2026-04-02
Cailian Wu, Tiantian Luo, Jinfeng Huang, Ruikang Mo
BackgroundCerebral ischemia–reperfusion injury (CIRI) remains a major cause of neurological disability and lacks effective neuroprotective interventions. Soy isoflavones (SI), phytoestrogens with antioxidant and anti-inflammatory properties, have shown neuroprotective potential. Given that ferroptosis contributes to CIRI pathogenesis and AMP-activated protein kinase (AMPK) regulates redox homeostasis, iron metabolism, and lipid peroxidation, we investigated whether SI protect against CIRI by activating AMPK and inhibiting ferroptosis.MethodsMale Sprague–Dawley rats subjected to middle cerebral artery occlusion (MCAO) were pretreated with SI (120 mg/kg, gavage) for 21 days. Neurological outcomes were assessed by infarct volume (TTC), brain water content, and behavioral scoring (Longa, mNSS). Ferroptosis was evaluated via cerebral Fe²+/total iron levels, oxidative stress indices (MDA, GSH, SOD, ROS), and protein expression of GPX4, ACSL4/3, xCT, and ferritin (FTH/FTMT). AMPK activation (p-AMPK/AMPK) was determined by Western blotting. Mechanistic validation employed RSL3 (ferroptosis inducer) and compound C (AMPK inhibitor).ResultsSI pretreatment significantly reduced infarct size, alleviated edema, and improved neurological function. SI attenuated cerebral iron accumulation, suppressed ROS and MDA production, and enhanced GSH and SOD activities. Western blot analysis revealed downregulation of ACSL4 and upregulation of GPX4, ACSL3, xCT, and ferritin, consistent with ferroptosis suppression. The protective effects of SI were abolished by RSL3, confirming ferroptosis dependence. Furthermore, MCAO suppressed AMPK activation, which was restored by SI; inhibition of AMPK with compound C intensified ferroptotic injury and negated SI’s benefits, whereas co-treatment with SI reversed these detrimental effects.ConclusionSI confer neuroprotection against CIRI by activating AMPK signaling and inhibiting ferroptosis. These findings highlight the AMPK–ferroptosis axis as a promising therapeutic target for ischemic stroke.
DOI: 10.3389/fimmu.2026.16639862026-04-02
Longbo Wang, Xiyang Sheng, Gengyuan Shi, Yongzhao Li, Dongdong Wang, Wei Wang, Chen Mi, Siyang Wang, Yongyue Du, Hanteng Yang
Liver transplantation (LT) has become the optimal therapeutic strategy for end-stage liver disease. Beyond chronic conditions, acute liver failure (ALF) and the emerging field of transplant oncology have also become critical indications for LT. It is important to note that the systemic and local immunometabolic states in these specific pathologies may differ significantly from those in traditional end-stage liver disease, presenting unique challenges for immune management. With advancements in surgical techniques and perioperative management, the long-term survival rates of patients have significantly improved. However, extended patient survival and an expanding donor pool have unmasked long-term complications such as post-transplant metabolic syndrome (PTMS). Furthermore, the patient’s systemic metabolic state influences both the metabolism of immune cells and the utilization of immunosuppressants, posing severe challenges to patient management. Studies indicate that following liver transplantation, distinct immune cells undergo dynamic adaptive changes in energy metabolism, which directly determine the outcomes of rejection, ischemia-reperfusion injury (IRI), and immune tolerance. This review systematically elucidates the mechanisms of immune cell metabolic remodeling. Furthermore, it explores the translational prospects of targeting immunometabolic pathways to optimize immunosuppressive regimens, mitigating IRI, and establish non-invasive biomarkers for immune monitoring, ultimately providing new insights for improving the long-term outcomes of liver transplant recipients.
