Frontiers in Immunology最新文献

Background: Pembrolizumab-induced immune-related oral mucositis (irOM) is a rare and often underrecognized toxicity. This study aimed to systematically characterize its clinical profile, histopathologic patterns, management strategies, and outcomes to support timely diagnosis and evidence-based care.

Methods: A comprehensive search of PubMed, EMBASE, Web of Science, WanFang Data, and CNKI was performed using a combination of MeSH terms (e.g., "Pembrolizumab," "Oral Mucositis," "Stomatitis," "Mucous Membrane Pemphigoid," and "Immune-Related Adverse Events") and free-text terms (e.g., "anti-PD-1" and "checkpoint inhibitor toxicity"), with Boolean operators (AND/OR) applied to maximize retrieval; reports published up to July 31, 2025, were included. The quality of case reports was evaluated using the JBI Critical Appraisal Checklist.

Results: Among 18 patients, the median age was 72 years (range 15, 88) and 72.2% were male. The median onset of irOM was 24 weeks (range 3, 66), consistent with a delayed presentation. Clinically, painful oral ulcers or erosions were most frequently observed (50.0%), followed by dysphagia or odynophagia (27.8%). Histopathologic evaluation most often revealed a pemphigoid-like pattern (27.8%) or mixed inflammatory infiltrates (22.2%), with additional findings including ulceration with granulation tissue, lichenoid mucositis, plasma cell infiltrates, and epithelial hyperplasia. Systemic corticosteroids were the mainstay of therapy (88.9%), while pembrolizumab was discontinued in one-third of cases (33.3%). Refractory disease occasionally required immunomodulatory agents such as methotrexate (16.7%) or infliximab (11.1%). Clinical outcomes were generally favorable, with 88.9% of patients achieving symptomatic improvement or remission and a median recovery time of 6 weeks (range 2, 52). On rechallenge, 3 of 4 patients had no recurrence.

Conclusion: Pembrolizumab-induced irOM usually develops after months of treatment, presenting as ulcerative mucositis, sometimes extending to the airway or esophagus. Biopsy may show pemphigoid-like changes. Corticosteroids are effective, and immunosuppressants can be used for refractory cases. Recovery is typically within weeks and rechallenge is feasible for select patients.

Interleukin-32 (IL-32) is a cytokine involved in a broad repertoire of immunopathological events across both physiological and disease contexts, encompassing immune modulation, inflammatory amplification, and tumor initiation and progression. IL-32 propagates systemic inflammatory cascades by vigorously inducing pivotal mediators such as TNF-α and IL-17. Consequently, its dysregulated expression has been implicated in diverse disorders, and it has emerged as a tractable therapeutic target. Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent inflammatory synovitis that inexorably erodes articular cartilage and subchondral bone, resulting in debilitating pain, swelling, joint stiffness, and irreversible functional decline. IL-32 is markedly upregulated in the RA synovium, synovial fluid, and peripheral blood, and its abundance is positively correlated with clinical indices of disease activity. Mechanistically, IL-32 induces several cytokines in RA especially TNF-α and IL-17-two master cytokines of RA pathogenesis-thereby amplifying synovial inflammation, osteoclastogenesis, and subsequent joint destruction. Preclinical studies have demonstrated that genetic or pharmacologic inhibition of IL-32 attenuates experimental arthritis severity, underscoring its therapeutic potential. Herein, we provide a comprehensive, up-to-date review of the current understanding of IL-32 biology in RA and its translational implications.

[This corrects the article DOI: 10.3389/fimmu.2025.1586315.].

