J Clin Immunol
· 2026 Feb · PMID 41670926
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Wiskott-Aldrich syndrome (WAS) is a rare x-linked monogenic immunodeficiency disease, caused by the mutation of WAS gene encoding WAS protein (WASp). Previous findings in WAS patients show B cell perturbations in the per...Wiskott-Aldrich syndrome (WAS) is a rare x-linked monogenic immunodeficiency disease, caused by the mutation of WAS gene encoding WAS protein (WASp). Previous findings in WAS patients show B cell perturbations in the periphery, characterized by diminished B-cell numbers and phenotype abnormalities, including reduced frequency of classical CD27 memory B cells (MBCs), accompanied by an unusual expansion of atypical CD21low MBCs. The mechanism underlying these abnormalities in MBCs developmental pathway has not been completely dissected. In this study, WASp knock-out mice undergone with acute lymphocytic choriomeningitis virus (LCMV) infection was used as a model to investigate the effects of WASp deficiency on the differentiation of MBCs and the possible mechanisms. We found that by day 11 after infection, the proportion of classical IgG2c MBCs was dramatically decreased, this was accompanied by a corresponding increase in the proportion of atypical CD21low MBCs. Using single-cell RNA sequencing (scRNA-seq), we also identified WASp deficiency promoted the formation of atypical MBCs during acute viral infection. Remarkably, our study revealed a marked reduction of WASp expression in atypical MBCs. Overall, our data show that WASp is differentially expressed in MBCs subsets, and manipulates the fate of MBCs during acute LCMV infection.
Yang J, Li G, Zhang J
… +11 more, Wang J, Yang Y, Guo Q, Yan K, Hu H, Xue J, Ma Y, Liang J, Yao Z, Zhang H, Li C
J Clin Immunol
· 2026 Feb · PMID 41653277
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PURPOSE: Immunodysregulation, Polyendocrinopathy, Enteropathy, and X-linked (IPEX) syndrome is a rare autoimmune disorder caused by mutations in the FOXP3 gene. Patients with IPEX frequently present with severe dermatiti...PURPOSE: Immunodysregulation, Polyendocrinopathy, Enteropathy, and X-linked (IPEX) syndrome is a rare autoimmune disorder caused by mutations in the FOXP3 gene. Patients with IPEX frequently present with severe dermatitis, diabetes, and enteropathy. This study explores the efficacy of Dupilumab (an anti-IL-4Rα monoclonal antibody) in treating persistent, severe dermatitis in an IPEX patient refractory to conventional treatments like sirolimus. METHODS: We conducted a clinical case study of a 2-year-old IPEX patient with refractory dermatitis. Whole-exome sequencing (WES) confirmed the FOXP3 mutation. Skin biopsies were analyzed for inflammatory gene expression by RNA sequencing and immunohistochemistry to characterize inflammatory pathways. Immune cell phenotyping was performed using flow cytometry pre- and post-treatment in peripheral blood mononuclear cells (PBMCs). The patient was treated with Dupilumab alongside sirolimus and prednisone. Clinical improvements were evaluated using the Eczema Area and Severity Index (EASI) score. RESULTS: Immunohistochemistry revealed elevated IL-13 expression. RNA sequencing of skin samples revealed upregulation of both Th1- and Th2-related genes, suggesting a dual inflammatory phenotype in IPEX dermatitis. The patient exhibited significant clinical improvement after 8 months of sustained Dupilumab therapy, with the EASI decreasing from 24.8 to 0.4. Flow cytometry demonstrated a reduction in Th1 and Th2 cell subsets post-treatment, accompanied by an increase in Treg and Th3 cell populations as well as enhanced expression of immunosuppressive markers such as CTLA-4 and CD39. CONCLUSION: Dupilumab appears promising as a therapeutic option for managing refractory dermatitis in IPEX, particularly by attenuating Th1/Th2 inflammation and promoting regulatory responses mediated by Treg and Th3 cells.