DOI: 10.3389/fimmu.2026.17766942026-04-02
Mayu Shiomi, Ryu Watanabe, Muneyuki Hatta, Shogo Matsuda, Takuya Kotani, Ayana Okazaki, Yuichi Masuda, Mikihito Shoji, Atsushi Manabe, Keiichiro Kadoba, Tsuneyasu Yoshida, Naoko Ito, Youhei Fujiki, Hirofumi Miyake, Wataru Yamamoto, Motomu Hashimoto
BackgroundThe long-term prognosis of patients with anti-neutrophil cytoplasmic antibody–associated vasculitis (AAV) has historically been poor. In recent years, the widespread use of novel targeted therapies has led to an increased emphasis on reduced-dose glucocorticoid (GC) strategies; however, owing to regional differences in the frequency and clinical characteristics of AAV subtypes, contemporary real-world evidence on long-term outcomes in Japanese patient populations remains limited.ObjectivesThe primary outcome was to elucidate subtype-specific clinical characteristics and five-year overall and relapse-free survival in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Secondary outcomes included temporal changes in treatment practices and prognosis, stratified by year of diagnosis.MethodsWe conducted a multicentre retrospective study using data from the REVEAL cohort. A total of 460 newly diagnosed, treatment-naïve cases were included (microscopic polyangiitis (MPA), n = 283; granulomatosis with polyangiitis (GPA), n = 66; eosinophilic granulomatosis with polyangiitis (EGPA), n = 111). Clinical characteristics, five-year relapse-free and overall survival were evaluated. To assess temporal changes in treatment practices and prognosis, patients were stratified by median year of diagnosis (2018) into pre-2018 and post-2019 groups.ResultsMPA showed the poorest prognosis among AAV subtypes, with a five-year overall survival rate of 67.6%. Older age and impaired renal function were independently associated with increased mortality (P < 0.001 and P = 0.0079, respectively). Over time, GC exposure was significantly reduced in the post-2019 group (P = 0.012), accompanied by fewer infection-related hospitalisations (P < 0.001). However, five-year overall and relapse-free survival did not differ between the pre-2018 and post-2019 groups. Notably, BVAS at 6 and 12 months were significantly higher (P = 0.0070 and P = 0.0057, respectively), and vasculitis-related mortality was more frequent in the post-2019 group (P = 0.0057).ConclusionMPA remained the AAV subtype with the poorest prognosis. Although GC exposure has decreased in recent years, this trend was not associated with improved clinical outcomes in the present cohort.
DOI: 10.3389/fimmu.2026.18074232026-04-02
Zhiying Chen, Muya Zhou, Xiaoyu Li, Yuqi Zhao, Zhengling Wang, Jinhua Hu, Jialu Hong, Shenrui Zhou, Feiyan Pan, Zhigang Hu, Lingfeng He, Tao Gao, Xiaodong Jiang, Zhiqiang Wang, Zhigang Guo
BackgroundCAR-T therapy is limited by off-target sequestration in liver, spleen, and lungs, which reduces tumor delivery and risks systemic toxicity. Genetic engineering approaches are complex and carry safety concerns, necessitating efficient non-genetic strategies to optimize CAR-T biodistribution.PurposeWe developed red blood cell membrane–chimeric liposomes (Rlip) as a biomimetic coating system to non-genetically modify CAR-T cells, aiming to enhance immune evasion, prolong circulatory persistence, and redirect trafficking toward tumors while preserving intrinsic effector function.MethodsRlip-CAR-T cells were prepared via simple incubation. In vitro characterization assessed coating stability, CD47-mediated macrophage resistance, phenotype preservation, and antigen-specific cytotoxicity. In vivo studies evaluated biodistribution, tumor infiltration, and efficacy in Nalm-6 systemic leukemia and 1806-luc subcutaneous ovarian cancer models.ResultsRlip coating stably presented CD47, functionally impairing macrophage phagocytosis and enhancing peripheral persistence without altering memory subsets, activation markers, or cytotoxicity. Rlip-CAR-T cells demonstrated markedly reduced off-target organ accumulation and increased intratumoral enrichment in both models, with superior tumor control and prolonged survival observed in the leukemia model.ConclusionsRlip surface engineering represents a universal, clinically translatable strategy to overcome CAR-T biodistribution barriers. By integrating erythrocyte-mimetic immune evasion with optimized tumor delivery, this approach improves CAR-T cell accumulation at tumor sites across hematologic and solid malignancies.
DOI: 10.3389/fimmu.2026.17991072026-04-02
Xin-Yang Bai, Gui-Lin Wang, Yue Zhang, Qian Cheng, Hui-Ning Feng, Linyu Wei, Hai-Yan Sheng, Yaling Yin, Sebastien Roger, Lin-Hua Jiang, Huifang Hou
Depression is a prevalent neuropsychiatric disorder with high incidence and causing severe disability, representing a clinically unmet challenge and thus demanding more effective therapeutics. Neuroinflammation in the central nervous system (CNS) is a pathological feature of depression and, with increasing recognition, it is also a critical depression-driving mechanism. In the CNS, the P2X7 receptor for extracellular ATP is expressed in microglia and astrocytes, and acts as a key mediator of neuroinflammation. Besides medicinal chemistry efforts in developing novel CNS-penetrable P2X7 antagonists, there is an increasing interest in exploring natural products as medications for CNS conditions including depression. In this mini-review, we discuss the recent progress in examining the therapeutic potential and mechanisms of compounds from natural products, using rodent models of depression, and revealing P2X7-mediated proinflammatory signaling pathways as an important target for their antidepressant actions.
