Clin Exp Immunol
· 2025 Jan · PMID 41039842
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Children with recurrent infections present a diagnostic challenge due to the wide overlap between normal childhood infections and primary immunodeficiency diseases. Predominantly antibody deficiencies are the most common...Children with recurrent infections present a diagnostic challenge due to the wide overlap between normal childhood infections and primary immunodeficiency diseases. Predominantly antibody deficiencies are the most common category of primary immunodeficiency disease in this population. While many predominantly antibody deficiency cases are identified through markedly low immunoglobulins levels or reduced B cell counts, some demonstrate subtler forms such as IgG subclass deficiency or specific antibody deficiency, which may present similar clinical symptoms but normal standard laboratory parameters. Diagnosing these conditions in children is particularly challenging due to the overlap with physiological immune immaturity and the high incidence of infections in early childhood. Clinicians must carefully distinguish between benign infection patterns and true immunodeficiencies to avoid missed diagnoses and unnecessary investigations. This review summarizes key findings on IgG subclass deficiency and specific antibody deficiency, highlights their clinical relevance in paediatric practice, and evaluates current challenges in diagnosis and classification. We also discuss the overlap between these conditions and propose a structured approach to improve diagnostic consistency. Addressing these knowledge gaps is essential to optimize care for children with recurrent infections and suspected antibody deficiencies.
Bagkou Dimakou D, Peters NE, Burns SO
… +2 more, Richter AG, Shields AM
Clin Exp Immunol
· 2025 Jan · PMID 41017320
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B-cell maturation antigen (BCMA) is a B cell surface receptor that regulates B cell activation, proliferation and survival. BCMA can be cleaved from the cell surface, producing soluble BCMA (sBCMA), which has been studie...B-cell maturation antigen (BCMA) is a B cell surface receptor that regulates B cell activation, proliferation and survival. BCMA can be cleaved from the cell surface, producing soluble BCMA (sBCMA), which has been studied as a disease biomarker in systemic lupus erythematosus, multiple sclerosis and multiple myeloma. Reduced sBCMA concentrations have been associated with the severity of different primary antibody deficiencies. We explored the relationship between sBCMA concentrations, humoral immune responses to SARS-CoV-2 vaccination and disease complications in 107 individuals with primary (PAD) and secondary antibody deficiency (SAD) enrolled in the COVID-19 in Antibody Deficiency (COV-AD) study. Serum sBCMA concentrations were significantly reduced in PAD compared to healthy controls and asymptomatic selective IgA deficiency. Individuals with X- linked agammaglobulinemia and common variable immunodeficiency (CVID) demonstrated the lowest serum concentrations of sBCMA. sBCMA concentrations in SAD were highly variable. Amongst individuals with CVID, peripheral blood CD19 count, but not sBCMA concentrations discriminated SARS-CoV-2 vaccine responders. sBCMA was significantly lower in individuals with CVID and bronchiectasis and outperformed serum IgA and IgM concentrations in discriminating this subgroup. sBCMA was not associated with any other complication of CVID. Our data highlights the potential of sBCMA as biomarker to support the assessment of antibody deficiency. In PAD, sBCMA may contribute to the risk stratification of disease severity and identify those at risk of bronchiectasis. In SAD, it may identify subgroups that would benefit from intensive monitoring and therapy.