de Winter JJH, Ibrahimov BM, Verheij FA
… +12 more, Brinkman ID, Stuut AHG, Schonewille P, Heijstek MW, van Rhenen A, van der Wagen LE, Daenen LGM, Janssen A, Hutten TJA, Kuball J, Leavis HL, de Witte MA
J Clin Immunol
· 2026 Feb · PMID 41634270
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PURPOSE: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is successful in pediatric patients with inborn errors of immunity (IEI), but its use in adults is complicated by pre-existing organ damage and incr...PURPOSE: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is successful in pediatric patients with inborn errors of immunity (IEI), but its use in adults is complicated by pre-existing organ damage and increased risk of treatment-related mortality. Ex vivo graft engineering using αβTCR/CD19 depletion has shown promising safety profiles in pediatric IEI, yet evidence in adults is limited. We assessed the feasibility and outcomes of αβTCR/CD19-depleted allo-HSCT in adults with IEI, focusing on engraftment, immune reconstitution, and clinical outcomes. METHODS: We included 9 adults with IEI and 1 with VEXAS (age 21-51). IEIs included CTLA4HI, APDS, DOCK8, ALPS, DADA2, CVID2, and HA20, with Immune Deficiency and Dysregulation Activity (IDDA) scores of 17-92. αβTCR/CD19-depleted allografts from related, unrelated or haplo-identical donors were used after antithymocyte globulin (ATG) and myeloablative conditioning (thiotepa, melphalan, and fludarabine). Post-transplant immunoprophylaxis included mycophenolate mofetil; 4/10 patients received additional transplant-associated immunosuppression. RESULTS: All patients achieved primary engraftment. One patient with secondary rejection successfully underwent a second allo-HSCT. 5 patients developed grade 2-4 acute GvHD; no chronic GvHD was observed. One patient with GvHD died from COVID-19. All remaining 9 patients were successfully tapered off immunosuppression and showed improved IDDA scores. At 6 months NK, γδT, B and CD8 + T cells normalized; CD4 + numbers reached 149 cells/µl at 1 year. Most patients were successfully vaccinated and could stop immunoglobulin substitution. CONCLUSION: In conclusion, ex vivo graft engineering using αβTCR/CD19 depletion was feasible in adults with IEI. Clinical outcomes are encouraging, but need to be confirmed in larger studies.
Alsaati N, Beigel K, Maurer K
… +9 more, Henrickson SE, Knight M, Green A, Giunta V, McGinn DE, Wang B, Crowley TB, McDonald-McGinn DM, Sullivan KE
J Clin Immunol
· 2026 Feb · PMID 41629437
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PURPOSE: 22q11.2 Deletion Syndrome has been primarily described as a disorder of T cell production secondary to thymic hypoplasia. However, there is great complexity in the clinical picture with infections, autoimmunity,...PURPOSE: 22q11.2 Deletion Syndrome has been primarily described as a disorder of T cell production secondary to thymic hypoplasia. However, there is great complexity in the clinical picture with infections, autoimmunity, and inflammation occurring. Emerging evidence suggests that qualitative T cell dysfunction occurs, and the goal of this study was to utilize single-cell RNA-seq to better define altered gene expression patterns to inform on the mechanisms associated with recurrent infections. METHODS: We utilized single-cell RNA-seq to define distinct populations in 22q11.2 Deletion Syndrome (N = 13) and controls (N = 11) as well as within a subcohort of patients with 22q11.2 Deletion Syndrome and recurrent infections. RESULTS: When we analyzed differentially expressed genes, we identified a signature of type I interferons across all cell types. Within the T cell compartment, and particularly within the follicular helper T cells, we identified a senescence signature. The alterations found in T cells were most substantial in the patients with recurrent infection. CONCLUSIONS: While T cell numbers can often normalize in patients with 22q11.2 Deletion Syndrome, our data indicate significantly altered function as defined by differentially expressed genes and aligned with what is known about T cell senescence. The effect was greatest in the patients with recurrent infection. This would be expected to impact T cell function and may account for ongoing symptoms, reduced B cell maturation, and possibly the risk of immune dysregulation.