DOI: 10.3389/fimmu.2026.18149132026-04-02
Chunxi Ke, Ni Ma, Gang Chen, Yuxu Yao, Jiang Ji, Qingqing Jiao
Urticaria is a mast cell-driven skin disease, characterized by itchiness and transient wheal development. Although histamine released from activated mast cells is central to disease pathogenesis, increasing clinical evidence indicates that a subset of patients exhibit limited efficacy to antihistamines and biologics such as omalizumab. This therapeutic limitation emphasizes the involvement of additional, non-histaminergic pathways in disease persistence. Recent studies highlight the pivotal role of neuroimmune interactions, the crosstalk between the immune and nervous systems, especially in modulating type 2 inflammation and itch. In urticaria, neuroimmune mechanisms amplify pruritic signaling, and promote neurogenic inflammation, and sustain mast cell activation, collectively contributing to chronicity and treatment resistance. Deciphering these neuroimmune loops provides new insight into urticaria pathophysiology and identifies potential molecular targets for therapy. A growing number of biologics targeting neuroimmune pathways are showing encouraging efficacy in early clinical trials. This review adopts a pruritus-centered perspective to synthesize updated advances in neuroimmune research related to urticaria and to outline future directions for mechanism-based therapy.
DOI: 10.3389/fimmu.2026.17829012026-04-02
Benedicta O. Dankyi, Takaaki Yuguchi, Rattanaporn Rojrung, Hikaru Nagaoka, Bernard N. Kanoi, Alfred B. Tiono, Issa Nebie, Alphonse Ouedraogo, Keiko Tanaka, Yoshihiro Miyake, Kazutoyo Miura, Jetsumon Sattabongkot, Sodiomon B. Sirima, Takafumi Tsuboi, Eizo Takashima
BackgroundMalaria remains a major global health burden, with children under five years in sub-Saharan Africa disproportionately affected. While immunity develops with repeated exposure, the specific correlates of protection in early childhood are not well defined. To address this, we assessed IgG and IgM antibody responses to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) domains in plasma samples from 80 Burkinabe children (aged 0–60 months) collected before (pre-malaria season) and during peak malaria transmission.MethodsUsing AlphaScreen, we measured antibody responses to 271 PfEMP1 (3D7) domains expressed via wheat germ cell-free synthesis.ResultsPre-season analysis showed that 96% of domains were IgG-reactive and IgG breadth increased with age, whereas 71% were IgM-reactive, but IgM breadth showed no age trend. IgG responses to 132 domains (49%) remained significantly associated with reduced risk of clinical malaria after false discovery rate (FDR) correction, including many non-adhesion domains. Five (5) IgM responses were nominally protective, but none remained significant after FDR correction. Fc-dependent opsonic phagocytosis assay using a subset of the top-ranked domains revealed that opsonic phagocytosis activity correlated with protection for only one antigen, suggesting that PfEMP1-specific antibodies may mediate protection through mechanisms beyond phagocytosis in children under 5 years old.ConclusionsThis study provides the first comprehensive characterization of IgG and IgM responses to a large panel of PfEMP1 domains in young children, revealing broad antibody recognition and selective opsonic phagocytosis activity. Findings from the study deepen our understanding of early-life immunity to malaria and help identify PfEMP1 regions of interest for future vaccine development.
DOI: 10.3389/fimmu.2026.17816702026-04-02
Jinhan Chen, Qian Xu, Yuou Ying, Jinsheng Yu, Yi Liu, Fangmin Zhao, Qijin Shu
BackgroundEsophageal cancer (EC) is one of the most aggressive malignant tumors, associated with high mortality rates. Pembrolizumab and nivolumab have been incorporated into immunotherapy regimens for advanced EC, but immune-related adverse events (irAEs) remain a major factor affecting antitumor efficacy. This study aims to conduct a comprehensive and systematic analysis of adverse events (AEs) associated with pembrolizumab and nivolumab in EC immunotherapy using the FAERS database, providing new insights to optimize clinical practice.MethodsAll AE reports related to pembrolizumab in EC were extracted from the FAERS database. Disproportionality analyses were performed using three algorithms, including the ROR, PRR, BCPNN. Based on Kaplan-Meier analysis with log-rank tests, the median time to onset and associated risk factors for relevant AEs were determined. Finally, univariable logistic regression analysis was used to identify risk factors for death associated with AEs.ResultA total of 3,669 AE reports related to pembrolizumab and 4,308 AE reports related to nivolumab were identified. Descriptive analysis showed that the number of AE reports increased year by year, and the number of reports was higher in the elderly population. The United States, Japan, and China were the primary reporting countries. The overall median time to onset for pembrolizumab-related PTs was 35 days, while that for nivolumab-related PTs was 52 days. In pembrolizumab, age ≥ 65 years was a risk factor for shorter median onset time, whereas in nivolumab, female gender was a risk factor for shorter median onset time. Among pembrolizumab-related AEs, weight was associated with a higher mortality risk. For nivolumab-related AEs, age, weight, increased cumulative number of adverse reactions, and earlier median onset time were associated with higher mortality risk.ConclusionThis real-world study is the first to analyze pembrolizumab and nivolumab irAEs in EC using the FAERS database, identifying high-signal events such as endocrine, hepatic, renal, gastrointestinal toxicities. Additional cardiovascular and pulmonary events are observed. Female and older patients experienced earlier irAEs. Increased mortality risk was associated with weight, cumulative number of AEs, and earlier irAE onset. These findings can guide personalized treatment, early intervention, and improve prognosis.