Tene H, Ngamaleu R, Djounda R
… +9 more, Minomo R, Ngale S, Besong M, Awanakam H, Nganou-Makamdop K, Essomba R, Bigoga J, Douek DC, Esemu Livo F
Clin Exp Immunol
· 2025 Jan · PMID 40982477
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Cytokine storm can result from uncontrolled pro-inflammatory cytokines released in SARS-CoV-2 infection that cause damage to several organs. Il-6 is one of the major mediators of cytokine storm. IFN-α2 has been reported...Cytokine storm can result from uncontrolled pro-inflammatory cytokines released in SARS-CoV-2 infection that cause damage to several organs. Il-6 is one of the major mediators of cytokine storm. IFN-α2 has been reported to have anti-viral potential and the pre-infection levels of pro-inflammatory cytokines have been suggested to drive the fate of the disease. There is a paucity of information on how anti-viral cytokines at the onset of infection affect the disease progression. This study aims to profile IL-2, IL-6, IL-10, and IFN-α2 expression levels for 44 days post-diagnosis and their effects on recovery. Peripheral venous blood was collected from 38 SARS-CoV-2 infected participants who came for diagnosis at the Centre for Research on Emerging and Re-emerging Diseases. IL-2, IL-6, IL-10, and IFN-α2 levels were measured using a Luminex panel. Males had higher SARS-CoV-2 viral load than females, although the difference was not statistically significant (P = 0.08). Age-related variation was also observed, with individuals aged 40-60 showing significantly higher viral load than those over 60 (P = 0.045). Cytokines analysis revealed that males had significantly higher levels of IFNα-2, IL-2, and IL-6 (P = 0.0031, P = 0.009, and P = 0.022 respectively) than females upon diagnosis, with cytokines levels decreasing over time in males but increasing in females. Cytokine levels trended higher in symptomatic individuals, although differences were not significant. These findings highlight the influence of sex, clinical status, and viral load on cytokine dynamics in COVID-19, with potential implications for understanding disease severity and immune response.
Adeniran AA, Giovannoni G, Baker D
… +1 more, James LK
Clin Exp Immunol
· 2025 Jan · PMID 40971810
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Epstein-Barr virus (EBV) is a ubiquitous herpesvirus with well-established oncogenic potential, contributing to various malignancies and immune-mediated diseases. Its capacity to infect and immortalize B-cells forms the...Epstein-Barr virus (EBV) is a ubiquitous herpesvirus with well-established oncogenic potential, contributing to various malignancies and immune-mediated diseases. Its capacity to infect and immortalize B-cells forms the basis for the generation of lymphoblastoid cell lines (LCLs), which serve as vital models in immunology, virology, and translational research. While conventional LCLs are produced by exogenous EBV infection of peripheral blood mononuclear cells, spontaneous lymphoblastoid cell lines (S-LCLs) can emerge without deliberate viral inoculation, particularly in EBV-seropositive individuals. This review highlights multiple methodologies used to establish S-LCLs, including the use of cyclosporin A, CpG DNA, checkpoint kinase inhibitors, and cytokine modulation, and presents findings from diverse clinical contexts such as autoimmune diseases, post-transplant lymphoproliferative disorders, and cancer. We discuss the biological mechanisms underpinning EBV latency and reactivation, emphasizing the viral transcriptional programmes that drive B-cell transformation and persistence. Additionally, we explore how cytokines, particularly IL-10, support S-LCL survival, and how sodium butyrate and antiviral agents like acyclovir can influence EBV reactivation and replication. The review also considers the diagnostic and therapeutic relevance of LCLs, including their potential as antigen-presenting cells, vaccine platforms, and models for cellular immunotherapies such as CAR T-cells and virus-specific cytotoxic T lymphocytes. By evaluating the generation, molecular features, and immunological significance of S-LCLs, this review underscores their value in modelling EBV-driven disease and advancing novel therapeutic strategies.