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
· 2026 Feb · PMID 41627598
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Monsalve DM, Numpaque-Morales L, Rojas M
… +2 more, Acosta-Ampudia Y, Ramírez-Santana C
J Clin Immunol
· 2026 Feb · PMID 41627524
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SARS-CoV-2 triggers immune responses, including neutrophil activation and neutrophil extracellular trap (NET) release, contributing to COVID-19 severity. A significant proportion of patients experience persistent or new...SARS-CoV-2 triggers immune responses, including neutrophil activation and neutrophil extracellular trap (NET) release, contributing to COVID-19 severity. A significant proportion of patients experience persistent or new symptoms after recovery, referred to as post-COVID syndrome (PCS), which may be associated with NET release persistence. This study aimed to investigate whether NET-related biomarkers remain elevated after acute SARS-CoV-2 infection and to explore their association with PCS. We conducted an analytical descriptive cohort study including patients with acute COVID-19 (n = 35), PCS (n = 35), and a pre-pandemic healthy control group (PPC; n = 35). Serum samples from participants were used to measure NET biomarkers, including MPO-DNA complexes, elastase-DNA complexes, and MPO levels. The capacity to induce NETosis in vitro was evaluated by incubating neutrophils with participant serum. Additionally, soluble immune markers, including cytokines, anti-SARS-CoV-2 antibodies, and autoantibodies, were assessed. A NETosis-based model was developed using NET biomarkers to distinguish between acute COVID-19 or PCS patients and PPC individuals. Our findings revealed a significant increase in NET biomarkers during acute COVID-19 that persisted in PCS. This pattern was consistent with the in vitro study, where sera from PCS patients induced NET release. Additionally, NET biomarkers correlated with neutrophil counts, cytokines, autoantibodies, and inflammatory markers during acute COVID-19 and PCS. The multivariate model of NET biomarkers exhibited a high accuracy in distinguishing acute COVID-19 with an area under the curve (AUC) of 0.99 (CI = 0.98–1.00) and PCS patients with an AUC of 0.91 (CI = 0.84–0.99) from PPC. These findings suggest that persistent NETosis may contribute to PCS pathophysiology, highlighting NETs as potential biomarkers and therapeutic targets in post-viral syndromes.
Karaçayır N, Yazol M, Yayla ENS
… +8 more, Şenol PE, Yıldız Ç, Belder N, Kutlar M, Küçükali B, Acun B, Yıldırım DG, Bakkaloğlu SA
J Clin Immunol
· 2026 Jan · PMID 41591550
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Behçet's disease (BD) is a chronic inflammatory disorder characterized by recurrent oral aphthous ulcers, genital ulcers, skin lesions, and uveitis. Recent genetic studies have identified monogenic diseases with phenotyp...Behçet's disease (BD) is a chronic inflammatory disorder characterized by recurrent oral aphthous ulcers, genital ulcers, skin lesions, and uveitis. Recent genetic studies have identified monogenic diseases with phenotypes resembling BD, including RELA-associated inflammatory disease (RAID), Haploinsufficiency of A20 (HA20), and otulipenia. The RelA gene encodes the RELA protein, which is involved in the nuclear factor kappa B (NF-κB) signaling pathway that regulates the transcription of genes associated with cell survival, apoptosis, and immune responses. In RAID, dysfunction of the NF-κB pathway leads to reduced cell survival and symptoms of BD, such as recurrent fever, chronic mucocutaneous ulceration, arthralgia, and colitis. Herein, we report a pediatric patient who presented with recurrent, severe oral and genital ulcers from the age of five years and was diagnosed with RAID following a documented RelA gene mutation. The patient responded to a combination of corticosteroids, colchicine and methotrexate. RAID should be considered in the differential diagnosis of patients with early onset recurrent fever and mucosal ulcerations.