DOI: 10.3389/fimmu.2026.17383512026-04-02
Jun Wang, Yanrong Yuan, Yan Zhang, Huili Liu, Jing Han, Yongxing Yan
ObjectivesVaricella-zoster virus (VZV) is a significant pathogen of viral central nervous system (CNS) infections. There are many studies on VZV-associated CNS infections, but there is currently a lack of large-sample comparative studies on VZV-associated CNS infections in immunocompetent and immunocompromised herpes zoster (HZ) patients. In this study, we compared the clinical characteristics and prognosis of VZV-associated CNS infections in immunocompetent and immunocompromised HZ patients.MethodsThis retrospective study, conducted at a tertiary hospital specializing in dermatology in East China, compares clinical characteristics, treatment, and prognosis at discharge in 117 immunocompetent and 49 immunocompromised HZ patients with VZV-associated CNS infection.ResultsCompared with the immunocompetent group, the incidence of encephalitis in immunocompromised HZ patients with VZV-associated CNS infections was significantly higher (P<0.05), and the prognosis at discharge was worse (P<0.01). Blood white blood cell (WBC), red blood cell (RBC), blood platelet counts (BPC), hemoglobin (Hb), total protein, prealbumin, and albumin contents decreased (all P<0.05), while adenosine deaminase (ADA) levels in cerebrospinal fluid (CSF) and blood C-reactive protein-to-albumin ratio (CAR), systemic immune-inflammation index (SII), C-reactive protein (CRP), and β2 microglobulin levels were higher (all P<0.05). Further analysis revealed that the time between neurological symptoms and antiviral therapy and the occurrence of encephalitis were independent risk factors for poor prognosis at discharge in immunocompetent HZ patients with CNS infections, while the independent risk factors for poor prognosis in the immunocompromised group were age and the time between neurological symptoms and antiviral therapy.ConclusionsImmunocompromised HZ patients have a higher incidence of encephalitis and worse prognosis. Regardless of immunocompetent or immunocompromised HZ patients with concurrent CNS infections, the time between neurological symptoms and antiviral therapy is an independent risk factor for prognosis at discharge, highlighting the importance of early intervention and treatment.
DOI: 10.3389/fimmu.2026.17957102026-04-02
Sutong Liu, Lihui Zhang, Wanyi Zhu, Weichen Ma, Qing Zhao, Minghao Liu, Wenxia Zhao
ObjectiveThis study aimed to evaluate the therapeutic effect of the traditional Chinese medicine compound Huatan Qushi Huoxue prescription (HQHF) on Metabolic Associated Fatty Liver Disease (MAFLD) and explore its underlying mechanisms through a multi-method approach.MethodsA high-fat diet-induced MAFLD mouse model was established to assess HQHF’s effects on liver pathology, biochemical markers, and oxidative stress. The bioactive components and potential targets of HQHF were identified through network pharmacology. MAFLD-related signaling pathways were explored by integrating data from the Gene Expression Omnibus (GEO) database, followed by molecular docking analyses. For experimental validation, key inflammatory cytokines and proteins (Interleukin-6 (IL-6), Interleukin-1α (IL-1α), Interleukin-1β (IL-1β), Matrix Metallopeptidase 9 (MMP9), Chemokine Ligand 2 (CCL2), and Intercellular Adhesion Molecule 1 (ICAM1)) were measured using Enzyme-Linked Immunosorbent Assay (ELISA), immunohistochemistry (IHC), and immunofluorescence.ResultsHistopathological analysis showed that HQHF significantly alleviated liver steatosis and inflammatory cell infiltration. Biochemical analysis indicated that HQHF reduced serum and liver triglyceride levels, serum total cholesterol, liver enzymes (Aspartate Aminotransferase, AST, and Alanine Aminotransferase, ALT), and malondialdehyde (MDA), while increasing glutathione (GSH) levels. Network pharmacology identified 33 bioactive components and 89 key targets, which were enriched in pathways including Mitogen-Activated Protein Kinase (MAPK), Toll-like Receptor (TLR), Interleukin-17 (IL-17), and Advanced Glycation End product-Receptor for Advanced Glycation End product (AGE-RAGE). Six core genes (MMP9, IL1α, CCL2, IL1β, IL6, ICAM-1) were highlighted. Molecular docking confirmed strong binding of major HQHF compounds (e.g., quercetin, baicalin) to these targets, and experimental assays further validated their downregulation in HQHF-treated mice.ConclusionHQHF exerts lipid-lowering and anti-inflammatory effects in MAFLD by regulating multiple targets and pathways related to lipid metabolism and inflammation.