Fiz-López A, De Prado Á, Arribas-Rodríguez E
… +10 more, G Del Hierro A, G de Castro C, Izquierdo S, Martín-Muñoz Á, Corrales-Cruz D, Cuesta-Sancho S, Garrote JA, Arranz E, Fernández-Salazar L, Bernardo D
Clin Exp Immunol
· 2025 Jan · PMID 40923099
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INTRODUCTION: Although celiac disease (CD) current and only treatment is a life-long strict gluten-free diet (GFD), some patients suffer from persistent duodenal lesions despite years into the diet. Hence, we aimed to st...INTRODUCTION: Although celiac disease (CD) current and only treatment is a life-long strict gluten-free diet (GFD), some patients suffer from persistent duodenal lesions despite years into the diet. Hence, we aimed to study the effect that the GFD elicits on the mucosal immune infiltrate from these patients. METHOD: To that end, duodenal biopsies were collected from non-celiac controls and CD patients, both at diagnosis and after at least one year into the GFD. The profile of duodenal intraepithelial lymphocytes (lymphogram) and the lamina propria immune infiltrate were determined by spectral cytometry. RESULTS: At diagnosis, all CD patients had mucosal atrophy, a compatible lymphogram, and an expansion of lamina propria NK cells, innate lymphoid cells, B-cells, Treg and Tγδ cells, all of them expressing high levels of Fas, and Integrins α4 and β7. However, despite all GFD-treated patients had negative serology, 68.4% of them displayed persistent villous atrophy (Marsh score ≥ 3), while 73.3% had a compatible lymphogram. Nevertheless, despite such persistent atrophy, the lamina propria mucosal immune infiltrate was normalized in all GFD-treated patients. Besides, time on the GFD, but not the persistence of mucosal atrophy, correlated with an increased expression of gut-homing migration markers on lamina propria effector T-cells from these patients. CONCLUSION: Hence, we hereby have proved how the lamina propria immune infiltrate, as opposed to intraepithelial lymphocytes, is normalized in GFD-treated CD patients despite persistent villous atrophy, suggesting that the epithelial layer may be the driver of such paradoxical persistent mucosal inflammation.
Peters AT, Han JK, Heffler E
… +7 more, McClenahan F, Caveney S, Le TT, Megally A, Spahn JD, Foster A, Sherrill JD
Clin Exp Immunol
· 2025 Jan · PMID 40919679
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Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disorder of the sinonasal mucosa, predominantly characterized by epithelial dysfunction and chronic heterogeneous mucosal inflammation. CRSwNP and asth...Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disorder of the sinonasal mucosa, predominantly characterized by epithelial dysfunction and chronic heterogeneous mucosal inflammation. CRSwNP and asthma are common comorbidities with overlapping pathophysiology, epithelial impairment, and activation of downstream type 2 inflammation. Thymic stromal lymphopoietin (TSLP) is an epithelial cytokine that sits at the top of the immunological cascade and initiates and amplifies type 2-dependent and -independent inflammatory responses. Although the role of TSLP in asthma has been well described, the role of TSLP in CRSwNP has yet to be comprehensively outlined. This review examines the evidence for TSLP as a key factor in CRSwNP pathogenesis. We explore what is known about TSLP expression patterns within the sinonasal mucosa, finding that TSLP expression is increased in patients with CRSwNP compared with healthy patients, and in eosinophilic- versus non-eosinophilic CRSwNP. We discuss the impact of environmental triggers and genetic factors on TSLP expression and activity, as well as other upstream regulators of TSLP signaling. We then consider the known mechanisms and effects of TSLP signaling on the recruitment and activation of various immune and structural cell types in CRSwNP. Finally, we consider the available evidence on the therapeutic potential of targeting TSLP signaling for the treatment of CRSwNP and discuss ongoing trials of promising therapeutic candidates.
Clin Exp Immunol
· 2025 Jan · PMID 40919665
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We attempted to perform a comprehensive bioinformatics analysis on osteoarthritis (OA) based on the NKT-related genes and explore the clinically related critical genes. Differentially expressed genes (DEGs) and NKT-relat...We attempted to perform a comprehensive bioinformatics analysis on osteoarthritis (OA) based on the NKT-related genes and explore the clinically related critical genes. Differentially expressed genes (DEGs) and NKT-related genes from WGCNA were obtained using the dataset GSE114007, followed by intersection analysis to obtain NKT-related DEGs. Lasso regression, support vector machine, and random forest were performed to screen feature genes, followed by verification with receiver operator curves and a nomogram model. Protein-protein interaction network, gene set enrichment analysis was performed based on the four marker genes. Finally, the immune infiltration of 64 types of immune cells was analyzed between OA samples and normal samples. The significance of biomarkers was validated in clinical samples and OA mice models. A total of four NKT-related biomarker genes (CCNJ, CFI, PREX2, and SMIM13) were identified. These genes were all upregulated in OA samples. CFI exerted promising diagnostic value for OA with an AUC of 0.994 in GSE114007 training dataset and 0.98 in the validation dataset. A significantly negative correlation between CFI and NKT cells and a significantly positive correlation between CFI and conventional dendritic cells (cDC) were found. All the biomarkers were determined to be upregulated in OA patients by clinical samples. CFI knockdown significantly reduced DC infiltration and inflammation in the knee joints of OA mice models. CFI has potential value in the pathogenesis of OA and can be used as a candidate biomarker for OA diagnosis and treatment.