J Clin Immunol
· 2026 Jan · PMID 41518476
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We describe a 3-year-old patient with xeroderma pigmentosum (XP) and genetically confirmed XPA deficiency who presented with recurrent infections in early childhood. Immunological assessment revealed mild hypogammaglobul...We describe a 3-year-old patient with xeroderma pigmentosum (XP) and genetically confirmed XPA deficiency who presented with recurrent infections in early childhood. Immunological assessment revealed mild hypogammaglobulinemia with IgG2 and IgG3 subclass deficiencies, as well as impaired humoral immunity demonstrated by a reduced antibody response to repeated vaccinations against bacterial antigens. Flow cytometric analysis further showed an altered distribution of peripheral T helper (TH) cell subsets. In addition, we report a second case: a 33-year-old XP patient with ERCC4 deficiency who also exhibited IgG3 subclass deficiency and reduced response to booster vaccination. Functional studies revealed defective nucleotide excision repair (NER) following UV-C exposure, along with reduced B-cell activation capacity. These findings suggest a potential link between XP and immunoglobulin subclass deficiencies, indicating a susceptibility to infections in affected individuals. We therefore recommend that patients diagnosed with XP undergo comprehensive immunological evaluation to allow early detection of immunodeficiency and timely intervention, including booster vaccinations or prophylactic measures such as low-dose antibiotics or immunoglobulin replacement therapy when indicated.
Yorgun Altunbas M, Sefer AP, Bilgic-Eltan S
… +41 more, Yildirimcakar C, Ozturk P, Dikici Ü, Tüsüz Önata E, Atik Ö, Eke-Gungor H, Kolukisa B, Bekis Bozkurt H, Kocatepe G, Kökcü Karadağ Şİ, İlhan Yalaki A, Canitez Oral Z, Iskender N, Kıratlı Yolcu TK, Şirin D, Gumusburun R, Tekcan D, Celik IK, Can S, Amirov R, Ozturk N, Bozkurt S, Colak BC, Mahmudov R, Yalcın Gungoren E, Karabiber E, Artac H, Ardeniz O, Eser Simsek I, Çelmeli F, Arikoglu T, Özçeker D, Kocacik Uygun D, Bingol A, Tepetam FM, Özdemir Ö, Ar MC, Arik Yilmaz E, Ozen A, Baris S, Karakoc-Aydiner E
J Clin Immunol
· 2026 Jan · PMID 41493669
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Patient-reported outcomes are critical to multidisciplinary, patient-centred approaches in diseases requiring lifelong management. Among inborn errors of immunity (IEIs), reports on this subject are typically limited to...Patient-reported outcomes are critical to multidisciplinary, patient-centred approaches in diseases requiring lifelong management. Among inborn errors of immunity (IEIs), reports on this subject are typically limited to specific diagnostic subgroups or focus narrowly on the route of immunoglobulin replacement therapy (IgRT), offering a restricted perspective. We aimed to evaluate the health-related quality of life (HRQoL) and IgRT-related treatment satisfaction (TS) of a heterogeneous cohort of IEI patients and identify factors influencing these outcomes to guide improving the health and well-being of IEI patients. We conducted a cross-sectional survey targeting IEI patients on IgRT, assessing TS (TSQM-9) and HRQoL (KINDL/SF-36). Patient/caregiver-reported data were integrated with clinical data to identify outcomes and influencing factors. The survey included 500 IEI patients (356 children, 144 adults) diagnosed 54% Primary Antibody Deficiency (PAD), 36% combined immunodeficiency, 7% immune-dysregulation, and 3% other IEIs. Non-PAD diagnoses, comorbidities, absence of school/work attendance, and IgRT-related systemic adverse reactions negatively impacted HRQoL. Severe infections and related hospitalizations adversely influenced both HRQoL and TS. The subcutaneous route of IgRT, particularly at home, was associated with higher TS due to its convenience and reduced school/work absenteeism. However, the IgRT route did not influence adult HRQoL. Patient-reported well-being and satisfaction in IEIs are multifactorial and cannot be solely attributed to the route of IgRT. Minimizing negative experiences related to the disease or its treatment and, where possible, encouraging patients to maintain school/work attendance or engage in activities that promote societal participation can enhance self-esteem, coping abilities, and overall well-being.
