lindahl H, Wahren-Borgström E
… +24 more, Geier CB, Sediva A, Fevang B, Milito C, Varandas C, Roca-Oporto C, Pulvirenti F, Hodl I, Malkusova I, Rivière JG, Litzman J, Walter JE, Hanitsch LG, Neth O, Kralickova P, Miller R, Shaffren S, Silva SL, Katzenstein T, Martelius T, Steiner UC, Smith CIE, Warnatz K, Bergman P
J Clin Immunol
· 2025 Nov · PMID 41240154
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X-linked agammaglobulinemia (XLA) is caused by loss-of-function variants in Bruton's tyrosine kinase, leading to absence of circulating B lymphocytes and inability to produce antibodies. Despite the fear that patients wi...X-linked agammaglobulinemia (XLA) is caused by loss-of-function variants in Bruton's tyrosine kinase, leading to absence of circulating B lymphocytes and inability to produce antibodies. Despite the fear that patients with XLA would be at high risk for severe infection when the novel virus SARS-CoV-2 emerged in the society with low pre-existing immunity, most patients with XLA did not suffer from severe disease. However, some patients were critically affected. Factors associated with hospitalization in patients with XLA remain poorly described. Thus, we designed a study to determine risk factors associated with hospitalization due to Covid-19 in patients with XLA. Data was collected from 17 sites in Europe and the US, comprising n = 81 patients, with hospitalization due to SARS-CoV-2 infection in 14 patients. Nearly 17% of patients with XLA required hospitalization due to Covid-19, but only 3 patients had ventilatory support. After correcting for the effect of the date of infection during the early pandemic, univariate and multiple logistic regression analysis showed that preexisting bronchiectasis and lower IgG serum trough levels (< 8 g/L) before infection were associated with an increased risk for hospitalization, with a high rate of superinfection. The lack of vaccination seemed to contribute to this risk, and ambulatory patients had higher amounts of CD4 T cells before infection compared to hospitalized patients. Thus, our data suggests a need for IgG trough levels above 8 g/L, especially in patients with bronchiectasis, to protect patients with XLA during viral infections such as Covid-19 and reduce morbidity due to superinfections.
Sormani J, Belot A, Nove-Josserand R
… +13 more, Picard C, Rosain J, Villard M, Viel S, Ouachee-Chardin M, Mercier E, Giannoli C, Moskovtchenko P, Rabeyrin M, Balme B, Durieu I, Mathieu AL, Reynaud Q
J Clin Immunol
· 2025 Nov · PMID 41219619
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Haploinsufficiency of cytotoxic T-lymphocyte associated protein 4 (CTLA4), a known cause of inborn errors of immunity, can lead to autoimmunity, inflammation, neoplasia and infections. A previously undescribed CTLA4 vari...Haploinsufficiency of cytotoxic T-lymphocyte associated protein 4 (CTLA4), a known cause of inborn errors of immunity, can lead to autoimmunity, inflammation, neoplasia and infections. A previously undescribed CTLA4 variant was identified in a patient who presented with life-threatening cutaneous infection caused by Pseudomonas aeruginosa, severe VZV infection, and Evans syndrome. Our aim was to assess the pathogenicity of the previously undescribed c.379T > G variant in the CTLA4 gene and explore its phenotypic presentation in relatives. We employed genetic and protein-based in silico analyses to evaluate the potential role of the c.379T > G variant in the CTLA4 gene. We subsequently studied CTLA4 expression ex vivo, analyzed the clinical presentation of affected carriers and compared the biological status across affected individuals, healthy carriers and noncarriers. In silico analyses revealed that the c.379T > G mutation, which is located within the ligand binding area of CTLA4, is highly pathogenic. Its clinical manifestations, which are sometimes fatal, include multiple infections, autoimmunity, inflammation of the central nervous system, lymphoproliferation and thymoma with Good's syndrome. Compared with its expression in healthy donors, the expression of CTLA4 following stimulation in memory regulatory T cells was decreased in affected individuals. Immunophenotyping revealed an increased proportion of immature and double-negative B cells in affected patients compared with their nonmutated relatives. Additionally, a reduction in naive T cells and an increase in CD4 + CD25-Foxp3 + cells were observed in carriers compared with controls. The c.379T > G variant of CTLA4, resulting in a p.Tyr127Asp substitution, is pathogenic and contributes to the development of a CTLA4 haploinsufficiency phenotype. This finding highlights the heterogeneous presentations of the disease, including oncological and neurological manifestations.