Naigeon M, Bitoun S, Roulleaux Dugage M
… +8 more, de Oliveira C, Berthot C, Besse B, Marabelle A, Danlos FX, Mariette X, Chaput N, Nocturne G
Clin Exp Immunol
· 2025 Jan · PMID 40916834
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Using flow cytometry, we assessed circulating T4sen and T8sen proportions at baseline and 3 months after initiating anti-TNF treatment in RA and SpA patients using flow cytometry. Circulating levels of cytokines were mea...Using flow cytometry, we assessed circulating T4sen and T8sen proportions at baseline and 3 months after initiating anti-TNF treatment in RA and SpA patients using flow cytometry. Circulating levels of cytokines were measured at baseline. These parameters were associated with demographic variables and disease activity. T4sen and T8sen were compared between RA, SpA, SjD, healthy donors, and cancer patients. T8sen, but not T4sen, accumulated more in patients with IMIDs than in patients with lung cancer and healthy donors. CMV-seropositivity was associated with the accumulation of T8sen. T8sen were associated with high IL-6 in SpA patients and high IP-10 in SjD patients. Anti-TNF did not impact the T8sen proportion of RA and SpA patients. There was a trend toward an increase in T8sen in anti-TNF nonresponders after 3 months of treatment. Senescent CD8 T cells are enriched in IMID patients, suggesting that immune aging is a shared feature of chronic inflammatory diseases. The association between T8sen and distinct inflammatory cytokines underscores the potential role of senescence in shaping immune responses in IMIDs.
Peters NE, Shields AM, Hambleton S
… +1 more, Richter AG
Clin Exp Immunol
· 2025 Jan · PMID 40916471
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Since its discovery in the late 18th century, the role of vaccination in preventing death and disease has expanded across many infectious diseases and cancer. Key to our understanding of vaccine immunogenicity and effica...Since its discovery in the late 18th century, the role of vaccination in preventing death and disease has expanded across many infectious diseases and cancer. Key to our understanding of vaccine immunogenicity and efficacy is knowledge of the immune system itself. Inborn errors of immunity (IEI) represent a heterogeneous group of disorders characterized by impaired function of the immune system. Patients with IEI can have variable responses to vaccinations, depending on the nature and extent of the defect. Studies performed during the recent COVID-19 pandemic have brought unique insight into vaccine immunogenicity in individuals with IEI, knowledge that can be extended to the growing number of patients with secondary immunodeficiency arising from malignancy, organ transplantation, autoimmune conditions, and their treatments. In this review, we describe vaccine immunogenicity in IEI alongside their equivalent secondary immunodeficiencies and discuss what lessons can be learned about immunization strategies more broadly.