Deng X, Gao Q, Shen K
… +10 more, Mu W, Ge T, Gu J, Yang X, Cheng J, Wang J, Zhang W, Li D, Zhou J, Xiao M
J Clin Immunol
· 2026 Jan · PMID 41483428
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The tumor necrosis factor (TNF) receptor superfamily member, transmembrane activator and CAML interactor (TACI) encoded by TNFRSF13B, are extensively involved in immune responses. In our previous work, TNFRSF13B exon 2 v...The tumor necrosis factor (TNF) receptor superfamily member, transmembrane activator and CAML interactor (TACI) encoded by TNFRSF13B, are extensively involved in immune responses. In our previous work, TNFRSF13B exon 2 variants were recurrently identified in chronic active Epstein-Barr virus disease (CAEBV). Here we aim to reveal the roles of TNFRSF13B variants in CAEBV, and investigate the feasibility of targeting TNFRSF13B/TACI as a new approach to control EBV infection. The lymphoblastoid cell lines (LCL) models carrying homozygous TNFRSF13B exon 2 frameshift mutations were constructed using CRISPR/Cas9. Immunological assays, transcriptomic analysis, and gene silencing experiments were performed on LCL models to measure the effect of TNFRSF13B exon 2 variants and explore the underlying mechanisms. TACI ligands and a TLR9 agonist were applied to modulate TACI signaling and EBV activities. Frameshift mutations in exon 2 of TNFRSF13B significantly up-regulated the short isoforms of TACI (TACI-S) at the expense of its long isoforms (TACI-L) in LCLs. The up-regulated TACI-S induced more intense activation of NF-κB, MAPK, and Rho signaling pathways, leading to the switch of EBV activities to lytic reactivation. The subsequent increased viral load and viral IL-10 provide a rational for the susceptibility of variant carriers to CAEBV. The BAFF trimer, an indirect TACI-signaling inhibitor, also significantly suppressed the EBV lytic program. Gene silencing experiments indicated that XBP-1 might be involved in the TACI-mediated regulation of EBV lytic activities in EBV-immortalized B cells. This study underscores the impact of TNFRSF13B variants on EBV infection and host immune responses, offering insights into CAEBV pathogenesis and potential therapeutic strategies.
Leonard SE, Ghanbari M, Lahousse L
… +4 more, van Meurs JBJ, van Hagen PM, Chaker L, Dalm VASH
J Clin Immunol
· 2025 Dec · PMID 41454991
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While smoking-induced epigenetic changes are increasingly recognized, the relationship between varying smoking history and immune protein profiles remains incompletely understood. This study investigates associations bet...While smoking-induced epigenetic changes are increasingly recognized, the relationship between varying smoking history and immune protein profiles remains incompletely understood. This study investigates associations between smoking history and circulating inflammatory cytokines and serum immunoglobulins, and explores DNA methylation as a potential mediator. We analyzed 2,119 participants from the Rotterdam Study, examining associations of smoking duration, pack-years, and cessation time with plasma inflammatory proteins, including six pro- and three anti-inflammatory cytokines (Olink) and three serum immunoglobulins (IgA, IgG, and IgM). Cytokines were z-transformed and multivariable (non)linear regression models were applied, adjusted for age, sex, BMI, alcohol use, and socioeconomic status. A distinct immune signature emerged, with (z-transformed) IL-6, IL-18, IL-17C, and IL-10 levels increasing with pack-years and smoking duration (β range: 0.0029 to 0.015). IgA and IgG displayed reverse J-shaped associations with pack-years (β range: –0.050 to 0.048) and levels declined with smoking duration (β = –0.0067 and –0.028, respectively). IL-6, IL-17A, and IL-10 decreased with cessation time (β range: -0.007 to -0.004), and IgG increased (β = 0.018). IgM responses differed by sex. Mediation analysis using PCA-derived CpG components did not support a role for DNA methylation in these associations. These findings reveal dose-dependent, pro-inflammatory immune dysregulation with cumulative smoking exposure and partial reversibility of IL-6 and IgG following cessation. The absence of mediation by DNA methylation suggests other pathways are involved. These findings support the use of cytokines and immunoglobulins as biomarkers for immune surveillance and recovery monitoring, reflecting an underlying inflammatory smoking signature.