IgA-mediated Anti-Laminin-γ1 (p200) pemphigoid is a rare subtype of subepidermal autoimmune blistering disease (AIBD) characterized by IgA autoantibodies targeting the laminin γ1 chain, a 200 kDa protein located at the dermal-epidermal junction. Patients typically exhibit skin-dominant blistering lesions, also mucosal involvement has been reported. We report a 73-year-old male patient diagnosed with IgA-mediated anti-Laminin-γ1 (p200) pemphigoid. He initially presented with prominent palmoplantar blisters erosions on the eyelids, lips and face, accompanied by mild pruritus. Skin biopsy demonstrated hyperkeratosis, parakeratosis, acanthosis, subepidermal blister formation, and mild perivascular lymphocytic infiltration in the superficial dermis. Direct immunofluorescence showed C3 deposits on the basement membrane. The patient was initially treated successfully with methylprednisolone. During the second recurrence, he presented with annular erythema topped with blisters and erosions on the lips. Comprehensive pemphigus and pemphigoid antibodies panel test showed Laminin γ1 IgA with a titer of 1:10. The rash recurred when corticosteroids were tapered. The patient was then treated with Stapokibart (CM310) in combination with corticosteroids, leading to complete resolution of the skin lesions and successful tapering of the corticosteroids. This case represents the first successful treatment of IgA-mediated anti-Laminin-γ1 (p200) pemphigoid using Stapokibart in combination with corticosteroid.

Background: Identifying patients who are most likely to benefit from the combination of bevacizumab and chemotherapy (Bev/CT) is essential for the optimal management of metastatic colorectal cancer (mCRC). The aim of this study is to investigate the utility of chronic inflammatory biomarkers in predicting clinical response to Bev/CT and outcomes in patients with mCRC.

Materials and methods: This study enrolled 364 patients with mCRC undergoing first-line Bev/CT therapy. The patients were randomly assigned to discovery (n=249) and validation (n=115) cohorts, maintaining an approximate 2:1 ratio. Two machine learning algorithms, least absolute shrinkage and selection operator (LASSO)-penalized Cox regression and random survival forest (RSF), were employed to identify significant inflammatory biomarkers. Logistic regression, Kaplan-Meier survival analysis, and Cox regression analyses were conducted to evaluate the associations between the clinical outcomes and a product of fibrinogen-pre-albumin ratio and systematic inflammatory ratio (SIR) (FPSIR) and clinical outcomes. The primary endpoints included clinical disease control rate (DCR) and progression-free survival (PFS), 2-year overall survival (OS) was designated as a secondary endpoint.

Results: Following the integration of inflammatory biomarkers identified through the LASSO and RSF algorithms, FPSIR was independently associated with PFS in both the discovery (p _log-rank<0.001, adjusted HR = 1.90, 95%CI=1.40-2.57) and validation cohorts (p _log-rank=0.01, adjusted HR = 1.89, 95%CI=1.21-2.98). Furthermore, FPSIR-H was significantly associated with worse 2-year OS in the two cohorts (discovery cohort: p _log-rank<0.001, adjusted HR = 2.15, 95%CI=1.49-3.10; validation cohort: p _log-rank=0.02, adjusted HR = 1.93, 95%CI=1.06-3.51). Survival nomograms that incorporated CEA, CA19-9 and FPSIR (CCF) score, along with peritoneum metastases, number of metastatic sites, surgical intervention, and treatment regimens could effectively estimate 2-year PFS (AUC = 0.83) and 18-month OS (AUC = 0.71) in the discovery cohort, demonstrating robust performance in the validation cohort (AUC = 0.76 and 0.75 for PFS and OS, respectively). Elevated FPSIR was correlated with diminished DCR in Bev/CT therapy (p < 0.01, adjusted OR = 2.24, 95% CI = 1.27-3.96). Serial measurements of FPSIR exhibited dynamic changes that effectively monitored the efficacy of Bev/CT treatment.

Conclusion: Pretreatment FPSIR was identified as a robust biomarker for predicting clinical efficacy and prognosis in mCRC patients receiving first-line Bev/CT, providing a promising strategy to address the long-standing challenge of treatment stratification.

CD36 is a multifunctional glycoprotein essential in fatty acid metabolism, angiogenesis, and atherogenesis, playing a critical role in immunological processes. This comprehensive review synthesizes current research to elucidate CD36's integral functions within the immune system, including its involvement in phagocytosis, inflammation, and the crucial interplay between innate and adaptive immune responses. We highlight novel insights into CD36 as a therapeutic target, presenting recent advances in targeting strategies for a spectrum of conditions such as inflammatory diseases, infections, metabolic disorders and cardiovascular diseases. By evaluating emerging research and clinical trials, this review proposes innovative approaches for exploiting CD36's therapeutic potential, aiming to inspire further research and development in disease treatment.