Kurimoto M, Watanabe T, Otsuka Y
… +11 more, Hara A, Omaru N, Sekai I, Masuta Y, Masaki S, Kamata K, Minaga K, Honjo H, Arai Y, Yamashita K, Kudo M
Clin Exp Immunol
· 2025 Jan · PMID 40916456
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Conventional dendritic cells (cDCs) in the gut express the vitamin A (VA)-converting enzyme retinal dehydrogenase 2 (RALDH2) and produce significant amounts of retinoic acid (RA). RA derived from gut cDCs contributes to...Conventional dendritic cells (cDCs) in the gut express the vitamin A (VA)-converting enzyme retinal dehydrogenase 2 (RALDH2) and produce significant amounts of retinoic acid (RA). RA derived from gut cDCs contributes to the generation of tolerogenic responses by promoting regulatory T-cell (Treg) differentiation while inhibiting Th1 and Th17 cell differentiation. In this study, we investigated whether similar RA-mediated immunoregulatory mechanisms operate in the pancreas using an experimental autoimmune pancreatitis (AIP) model. Our previous studies have shown that activated cDCs and plasmacytoid DCs (pDCs) play crucial roles in the induction and maturation phases of experimental AIP, respectively. Pancreatic cDCs produce IFN-α/β, CXCL9, and CXCL10, which attract CD4+CXCR3+ T cells to the pancreas during the induction phase. These CD4+CXCR3+ T cells, in turn, produce CCL25, recruiting CCR9+ pDCs that secrete IFN-α/β, CXCL9, and CXCL10 during the maturation phase. Under homeostatic conditions, RALDH2 expression was higher in pancreatic cDCs than in pDCs. Pancreatic cDCs isolated from VA-deficient mice promoted CD4+ T-cell production of IFN-γ and CCL25-the latter being a chemokine implicated in AIP pathogenesis. VA deficiency increased susceptibility to experimental AIP through a process dependent on the pancreatic accumulation of CD4+CXCR3+ T cells producing CCL25. Conversely, activation of RA-mediated signaling pathways by Am80 protected mice from severe AIP by reducing the accumulation of CXCR3+ T cells producing CCL25. Collectively, these findings suggest that RA produced by cDCs protects against AIP development by inhibiting the pancreatic accumulation of CD4+CXCR3+ T cells. RA-mediated immunoregulation may serve as a potential therapeutic target for AIP.
Wu W, Yue S, Wang X
… +4 more, Li W, Xu L, Guan Y, Liang CZ
Clin Exp Immunol
· 2025 Jan · PMID 40887935
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Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent urological disorder characterized by urinary symptoms, pelvic pain, and sexual dysfunction. The potential inhibitory effects of docosahexaenoic ac...Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent urological disorder characterized by urinary symptoms, pelvic pain, and sexual dysfunction. The potential inhibitory effects of docosahexaenoic acid (DHA) in relation to dietary consumption on autoimmune disorders have been acknowledged. Nevertheless, the effect of consuming DHA on CP/CPPS is still uncertain. Therefore, we established an experimental autoimmune prostatitis (EAP) model, which is frequently employed in CP/CPPS research. This study aimed to investigate the effects of dietary docosahexaenoic acid (DHA) intake on EAP and to elucidate the underlying mechanisms involved. During the establishment of EAP, non-obese diabetic (NOD) mice were administered either DHA-enriched water or conventional water. The severity of EAP and the Th17 cell responses were evaluated. Furthermore, we investigated the impact of the PPARγ inhibitor GW9662 and the NF-κB activator PMA on mice with EAP that were administered DHA. The findings demonstrated that consumption of DHA reduced the severity of EAP and inhibited the production of Th17 cells. DHA was found to hinder the development of Th17 cells through the PPARγ/NF-κB/IL-17A pathway, as demonstrated by in vitro assays. The administration of GW9662 and PMA resulted in an increase in Th17 cell production, worsening the symptoms of EAP alleviated by the consumption of DHA. The present study revealed that the consumption of DHA mitigates EAP by stimulating the PPARγ/NF-κB/IL-17A pathway, thereby influencing the process of Th17 cell differentiation. The results provide a valuable understanding of the molecular pathways that contribute to the beneficial impacts of dietary variables, including DHA, on CP/CPPS.