Zhang X, Song X, Fang L
… +8 more, Zang B, Li J, Yang Y, Xu M, Han Y, Liu Q, Zhu H, Liu B
J Clin Immunol
· 2025 Dec · PMID 41454184
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OBJECTIVE: The presence of unique monocyte subsets and sub-populations plays a significant role in the onset and progression of rheumatic diseases. This study aimed to characterize variations in monocyte subsets and sub-...OBJECTIVE: The presence of unique monocyte subsets and sub-populations plays a significant role in the onset and progression of rheumatic diseases. This study aimed to characterize variations in monocyte subsets and sub-populations and functional roles in patients with primary Sjögren's syndrome (pSS) using single-cell RNA sequencing (scRNA-seq). METHOD: Monocyte samples from patients with pSS and healthy controls (HCs) were analyzed using single-cell RNA sequencing (scRNA-seq). This approach identified divergent gene expression patterns, transcription factors, and immune cells interactions within monocyte subset and sub-populations, highlighting pathways potentially involved in the pathogenesis of pSS. RESULTS: The scRNA-seq analysis delineated three major monocyte subsets: classical monocytes (CD14CD16), non-classical monocytes (CD14CD16), and cDC2, with further identification of sub-populations within the classical and non-classical monocyte subsets. A notable increase in the proportions of classical monocyte sub-population 2 and non-classical monocyte sub-population 2 was observed in pSS patients. Compared to the HCs, pSS patients exhibited enhanced immune cell interactions within monocyte subsets. Furthermore, in pSS patients, the dominant increased pathways within monocytes were those related to viral responses, interferon activity, and oxidative phosphorylation. Additionally, significantly elevated expression levels of IFI44, IFI44L, HBA2, LY6E, XAF1, EPSTI1, APOBEC3A, and IFIT3 were identified in pSS monocytes. CONCLUSION: This research revealed irregular alterations in monocyte subsets and sub-populations, transcription factors, and gene expression patterns within pSS patients, pinpointing prospective biomarkers in pSS as viable targets for therapeutic intervention.
Luo Y, Argüello G, Acevedo D
… +13 more, Jou C, Codina A, Márquez J, Vlagea A, Peiró S, Bolaño V, Freixedas A, Deyà-Martínez A, García-García A, Martí-Castellote C, Juan M, Esteve-Solé A, Alsina L
J Clin Immunol
· 2025 Dec · PMID 41452432
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Type II interferon (IFN) immunity is crucial for controlling intramacrophagic infections, driven by the interaction between innate immunity (macrophage-derived IL-12) and adaptive immunity (Th-derived IFN-γ). This study...Type II interferon (IFN) immunity is crucial for controlling intramacrophagic infections, driven by the interaction between innate immunity (macrophage-derived IL-12) and adaptive immunity (Th-derived IFN-γ). This study examines the maturation of type II IFN immunity in 55 healthy children (ages 1-18) to enable proper identification of deficiencies as part of the diagnostic evaluation of Mendelian Susceptibility to Mycobacterial Diseases (MSMD). The IL-12/IFN-γ axis was assessed through: (1) cytokine production after mycobacterial stimulation (Luminex and ELISA for IFN-γ, IL-12p70, TNF, CXCL10, IL-1RA, IL-10, IL-1β and IL-6), (2) IFN-γR1/R2 expression on monocytes, and (3) STAT1 phosphorylation/dephosphorylation. T cell maturation (primary IFN-γ source) was evaluated via immunophenotyping (naïve/memory/activated, Th1; Th2; Th17; Th1/17; Tfh) and proliferation assays. Main findings: (1) stable expression/production of key components of the IL-12/IFN-γ axis (IFN-γ, IL-12, TNF, IFN-γR1/2, and STAT1 activity) across ages confirming the stability of innate immune function throughout childhood; (2) increasing responses to IFN-γ with age reflected by increased CXCL10 production, and increase in the IFN-γ counter-acting anti-inflammatory cytokines (IL-10, IL-1RA); and (3) progressive T cell maturation, including Th1, Th17 and Th1/17 subsets, with significant milestones between 6 and 8.6 years, while T cell proliferative capacity remained stable. These observations highlight the stability of IL-12/IFN-γ axis innate components with age, accompanied by enhanced downstream IFN-γ signaling, aligning with the maturation of Th cell compartment. These underscore the limited benefit of age-specific controls in the evaluation of IL-12/IFN-γ axis in MSMD diagnosis, while emphasizing the importance of T cell maturation in the overall type II IFN immunity.