Lumry WR, Palumbo M, Hsu C
… +10 more, Hussain I, McNeil D, Bridges T, Wedner HJ, Scarupa M, Mondou E, Nanaware-Kharade N, Hanna K, Coll MQ, Oliveras J
J Clin Immunol
· 2025 Nov · PMID 41219556
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Intravenous immunoglobulin (IVIG) therapy is a well-documented and effective treatment for primary immunodeficiencies (PI). Subcutaneous immunoglobulins (SCIG) have emerged as an effective alternative for some patients t...Intravenous immunoglobulin (IVIG) therapy is a well-documented and effective treatment for primary immunodeficiencies (PI). Subcutaneous immunoglobulins (SCIG) have emerged as an effective alternative for some patients that offers additional flexibility.Currently, caprylate/chromatography purified IGSC (human) 20% is approved to treat PI in North America and many countries worldwide. In this multi-center, open-label study, the pharmacokinetics (PK), efficacy, and safety of IGSC 20% were studied after biweekly (every two weeks) dosing for 16 weeks and compared to weekly IGSC 20% administration for 16 weeks in treatment-experienced PI patients. A loading/weekly maintenance SC regimen was also studied in PI patients naïve to IG treatment.In treatment-experienced patients, the least squares mean ratio of steady-state AUC0−7 days for biweekly dosing showed non-inferiority to weekly dosing (90% confidence interval 1.0030–1.0685). Other PK parameters (Cmax, Tmax, steady state trough) were similar between treatments. Efficacy and safety measures were qualitatively similar to previously published results. No serious bacterial infections were reported. Annual rates for any type of infection were similar between the treatment groups. All severe treatment-related adverse events (AEs) were unrelated to treatment. Only mild to moderate suspected adverse drug reactions were observed.PK analyses showed that biweekly dosing of IGSC 20% was non-inferior to weekly dosing in treatment-experienced PI patients. Biweekly dosing had similar patterns to weekly in prevention of serious bacterial infections, rates of all infections and hospitalizations for infections. The IGSC loading/maintenance dosing regimen in naïve patients was safe and effective during the observation period.
J Clin Immunol
· 2025 Nov · PMID 41207983
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BACKGROUND: IgA vasculitis (IgAV) is an autoimmune disorder characterized by inflammation of the small blood vessels. The pathogenesis of IgAV is believed to involve a complex interplay between immune cells, metabolites,...BACKGROUND: IgA vasculitis (IgAV) is an autoimmune disorder characterized by inflammation of the small blood vessels. The pathogenesis of IgAV is believed to involve a complex interplay between immune cells, metabolites, and inflammatory cytokines (ICs). METHODS: We performed two-sample Mendelian randomization (MR) analysis to examine the causal relationship between immune cell traits, metabolites, ICs, and IgAV. Genetic variants associated with exposure, mediators and outcome were extracted from large-scale genome-wide association studies (GWAS). The inverse variance weighted (IVW) method was used as the primary approach, supported by MR Egger, weighted median, simple mode, and weighted mode methods. RESULTS: In this study, we identified 25 immune cells, 6 metabolites (Threonate, Carnitine C5:1, Chiro-inositol, Carnitine C18:2, 3-formylindole, Cholate to phosphate ratio) and 2 ICs (T - cell surface glycoprotein CD5, Osteoprotegerin) associated with IgAV. Meanwhile, we identified 5 immune cell-metabolites-IgAV pathways (CD28CD45RACD8dim AC-3-formylindole-IgAV; CD28 CD45RA CD8dim AC-Cholate to phosphate ratio-IgAV; CD28 CD45RA CD8br%T cell-3-formylindole-IgAV; CD25 on IgD CD38 unswmem-Chiro-inositol- IgAV; HLA DR on CD14 CD16 monocyte-Chiro-inositol-IgAV; CD39 secreting Treg %secreting Treg-Threonate-IgAV) and 4 immune cells-ICs-IgAV pathways (IgD CD38 AC-Osteoprotegerin-IgAV; CD45 on T-Osteoprotegerin-IgAV; HLA DR on CD14 CD16 monocyte-CD5-IgAV; HLA DR on CD14CD16 monocyte-CD5-IgAV). CONCLUSIONS: These results highlight the need for further research to investigate the underlying mechanisms and identify potential therapeutic targets for the treatment of IgAV.