Background: Guselkumab, a monoclonal antibody targeting IL-23p19, has shown durable efficacy and safety in global phase III trials and real-world studies. However, in Chinese populations, comprehensive real-world evidence regarding its effects across disease severities, body areas, and metabolic parameters remains limited.

Objective: To conduct a multidimensional evaluation of guselkumab in moderate to severe plaque psoriasis based on Chinese clinical practice standards.

Methods: This retrospective analysis enrolled 90 patients receiving guselkumab and assessed efficacy from multiple dimensions, along with adverse events, drug survival, and metabolic indicators. Composite indices were used to evaluate coronary artery disease (CAD) and insulin resistance risk.

Results: Guselkumab showed sustained efficacy over 76 weeks in Chinese patients. Body area analysis showed significantly faster clearance of head lesions, with 40.0% of patients achieving complete clearance at week 4, compared to only 16.0% for lower extremities (P < 0.01). Baseline disease severity and switching to guselkumab due to inadequate response to prior biologics did not significantly affect treatment outcomes (P > 0.05). Predictors of PASI 100 at week 52 included normal BMI (OR = 6.10, 95% CI: 1.54-23.96), no phototherapy history (OR = 0.17, 95% CI: 0.04-0.71), and biologic-naïve status (OR = 0.14, 95% CI: 0.03-0.62). Mean fasting blood glucose (FBG) increased from 5.51 (0.74) to 5.65 (0.75) mmol/L at week 52 (P = 0.02). The Within Normal Limits (WNL) subgroup showed transient elevations in total cholesterol (week 28, P = 0.049) and triglycerides (week 28, P = 0.009). Although these indicators increased, they remained within the normal range. The Abnormal Without Treatment (AWT) subgroup exhibited decreased uric acid (UA) at week 52 (471.00 ± 51.06 to 418.72 ± 64.35 μmol/L; P = 0.004). Composite indices indicated no increased CAD or insulin resistance risk. Injection site reactions (32.2%) were the most common adverse events. Drug survival was 78.9% at 76 weeks.

Conclusion: This study confirms the durable efficacy and safety of guselkumab in Chinese patients with plaque psoriasis, with early response heterogeneity favoring the head. Treatment did not increase CAD or insulin resistance risk. Normal BMI and biologic-naïve status were associated with superior efficacy, supporting precision management strategies that integrate cutaneous and systemic monitoring.

Introduction: Mild ischemic stroke accounts for over half of all stroke cases, yet how peripheral immune responses evolve over time-and how they differ by infarct location-remains poorly defined.

Methods: Peripheral blood was collected from ten patients with mild ischemic stroke and five matched controls at days 1, 3, and 7 after onset. Patients were stratified by cortical or subcortical infarction. High-dimensional mass cytometry was used to characterize immune cell composition and immune checkpoint expression.

Results: Subcortical infarction was associated with sustained expansion of classical monocytes, persistent reduction of intermediate monocytes, and delayed PD-1/PD-L1 regulatory signaling, indicating prolonged myeloid-driven inflammation. In contrast, cortical infarction exhibited a more balanced monocyte profile and earlier PD-1 upregulation on dendritic cells and classical monocytes. CD4⁺ and CD8⁺ T-cell subsets showed distinct, location-dependent dynamics: cortical infarction induced earlier modulation of memory and regulatory phenotypes, whereas subcortical infarction produced slower but more persistent shifts. CCR5-defined CD8⁺ T-cell subsets also differed markedly, with subcortical infarction showing enrichment of CCR5⁺ effector cells, reduced checkpoint expression, and contraction of the CCR5⁻ compartment.

Discussion: Peripheral immune remodeling in mild ischemic stroke displays clear infarct location-specific trajectories. These findings highlight infarct topology as a critical determinant of post-stroke immune regulation and support the development of location-adapted immunomodulatory strategies.