DOI: 10.3389/fimmu.2026.17510332026-04-02
Ying-Ao Liu, Xiang Gao, Wei Gao, Zeliang Hu, Fangzhou Wang, Yuanxu Qu, Yamin Zheng
BackgroundImmunoglobulin G4-related disease (IgG4-RD) is an immune-mediated chronic fibroinflammatory condition that can affect multiple organ systems. IgG4-related sclerosing cholangitis (IgG4-SC) is its manifestation involving the biliary tract. Due to atypical clinical presentations in some cases and insufficient awareness among clinicians, IgG4-SC is frequently misdiagnosed as cholangiocarcinoma, and multiple instances of inappropriate treatment as a result have been documented.Case presentationHere we report a case of IgG4-SC that presented diagnostic challenges preoperatively and was followed by rare pancytopenia after surgery. The patient was a 50-year-old man who sought medical attention due to elevated transaminases for eight months, without obvious clinical symptoms. Among serum tumor markers, the level of protein induced by vitamin K absence/antagonist-II (PIVKA-II) was elevated. Examinations including magnetic resonance cholangiopancreatography (MRCP), contrast-enhanced abdominal computed tomography (CT), and positron emission tomography-computed tomography (PET-CT) all suggested malignant stricture at the hepatic hilum. A needle biopsy indicated dysplastic changes but was inconclusive for cholangiocarcinoma. Although IgG4-SC was considered, multiple serum IgG4 measurements remained within the normal range. With an initial clinical diagnosis of cholangiocarcinoma, the patient underwent surgical resection. Intraoperative frozen section analysis indicated an inflammatory process. Postoperatively, the patient developed pancytopenia that responded poorly to conventional supportive treatment. The condition was ultimately diagnosed as IgG4-SC based on postoperative histopathology. Corticosteroid therapy led to the normalization of the patient’s blood counts, transaminases, and bilirubin levels.ConclusionIgG4-SC can present with a spectrum of atypical features, such as isolated biliary strictures, absence of characteristic symptoms, normal IgG4 levels, and imaging findings resembling cholangiocarcinoma. Therefore, in cases clinically suspicious for cholangiocarcinoma, differentiating IgG4-SC warrants serious consideration. Every effort should be made to complete preoperative biopsy and histopathological assessment. For cases where differentiation remains difficult despite comprehensive evaluation, surgical intervention with intraoperative frozen section biopsy is necessary to establish a definitive diagnosis and avoid delayed treatment. Furthermore, this case suggests that IgG4-SC may also involve the hematopoietic system, manifesting as pancytopenia, which can respond effectively to corticosteroid therapy.
DOI: 10.3389/fimmu.2026.17134562026-04-02
Xiyao Yu, Kai Fu
Melanoma, owing to its high tumour mutational burden (TMB) and inherent immunogenicity, has emerged as a prime target for neoantigen-based customised cancer vaccines. Such vaccines may synergise with immune checkpoint inhibitors (ICIs) by harnessing patient-specific mutations to trigger targeted T-cell responses. This review systematically summarises and evaluates the clinical evidence and molecular mechanisms underlying customised neoantigen vaccines in melanoma, based on key clinical trial data. A central finding is that vaccine platform choice strongly influences, rather than rigidly determines, the dominant immunological pathway. Messenger RNA (mRNA) platforms generally favour endogenous antigen expression and MHC class I presentation, often eliciting robust CD8+ cytotoxic T-cell responses. By contrast, synthetic long peptide (SLP) platforms are typically processed as exogenous antigens and frequently engage MHC class II presentation, thereby promoting substantial CD4+ T-helper responses. However, this distinction is not absolute, because exogenous peptides can also be cross-presented on MHC class I by professional antigen-presenting cells, enabling CD8+ T-cell priming under appropriate conditions. Clinical data reflects this, with the mRNA vaccine mRNA-4157 (KEYNOTE-942) demonstrating a significant recurrence-free survival (RFS) benefit in the adjuvant setting. This efficacy, however, is contingent on the “hot” tumour microenvironment (TME) of melanoma; “cold” tumours like glioblastoma (GBM) and ovarian cancer (OvCa) present TME-specific barriers (e.g., the Blood-Brain Barrier, immune exclusion) that demand distinct, combination-based vaccine strategies. This review deconstructs this heterogeneity and defines the primary bottlenecks to broad clinical adoption: (1) the need to bridge the “validation gap” by correlating AI prediction accuracy with clinical outcomes; (2) the formidable economic and logistical barriers, including a clinically vulnerable 8–16 week manufacturing wait that poses psychological and clinical risks to patients; and (3) navigating adaptive regulatory pathways for “n-of-1” therapeutics. The field awaits the pivotal Phase III clinical trial of V940-001 (NCT05933577), whose timeline has been extended to 2029. This reflects the logistical and biological complexities inherent in developing personalised vaccines, highlighting challenges in both manufacturing and subject recruitment. These remain key obstacles impeding the widespread clinical application of such vaccines.