Kunc M, Whitehead BJ, Østergaard LJ
… +4 more, Tolstrup M, Benn CS, Wejse CM, Nejsum P
J Clin Immunol
· 2025 Dec · PMID 41436670
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Trained immunity, a de-facto innate immune memory, has been extensively studied in response to live-attenuated vaccines, but its presence following the new COVID-19 vaccines has not yet been fully elucidated. In this stu...Trained immunity, a de-facto innate immune memory, has been extensively studied in response to live-attenuated vaccines, but its presence following the new COVID-19 vaccines has not yet been fully elucidated. In this study, we investigate markers of trained immunity in individuals vaccinated with mRNA-1273 or BNT162b2. As part of the vaccine roll-out in Denmark and recruited for a comparative study. Our primary objective was to determine whether these vaccines elicit lasting changes in innate immune responses, particularly in monocyte populations and cytokine production following stimulation with a panel of agonists. The study was conducted at four time points: Day-0 (pre-vaccination), Day-28, Day-90, and Day-180 post-vaccination. We observed no significant differences in monocyte subpopulations between vaccine groups; however, cytokine and chemokine analysis revealed distinct immune signatures. While IL-6 and TNFα production remained unchanged after ex-vivo restimulation in the BNT162b2 group, individuals vaccinated with mRNA-1273 exhibited a sustained increase in the production of these cytokines, persisting for up to 180 days post-vaccination. Additionally, CCL2, a key chemokine involved in monocyte recruitment, was upregulated following mRNA-1273 vaccination but decreased in the BNT162b2 group, further supporting the finding of differential innate immune responses between the two vaccines. In conclusion, our study provides evidence that mRNA-1273, but not BNT162b2, induces immune responses consistent with the concept of trained immunity. These results highlight the potential for mRNA vaccine platforms to shape innate immunity, with implications for future vaccine design aimed at enhancing non-specific and specific protection against infectious diseases.
Xu K, Zhang B, Zhao S
… +4 more, Zhang Y, Wu N, Shen M, Zeng X
J Clin Immunol
· 2025 Dec · PMID 41390883
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PURPOSE: Pathogenic variants in BTK cause X-linked agammaglobulinemia (XLA), yet some cases remain undiagnosed despite extensive genetic testing. Additionally, autoimmune complications have been increasingly reported, bu...PURPOSE: Pathogenic variants in BTK cause X-linked agammaglobulinemia (XLA), yet some cases remain undiagnosed despite extensive genetic testing. Additionally, autoimmune complications have been increasingly reported, but the underlying etiology is still unclear. This study aimed to use RNA sequencing (RNA-seq) to resolve an undiagnosed case and characterize transcriptomic features associated with disease mechanisms of XLA. METHODS: We performed genome sequencing and RNA-seq, detected outliers against 89 controls to identify disease-causing variants, and validated functional consequences through RT-PCR. We further conducted gene set enrichment analysis (GSEA) to delineate the transcriptomic features of XLA. RESULTS: We recruited an 18-year-old male who experienced recurrent infections since infancy but developed idiopathic portal hypertension recently. He had received four noninformative genetic test results. RNA-seq enabled the identification of significantly decreased BTK expression caused by a de novo hemizygous variant (NM_000061.3:c.-32A > G) located in the 5’ UTR. Outlier analysis revealed reduced expression of genes critical for not only immunoglobulin synthesis, but also T-cell development and inflammation intensification, such as IGHM, TRBV24-1, and PLVAP. GSEA additionally revealed significant enrichment in pathways associated with immune response and inflammatory response, suggesting broader immune dysregulation. These findings align with the growing recognition of autoimmune complications in XLA. CONCLUSION: This study emphasizes the clinical utility of RNA-seq and provides a comprehensive expression profile of XLA. These findings can guide future molecular analyses in undiagnosed cases and enhance understanding of autoimmune complications in XLA, suggesting a Multidisciplinary Team approach in both diagnostic and treatment processes.