INTRODUCTION: We describe the immunophenotyping and genetic analysis of HIV-uninfected apparently immunocompetent adults presenting with disseminated cryptococcosis. Cryptococci are environmentally ubiquitous fungi that...INTRODUCTION: We describe the immunophenotyping and genetic analysis of HIV-uninfected apparently immunocompetent adults presenting with disseminated cryptococcosis. Cryptococci are environmentally ubiquitous fungi that may cause disseminated infection including meningitis. Cryptococcosis occurs predominantly in immunocompromised hosts and most commonly in the context of human immunodeficiency virus (HIV) infection. In apparently immunocompetent patients, cryptococcal disease is rare, often diagnosed later and associated with higher mortality. The immunologic work-up and management of this patient group is challenging and poorly studied. METHODS: Between 2015-2021, eight apparently immunocompetent adults at the time of diagnosis with cryptococcosis underwent extensive diagnostic immunological work-up including T-/B-cell subsets, immunoglobulins, T-cell proliferation and phenotyping, serum-specific antibody responses, mannose binding lectin, measurement of selected cytokines, anti-cytokine autoantibodies and targeted genetic next-generation sequencing. RESULTS: The production of interleukin (IL)-17 following phytohaemagglutinin (PHA) stimulation was significantly reduced in all eight patients with cryptococcosis compared to healthy controls (median IL-17 concentration in whole blood stimulation assay 88.1pg/mL in patients; 452.1pg/mL in controls, p=0.0047). In 5/5 patients tested, the percentage of CD4+ T-cells positive for IL-17, including memory CD4+CD45RO+ IL-17+ T-cells, after stimulation with staphylococcal enterotoxin B (SEB) was significantly reduced (<=0.4% cells). Reduced IgM+ memory B-cells were noted in 4/5 tested. 4/8 patients were found to have CD4 lymphopaenia. One patient with Cryptococcus gattii infection had autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). No underlying genetic causes were identified. CONCLUSION: Patients had several immunological risk factors, but reduced IL-17 production was a striking feature across the cohort - a phenotype that may facilitate tailored immunotherapeutic approaches.Graphical Abstract.
Meng Y, Zhang F, Jin Y
… +4 more, Wen Z, Chen F, Jiang N, Liao H
Clin Exp Immunol
· 2025 Jan · PMID 40838424
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Recent studies on cancer cells and the immune microenvironment have offered valuable insights into personalized diagnostics, targeted therapies, and individualized prognosis evaluation. A comprehensive understanding of n...Recent studies on cancer cells and the immune microenvironment have offered valuable insights into personalized diagnostics, targeted therapies, and individualized prognosis evaluation. A comprehensive understanding of new and existing biomarkers in both healthy and diseased conditions is essential for advancing these goals. CD56, also known as the neural cell adhesion molecule, is a well-established phenotypic marker of natural killer cells. It is also expressed by various immune cells under healthy conditions, such as T cells, dendritic cells, and monocytes. Despite its widespread expression, the functions of CD56 are still poorly understood. In patients with infectious, autoimmune, or malignant diseases, changes in the proportion, phenotype, and function of CD56+ immune cells have been observed. In patients with hematolymphoid disorders, malignant cells may exhibit aberrant CD56 expression, making it a valuable diagnostic and prognostic marker. CD56 also holds potential as a therapeutic target. In this review, we summarize the current understanding of CD56 expression and function across various immune cells in infectious, immune-related, and cancerous conditions. We also explore its diagnostic, prognostic, and therapeutic significance in hematological malignancies. This review aims to present a comprehensive overview of CD56 in hematolymphoid disorders, offering insights into how CD56 and its associated immune cells could inform future immunotherapeutic strategies.
Gamma-aminobutyric acid receptors (GABARs) primarily function by suppressing inflammatory responses, modulating neuronal excitability, and maintaining intracellular homeostasis, whereas N-methyl-D-aspartate receptors (NM...Gamma-aminobutyric acid receptors (GABARs) primarily function by suppressing inflammatory responses, modulating neuronal excitability, and maintaining intracellular homeostasis, whereas N-methyl-D-aspartate receptors (NMDARs) play a key role in mediating pathological processes through the regulation of excitatory neurotransmission and immune responses. Viral infections have the capacity to modify the expression and functionality of these receptors, either directly or indirectly, thereby contributing to dysregulation within the neurological and immune systems and triggering a range of disease states. This review offers a comprehensive analysis of the mechanisms through which various viral infections interact with GABARs and NMDARs, emphasizing the possible intricate roles these receptors play in viral pathogenesis. Additionally, it underscores their potential as therapeutic targets for antiviral interventions, particularly in addressing immune dysregulation and neurological disorders.