DOI: 10.3389/fimmu.2026.18081462026-04-02
Kaiqi Yang, Weihong Chen, Yasai Tang, Shuyi Chang, Ruohan Sun, Peiyuan Lv, Yanhong Dong
BackgroundStiff-person syndrome (SPS) is a rare neuroimmune disorder that is associated with a variety of symptoms and varying degrees of disability. SPS has multiple phenotypes and different immunological bases, and the lack of clinical awareness of these various clinical phenotypes often leads to misdiagnosis and inappropriate treatment of SPS patients in the early stage of the disease course.Case descriptionWe report a distinctive case of SPS with a 4-year follow-up. The patient was a 56-year-old middle-aged woman who initially presented with diplopia and atypical muscle tension. Treatment with baclofen and lorazepam showed poor efficacy, and she was once misdiagnosed with anxiety and depression as well as oculomotor nerve palsy. During the 4-year follow-up period, the patient gradually developed typical clinical manifestations and signs of SPS and was diagnosed with positive GAD antibodies. In the later stage, the patient’s symptoms were exacerbated by the serotonin receptor partial agonist tandospirone; further testing revealed a significant increase in GAD antibody titer.ResultsAs the patient could not tolerate hormone pulse therapy, she was administered rituximab and two sessions of intravenous immunoglobulin (IVIG). After adjustment of the relevant treatment regimen, the patient’s symptoms were significantly alleviated.ConclusionSPS is relatively uncommon and prone to misdiagnosis. Therefore, we need to understand the various clinical manifestations of SPS, achieve early intervention, and thereby improve the prognosis and quality of life of patients.
DOI: 10.3389/fimmu.2026.17497932026-04-02
Yan-Jiao Chen, Gabriel Shimizu Bassi, Yong-Qing Yang
Asthma exacerbations are predominantly triggered by respiratory viral infections, yet current therapies largely fail to restore effective antiviral immunity. Emerging data indicate that this failure is tightly coupled to dysregulated immunometabolism within the asthmatic lung. This review advances the concept of a dendritic cell–natural killer (DC–NK) metabolic checkpoint, whereby the metabolic state of DCs, regulated by autophagy and AMPK/mTOR signaling, licenses NK cells for antiviral effector function. In type 2-high, type 2−low, and obesity-related asthma endotypes, chronic hypoxia, HIF−1α stabilization, ORMDL3–ceramide signaling, and systemic metabolic stress converge to induce highly glycolytic, Th2/Th17−polarizing DCs in a lactate-rich, acidic microenvironment. We propose that these DCs modulate NK cell metabolism through three interlinked axes: (i) cytokine-mediated metabolic licensing (IL−12, IL−15, IL−18), (ii) exosome-mediated delivery of activating versus metabolically suppressive cargo, and (iii) intense perisynaptic nutrient competition that depletes local glucose while lactate accumulation and acidosis further inhibit NK cell function. The result is a “double metabolic hit” that renders lung-resident NK cells metabolically exhausted, IFN−γ−deficient, and unable to clear virally infected targets despite preserved cytotoxic machinery. Although many mechanistic insights derive from murine and in vitro models, converging human metabolomic, genetic, and functional data support this framework and define clear research gaps. If validated in human studies, targeting the DC-NK cell metabolic checkpoint with agents that restore autophagic plasticity, rebalance AMPK/mTOR signaling, or normalize airway nutrient and pH landscapes may represent a promising strategy to prevent viral-triggered asthma exacerbations.
DOI: 10.3389/fimmu.2026.17982092026-04-01
Bingbing Li, Cong Fu, Yuning Ren, Xiaoling Zhang
NELL2, a neuron-specific secreted glycoprotein, has emerged as a key regulator in multiple physiological and pathological contexts, including neurodegeneration, immunity, reproduction and cancer. Despite its diverse roles, the context-dependent duality of NELL2-acting as both an oncogene and tumor suppressor, a neuroprotectant and contributor to hyperexcitability-remains mechanistically unclear. Moreover, the tissue-specific signaling cross-talk of NELL2 complicates its therapeutic targeting. Research on NELL2 holds transformative potential for precision medicine, offering insights into cancer therapy, neurodegenerative disease intervention, and infertility treatment, while highlighting the need for mechanistic clarity and context-specific strategies to realize its diagnostic and therapeutic promise. Here, we consolidated research advances of NELL2, delineating its structural features, regulatory networks, and context-dependent roles in neurodegeneration, immunity, reproduction and cancer. By highlighting unresolved mechanistic ambiguities and therapeutic translatability, our work helps to illuminate potential of NELL2 as a diagnostic marker and therapeutic target across diverse diseases.