Purpose: The purpose of this research study was to investigate the impact of isoimperatorin on Aspergillus fumigatus (A. fumigatus) keratitis and elucidate its underlying mechanisms via the TLR4/MyD88/IKK/NF-κB signaling pathway.

Materials and methods: The targets of the active ingredient isoimperatorin were identified via network pharmacology. Key interactions between isoimperatorin and its predicted targets were validated using molecular docking. In vitro RAW264.7 macrophage cells of A. fumigatus keratitis, the effects of isoimperatorin on inflammatory signaling and cell apoptosis were assessed using western blotting, immunofluorescence, and flow cytometry. In vivo C57BL/6 mouse models of A. fumigatus keratitis, the effects of isoimperatorin on inflammatory signaling, neutrophil infiltration, macrophage polarization, and cell apoptosis were assessed using quantitative real-time polymerase chain reaction (qRT-PCR), western blotting and immunofluorescence.

Results: Isoimperatorin inhibited TLR4/MyD88 complex formation and IKK/NF-κB phosphorylation, downregulated pro-inflammatory cytokines, reduced neutrophil infiltration, and promoted macrophage polarization from the M1 to the M2 phenotype. Additionally, it inhibited cell apoptosis and alleviated corneal epithelial damage.

Conclusion: This study demonstrates that isoimperatorin exerts a protective effect against A. fumigatus keratitis primarily by modulating the host immune response. The mechanism is mediated through the multi-target inhibition of the TLR4/MyD88/IKK/NF-κB pathway, leading to a coordinated reduction in inflammation and tissue damage. These findings highlight the therapeutic potential of isoimperatorin as a novel immunomodulatory strategy for managing fungal keratitis.

Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, yet the epigenetic mechanisms underlying its pathogenesis remain incompletely understood. Histone crotonylation, a novel post-translational modification, has been implicated in neuroinflammation. However, its role in AD-related cognitive impairment has not been elucidated.

Methods: Histone crotonylation was examined in 5xFAD and Aβ42-injected mice. Crotonic acid was administered intracerebroventricular (ICV) to elevate hippocampal histone crotonylation in wild-type mice. Cognitive function was assessed using behavioral tests. Synaptic integrity was evaluated via western blotting and Golgi staining. Microglial activation and co-localization of H3K18cr were determined by immunofluorescence. Transcriptomic analysis identified differentially expressed genes and enriched pathways. The role of signal transducer and activator of transcription 1 (STAT1) was validated in BV2 microglial cells using the STAT1 inhibitor fludarabine.

Results: Hippocampal pan-histone H3 crotonylation (H3Kcr) and H3K18cr were significantly upregulated in both 5xFAD and Aβ42-injected mice compared to controls. ICV injection of crotonic acid markedly elevated hippocampal H3Kcr and H3K18cr levels and induced significant cognitive deficits, shown by impaired novel object recognition and fear conditioning performance. Crotonic acid treatment resulted in synaptic dysfunction, including reduced synaptic markers (SYN1, SYT, GluA2, GluN2B) and decreased CA1 dendritic spine density. Crotonic acid also induced microgliosis with elevated Iba1 expression. H3K18cr was specifically upregulated in microglia, with no significant changes observed in neurons or astrocytes. Transcriptomic analysis identified 478 differentially expressed genes enriched predominantly in immune-related pathways, with STAT1 highlighted as a key upstream transcription factor. In BV2 cells, crotonic acid significantly increased total and phosphorylated STAT1 (Tyr701) levels via a JAK1-independent mechanism. Treatment with fludarabine effectively suppressed STAT1 expression and attenuated the production of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β.

Conclusion: This study provides the first evidence that elevated microglial H3K18cr contributes to AD-related cognitive impairment by promoting STAT1 expression and subsequent neuroinflammation. These findings identify microglial histone crotonylation as a novel epigenetic mechanism in AD pathogenesis and suggest that targeting the H3K18cr-STAT1 axis may represent a potential therapeutic strategy for AD.