Debombourg M, Oriol G, Dupre C
… +12 more, Albert-Vega C, Venet F, Rimmelé T, REALISM Study Group, Conrad A, Ader F, Alcazer V, VaccHemInf Study Group, Brengel-Pesce K, Fleurie A, Trouillet-Assant S, Mouton W
Clin Exp Immunol
· 2025 Jan · PMID 40796210
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Growing evidence suggests that conventional immunomonitoring alone may not be sufficient to fully capture the complexity of immune dysfunctions. Immune functional assays (IFAs) have therefore emerged as valuable compleme...Growing evidence suggests that conventional immunomonitoring alone may not be sufficient to fully capture the complexity of immune dysfunctions. Immune functional assays (IFAs) have therefore emerged as valuable complementary tools, offering functional insights that extend beyond traditional phenotypic or quantitative approaches. Nevertheless, although in vitro stimulation represents a central component of IFAs, its specific contribution has never been rigorously evaluated, raising the critical question of whether this step is truly essential for detecting clinically relevant immune dysfunctions. To address this question, the present study compared gene expression levels (Nanostring) obtained from samples stimulated (TruCulture) or unstimulated (PaxGene) using the same analytical pipeline, in two distinct clinical settings: immune reconstitution following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and sepsis progression. In allo-HSCT patients, post-stimulation data revealed immune heterogeneity and alterations related to ongoing immunosuppressive treatment or infectious event, not detected using unstimulated transcriptomic or cellular profiles alone. Similarly, post-stimulation transcriptomic profiles in patients with sepsis revealed immune clusters linked to disease severity and outcomes, surpassing traditional markers like mHLA-DR, while analyses from the unstimulated datasets failed to generate clinically relevant stratification. These findings emphasize the value of IFAs in uncovering immune function alterations that unstimulated assessments may miss, which could offer deeper insights into immune dysfunction. This study supports the use of IFAs as complementary tools to current clinical practices to enhance patient management by offering a functional view of immune system dynamics.
Gao J, Zhang Z, Jin Y
… +5 more, Zhang N, Fu Y, Jiang X, Wang X, Wen Z
Clin Exp Immunol
· 2025 Jan · PMID 40755275
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Primary graft dysfunction (PGD) represents a clinical acute lung injury syndrome occurring within 72 hours after lung transplantation, remaining the main cause of early mortality after lung transplantation. However, very...Primary graft dysfunction (PGD) represents a clinical acute lung injury syndrome occurring within 72 hours after lung transplantation, remaining the main cause of early mortality after lung transplantation. However, very few effective and specific therapies are available, except for supportive treatment. Broad cellular and molecular mechanisms contribute to PGD, yet the precise mechanism remains poorly understood. The major underlying pathophysiology of PGD is ischemia-reperfusion injury (IRI), which inevitably occurs during lung transplantation. Ischemia and subsequent reperfusion of donor lungs commonly trigger cellular and molecular dysfunction, causing disorders of metabolism and ionic homeostasis, release of reactive oxygen species (ROS), dysfunction of mitochondria, secretion of inflammatory cytokines, and activation of innate immunity. These events induce both programmed and non-programmed cell death, leading to vascular and alveolar epithelial damage, pulmonary edema, and impaired gas exchange. Innate immune activation during lung ischemia-reperfusion unfolds in two distinct phases, with the early phase primarily driven by donor-derived immune cells and the late phase mainly driven by recipient-derived immune cells. This review systematically summarizes the pathophysiology of PGD from the perspective of cellular and molecular aspects, especially emphasizing the process of programmed cell death and dynamic innate immune cell migration, which might potentially provide novel insights into the prevention and targeted therapy for IRI and PGD after lung transplantation.