DOI: 10.3389/fimmu.2026.17809092026-04-01
Xiaoya Zhang, Danmei Zhang, Jin Guo, Chunxia Shi, Zuojiong Gong
Mitochondria are central regulators of immunometabolism, and emerging evidence identifies intercellular mitochondrial transfer as a key driver of immune microenvironment remodeling. Beyond energy production, transferred mitochondria reshape immune niches by reprogramming metabolic fitness, redox balance, inflammatory tone, and immune cell interactions. Through multiple transfer routes, including tunneling nanotubes, extracellular vesicles, and gap junctions, mitochondrial exchange modulates immune activation, immunosuppression, and tolerance across diverse physiological and pathological contexts. In this review, we summarize current mechanisms of mitochondrial transfer and highlight how this process directionally remodels the immune microenvironment in inflammation, cancer, and autoimmune diseases. We further discuss therapeutic strategies aimed at modulating mitochondrial transfer to reprogram immune responses, providing new perspectives for immunomodulation and disease intervention.
DOI: 10.3389/fimmu.2026.17432612026-04-01
Hongxia Yang, Zulin Pan, Ying Yang, Yaxuan Wang, Biqi Cheng, Guoyan Qi
The co-occurrence of myasthenia gravis (MG), inflammatory myopathy (IM), and fulminant myocarditis (FM) has rarely been reported. The few previous articles were mostly case reports or small sample data analysis, and the etiology was mostly attributed to thymoma and/or the application of immune checkpoint inhibitors (ICIs). We report a 74-year-old woman with an acute onset of general weakness, chest tightness, shortness of breath, dysarthria, masticatory weakness and dysphagia, without myalgia or rash. Acetylcholine receptor antibody was positive. Serum creatine kinase, transaminase, and myoglobin were higher than normal. A variety of autoimmune antibodies including anti-Ro-52, JO-1, nRNP and dsDNA antibodies were positive. Chest CT showed no thymoma, bronchiectasis with infection in both lungs. Some of them showed interstitial changes. Electromyography repetitive nerve stimulation of the bilateral deltoid muscle demonstrated a decremental response at low frequencies without an incremental response at high frequencies. Needle electromyography revealed spontaneous potentials. Echocardiography showed that left ventricular wall motion was generally reduced, left ventricular systolic function was reduced, and cardiac function was EF18%. Muscle biopsy suggested myogenic injury. The patient was diagnosed with MG-IM-FM coexisting without thymoma and without ICIs. After treatment with Efgartigimod combined with intravenous methylprednisolone, the symptoms were relieved, serum creatine kinase, myoglobin and other laboratory indicators and cardiac function returned to normal. MG-IM-FM is a complex disease with rapid onset, rapid progression and critical condition. Clinicians should be on high alert and early intervention is the key to improve the prognosis. The immune mechanism of its occurrence is still unclear and needs to be further studied. Traditional glucocorticoid is still the first-line drug, but the new targeted drug Efgartigimod has less adverse reactions and faster onset of action, which may become a good choice, but needs to be verified by a larger sample.
DOI: 10.3389/fimmu.2026.17690652026-04-01
Camille D. Clamagirand, Christoph Ratswohl, Marc W. Schmid, Theresia Eich, Nadine Anslinger, Daniel F. Legler, Jérémie Rossy
Dendritic cell activation of CD8+ T cells at the immunological synapse is critical for immunity, but the structural organization of the dendritic cell side and its impact on T cell fate remain poorly defined. Using bone marrow-derived dendritic cells (BMDCs) as a model, we describe two stable subpopulations distinguished by their capacity to form morphologically distinct synapses. We demonstrate that this architectural divergence is governed by the differential expression of the co-stimulatory molecule CD70: CD70high BMDCs form spiky “firework” synapses driven by a filopodia-based cytoskeletal program, while CD70low BMDCs form smooth “pancake” synapses. This structural dichotomy functionally dictates T cell programming. CD70high dendritic cells prime potent, terminally differentiated Tc1 effector cells. In contrast, IL-6-secreting CD70low dendritic cells generate memory T cells with a Tc17-like functional profile and robust recall capacity. Our work reveals that DC synapse architecture is a key determinant of T cell fate, linking the physical organization of the cell to distinct immunological outcomes.