Bergmans B, Fontane Pennock-Janssen L, van Puijenbroek E
… +4 more, van Hout R, Murk JL, de Vries E, unPAD consortium
J Clin Immunol
· 2025 Dec · PMID 41384995
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INTRODUCTION: Primary 'predominantly antibody deficiencies' (PADs) are rare disorders characterized by increased susceptibility to infections, autoimmunity, allergies, and malignancies. Their low prevalence and heterogen...INTRODUCTION: Primary 'predominantly antibody deficiencies' (PADs) are rare disorders characterized by increased susceptibility to infections, autoimmunity, allergies, and malignancies. Their low prevalence and heterogeneity often delay diagnosis, increasing morbidity and mortality. This study identifies infection patterns in PAD patients and analyzes predictors of bronchiectasis presence at PAD diagnosis (BPAD), aiming to facilitate early diagnosis and improve prognosis. METHODS: Using fully monitored data on PAD patients without identified genetic origin from the ESID Registry, infection types and pathogens across PADs were compared (chi-square analysis) and predictive factors for BPAD were identified (generalized mixed-effects logistic regression). Additionally, five machine learning classifiers (logistic regression, (bagged) decision tree, random forest and support vector machines) were trained and evaluated by area under the receiver operating characteristics curve (ROC-AUC), confusion matrices and F1-score. RESULTS: Recurrent respiratory infections were predominant in our cohort of 861 patients from 11 centers. Cultures were conducted in only 5.9-12.3% of infections. Encapsulated bacteria were most frequently isolated. The number of organ systems affected by recurrent infections, occurrence of specific serious bacterial infections, number of identified encapsulated bacteria and common variable immunodeficiency disorders (CVID) diagnosis were predictive of BPAD. Machine learning models achieved moderate discrimination (ROC-AUC range 0.679-0.746). DISCUSSION: This study highlights the predominance of recurrent and encapsulated bacterial respiratory tract infections in PAD and the underutilization of microbiological cultures. Generalized mixed-effects logistic regression best predicted BPAD. Clinicians should consider immunologic evaluation in patients presenting with serious bacterial infections, multi-system recurrent infections or the repeated isolation of encapsulated bacteria in unusually severe or recurrent infections.
Humer B, Berentschot JC, van Helden-Meeuwsen CG
… +8 more, Bek LM, de Bie M, Defesche TM, Boly CA, Drost M, Hellemons ME, Dik WA, Versnel MA
J Clin Immunol
· 2025 Dec · PMID 41372563
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PURPOSE: Long COVID (LC) is a long-term debilitating disease of which the exact pathophysiology is unknown. A dysregulated immune response resulting in hyperresponsive immune cells is hypothesized as a key mechanism in t...PURPOSE: Long COVID (LC) is a long-term debilitating disease of which the exact pathophysiology is unknown. A dysregulated immune response resulting in hyperresponsive immune cells is hypothesized as a key mechanism in the development of LC. Several studies suggest that acute infections can leave lasting epigenetic changes, which result in heightened immune reactivity. Upon stimulation, these primed immune cells may exhibit exaggerated responses. This form of epigenetic memory can contribute to altered immune dynamics, particularly in response to induction of type I Interferons (IFN-I) pathway activation using a viral mimic. Therefore, we investigated if LC patients exhibit a hyperresponsive response towards viral mimics in comparison with healthy controls (HC). METHODS: PBMCs of two distinct LC cohorts, characterized by a different disease course and duration, were collected and transfected using Lyovec with the cGAS and RIG-I agonists G3-YSD and 3p-RNA followed by measurement of IFN-I bioactivity with a reporter cell line. RESULTS: Transfection of PBMCs of LC patients with the cGAS and RIG-I agonists resulted in increased IFN-I bioactivity in comparison with HC. Unsupervised hierarchical clustering revealed two distinct clusters, each predominantly composed of either patients or HC. In addition, a moderate correlation between RIG-I stimulation with 3p-RNA and fatigue severity scores was found. CONCLUSION: These data show a hyperresponsive phenotype of immune cells of LC patients upon stimulation with viral mimics. The current availability of biologicals and small molecule inhibitors that interfere with aberrant IFN-I pathway activation underscores the importance of pursuing future investigations into this phenomenon.