Werner F, Wittner J, Lehmann CHK
… +13 more, Wahlbuhl M, Allabauer I, Hoffmann A, Schnell A, Krickau T, Hackstein H, Dietel-Schor B, Rush JS, Regnier CH, Jäck HM, Woelfle J, Schuh W, Hoerning A
Clin Exp Immunol
· 2025 Jan · PMID 40726134
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CD40-CD40L interaction is crucial for the interplay between B and T cells and determines B-cell fate. Here, we investigated the effects of CD40-CD40L inhibition on B-cell subsets and cytokine production using the non-dep...CD40-CD40L interaction is crucial for the interplay between B and T cells and determines B-cell fate. Here, we investigated the effects of CD40-CD40L inhibition on B-cell subsets and cytokine production using the non-depleting monoclonal anti-CD40 antibody CFZ534. CFZ534 had no impact on B-cell viability but inhibited TLR9-agonistic (CpG-ODN) CD40L- as well as CD40L-mediated proliferation. The plasmablast subset was reduced after stimulation with CpG-ODN + CD40L, but this effect was completely restored by CFZ534-mediated CD40 blockade. IgG as well as IgM-secreting cells were significantly reduced in the presence of CFZ534 upon CD40L stimulation. CpG-ODN, but not CD40L, induced Granzyme B production in B cells after CD40-blockade and CpG-ODN/CD40L stimulation. Moreover, we found that IL-10 and Granzyme B were produced by separate B-cell subsets. Hence, CD40-blockade mediated by CFZ534 increased Granzyme B production and decreased IL-10 production in CD24hiCD38hi B cells with a transitional phenotype and led to a significant decrease in the expression of the pro-inflammatory cytokines IL-6, IL-12p35, and IL-23p19 and TNFα in a B and CD4 + TH-cell co-culture system. Based on these preclinical results, CD40 blockade by the Fc-silent, non-depleting monoclonal antibody CFZ534 exerts an anti-inflammatory effect on B cells, including hampering the IgG class switch without affecting their viability.
Potjewijd J, Koenen HJPM, van der Made CI
… +9 more, van Rijssen E, He X, Ysermans R, Ungethum L, Theunissen R, Schurgers LJ, Damoiseaux J, van Paassen P, Smeets RL
Clin Exp Immunol
· 2025 Jan · PMID 40719110
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Heterozygous loss-of-function mutations in the TNFAIP3 gene lead to A20 haploinsufficiency (HA20). A20 protein is a negative feedback regulator of NF-κB signaling. Traditionally, HA20 is associated with Behçet's disease-...Heterozygous loss-of-function mutations in the TNFAIP3 gene lead to A20 haploinsufficiency (HA20). A20 protein is a negative feedback regulator of NF-κB signaling. Traditionally, HA20 is associated with Behçet's disease-like symptoms, however, recent findings suggest it may also manifest with a broader array of autoimmune diseases. Here, we describe a novel TNFAIP3 variant in a Dutch family, predominantly presenting with polyautoimmunity rather than autoinflammatory manifestations. We evaluated two patients from a Dutch family with autoimmune symptoms. Whole-exome sequencing (WES) identified a heterozygous c.608T>G (p.Leu203Arg) missense variant in TNFAIP3, located within the OTU domain. Functional analyses included immunoblotting of peripheral blood mononuclear cells (PBMCs) and an overexpression model using transfected HEK293T cells. A20 protein expression was evaluated, while phosphoflow cytometry assessed phosphorylation of key signaling molecules in the NF-κB, STAT and mTOR pathways. Inflammatory cytokine production was measured in cell culture supernatants. Overexpression of this missense A20 variant in HEK293T enhanced NF-κB signaling, reflected by increased TRAF6 expression and IκBα phosphorylation. Patient-derived PBMCs demonstrated reduced A20 expression, increased phosphorylation within the NF-κB, STAT1, and mTOR pathways, and elevated production of pro-inflammatory cytokines. These molecular alterations suggest disrupted immune regulation contributing to the observed autoimmune phenotype. The identification of this novel TNFAIP3 variant contributing to HA20 expands the clinical spectrum to include predominant autoimmune manifestations. In addition to NF-κB and STAT1 activation, we discovered mTOR pathway activation, shedding new light on A20's function and progression toward autoimmunity. Furthermore, the involvement of mTOR pathway also provides new therapeutic possibilities.