DOI: 10.3389/fimmu.2026.17166442026-04-01
Yi Dong, Yu Zhong, Huahong Zhou, Dong Cheng
BackgroundRheumatoid arthritis (RA) is an autoimmune disease characterized by chronic systemic inflammation, posing a high risk of death, particularly from cardiovascular events. Finding simple and cost-effective prognostic biomarkers is crucial for risk stratification and improved patient management. The neutrophil-to-lymphocyte ratio (NLR), as a systemic inflammatory marker, has shown prognostic value in various diseases, but its comprehensive evidence in RA remains unclear.MethodsFollowing the PRISMA 2020 guidelines, relevant literature up to October 2025 was systematically searched in PubMed, Embase, Web of Science, and Cochrane databases. Observational studies were included. Random-effects models were used to pool odds ratios (OR) and 95% confidence intervals (CI). Robustness and publication bias were assessed using heterogeneity tests (I²), sensitivity analyses, and Egger’s tests. Evidence quality was graded using the GRADE system.ResultsOverall, seven studies were analyzed, and the meta-analytic findings indicated that elevated NLR was significantly correlated with all-cause mortality (OR = 1.70, 95%CI: 1.39-2.09, P<0.00001) and cardiovascular mortality (OR = 2.60, 95%CI: 1.61-4.21, P = 0.0001) in RA patients, and also with reduced disease remission rate (OR = 0.81, 95%CI: 0.68-0.96, P = 0.02). Heterogeneity for all outcomes was low (I²=0-16%), sensitivity analysis confirmed robustness, and publication bias was not statistically significant. GRADE assessment indicated low quality of evidence for all-cause mortality, moderate for cardiovascular mortality, and very low quality for remission rate.ConclusionAnalysis based on a multivariate adjusted model showed that high NLR is an important predictor of poor prognosis in RA patients. As an economical and readily available inflammatory marker, it holds promise for use in RA risk stratification and personalized treatment decision support, but further prospective studies are required to clarify the causal relationship and optimize the clinical cutoff value.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD420251234933,
DOI: 10.3389/fimmu.2026.17705652026-04-01
Mengye Ma, Peipei Ye, Jieting Pan, Yu Zhang, Weilei Yan, Bingqing Xu, Jiaxin Ding, Liming Jiang
Dengue virus (DENV), as a widely circulating arbovirus, is prone to causing dengue fever and poses a serious threat to human health. Nevertheless, there is currently no ideal safe and effective vaccine for DENV. In particular, vaccination with approved DENV vaccines may increase the chance of infection with heterotypic serotypes of DENV and the risk of severe dengue upon infection. Antibody-dependent enhancement (ADE) is considered a major mechanism contributing to severe disease in secondary infections, which seriously restricts the safety and efficacy of the vaccine. Notably, many studies have shown that DENV T cell epitopes induce cellular immunity by producing large amounts of cytokines, which may contribute to controlling DENV infection and potentially modulating ADE risk. However, the relationship between T cell responses and ADE is complex and requires careful balance to avoid immunopathology. Additionally, the novel mRNA-LNP vaccine has shown promise in preclinical models due to its superior stability and controllability. This review highlights the potential of T cell epitope-based vaccines to complement existing strategies of DENV vaccine development and provide new ideas for the prevention and treatment of DENV.
DOI: 10.3389/fimmu.2026.17858872026-04-01
Gloria Pokuaa Manu, Joseph H. K. Bonney, Flavia Kaduni Bawa, Peter Kojo Quashie, Kwadwo Asamoah Kusi, Linda Eva Amoah
BackgroundThe emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had immense global consequences, leading to widespread illness, deaths, and devastated economies. Despite this, Africa has experienced a high prevalence of asymptomatic coronavirus disease 2019 (COVID-19) and mild cases. While reported cases and deaths have been lower, limited testing and undiagnosed infections make it difficult to determine the true burden of the disease. Understanding the unique immune response and the variations in genetics affect COVID-19 outcomes in African populations is important for shaping future public health responses. This review examines key immune factors and genetic variations in key host proteins that may help explain why COVID-19 was less severe in Africa.MethodologyA systematic review was conducted following PRISMA guidelines to identify studies published between 2019 and January 2026 that investigated immunological responses and genetic variations associated with COVID-19 in African populations. Literature searches were performed in PubMed, Scopus, and African Journals Online (AJOL). Inclusion criteria focused on studies reporting responses from cytokines, T-cells, antibodies or host genetic factors. After screening 4,170 records and removing duplicates, 420 studies were assessed for abstracts, and 240 full texts were reviewed. A total of 40 studies were included, and data synthesized narratively due to heterogeneity in study designs and outcomes.ResultsOf the 40 studies analyzed from 19 African populations, 26 focused on immunological responses and 9 on host genetic factors. Immune studies revealed widespread pre-existing immunity, including cross-reactive antibodies (especially to the N proteins) and polyfunctional T-cell responses, likely shaped by exposure to malaria, helminths, and other coronaviruses. Severe COVID-19 cases showed elevated IL-6, TNF-α, and IFN-γ, while asymptomatic individuals had broader, milder cytokine profiles. Antibody responses were robust across disease severities, with long-lasting IgG activity. Genetic studies identified HLA-B41, B42, C16, and C17 as risk alleles, while HLA-DQB106, DQB103, and B*15 conferred protection. ACE2 polymorphisms including rs2285666, rs73635825 were reportedly prevalent in Africans and were linked to varied ACE2 expression, viral load, and disease severity.ConclusionThe findings suggest that immune and genetic adaptations in African populations may have modulated susceptibility and severity of SARS-CoV-2 infection outcomes in Africans.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/view, identifier CRD420251121731.
DOI: 10.3389/fimmu.2026.1782808