J Clin Immunol
· 2025 Nov · PMID 41207919
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Combined immunodeficiency due to CARMIL2 mutations is a rare autosomal recessive primary immunodeficiency characterized by impaired T-cell activation and function, leading to diverse clinical manifestations. Fewer than 5...Combined immunodeficiency due to CARMIL2 mutations is a rare autosomal recessive primary immunodeficiency characterized by impaired T-cell activation and function, leading to diverse clinical manifestations. Fewer than 50 cases have been reported worldwide. We describe the clinical and genetic features of five patients from Palestine with homozygous CARMIL2 mutations, including the first documented case of recurrent visceral leishmaniasis associated with this gene defect. This retrospective case series was conducted using whole-exome sequencing to confirm the diagnosis. All patients exhibited significant immunologic symptoms, including chronic dermatitis, cutaneous warts, recurrent respiratory infections, and mucocutaneous candidiasis. Two developed cytomegalovirus-related disease. Genetic analysis revealed two novel homozygous variants: NM_001317026.3:c.1865 C > T (p.Ala622Val) in four patients, and c.1973 C > T (p.Ala658Val) in one. Notably, one adult male developed recurrent visceral leishmaniasis, an unusual presentation not previously reported in the context of CARMIL2 deficiency. Consanguinity was identified in two families. All patients required immunomodulatory therapy, and four were evaluated for hematopoietic stem cell transplantation. This case series underscores the clinical heterogeneity of CARMIL2-associated immunodeficiency and highlights the importance of genetic testing in patients with recurrent or atypical infections, particularly in populations with a high prevalence of consanguinity. The novel link to visceral leishmaniasis expands the known phenotypic spectrum of this condition.
Blom M, Duintjer AJ, Pico-Knijnenburg I
… +4 more, Imholz S, Balkassmi S, van Duyvenvoorde HA, van der Burg M
J Clin Immunol
· 2025 Nov · PMID 41203922
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PURPOSE: Patients with X-linked agammaglobulinemia (XLA) suffer from severe, recurrent infections potentially leading to life-threatening complications. Early diagnosis and timely treatment can prevent infections and sec...PURPOSE: Patients with X-linked agammaglobulinemia (XLA) suffer from severe, recurrent infections potentially leading to life-threatening complications. Early diagnosis and timely treatment can prevent infections and secondary complications, emphasizing a role for newborn screening (NBS). NBS for XLA is based on quantification of kappa-deleting recombination excision circles (KRECs). KREC-based screening could result in a large number of false-positive referrals associated with high impact for parents and health care systems, indicating the need for a second tier test. METHODS: KRECs were measured in NBS cards (N = 110,491) with a multiplex TREC/KREC qPCR assay. As second tier test options, an alternative qPCR multiplex assay, epigenetic immune cell counting for relative B-cell quantification and targeted next-generation sequencing with B-cell deficiency gene panel including 73 genes were performed on NBS cards of newborns with low KRECs. RESULTS: In total, 136/110,491 newborns had KRECs below cut-off. With the alternative qPCR multiplex assay, 16/110 of these newborns (14.5%) had KRECs above cut-off and would not have been referred. With epigenetic immune cell counting, 16.5% (17/103) had relative B-cell counts in the range of healthy controls. Targeted NGS showed promising results as 87 out of 103 (84%) newborns with low KRECs did not show any pathogenic/likely pathogenic variants and would not have been referred for follow-up diagnostics. CONCLUSION: Several second tier tests can potentially reduce the number of false-positive referrals in NBS for XLA. NGS seems to be the most effective technique in NBS for XLA and other forms of agammaglobulinemia. Our results show promising first steps towards the implementation of NBS for XLA.