Frontiers in Immunology最新文献

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known as the etiological agent of coronavirus disease 2019 (COVID-19). Extrapulmonary manifestations of COVID-19 have gained increasing recognition as significant contributors to disease severity and long-term complications. The aim of this study is to investigate the neuroprotective properties of vaccines based on modified Vaccinia Virus Ankara (MVA) against SARS-CoV-2 infection in K18-hACE2 mice using different immunization protocols. Animals received PBS, vector, recombinant MVA expressing native (S) or stabilized (ST) SARS-CoV-2 spike protein, nucleocapsid protein (N) or both ST and N protein twice, followed by infection with SARS-CoV-2 four weeks later. In further experiments, mice were immunized only once and infected two days (Emergency experiment) or four weeks (Prime experiment) later. Both the control groups and the animals immunized with vaccines expressing only N-protein showed mild to moderate, lymphohistiocytic meningoencephalitis, microgliosis and numerous virus antigen-positive neurons in the brains and to a lesser extent in the retinas. Groups immunized four weeks prior to infection with vaccines containing viral spike protein showed no or minimal inflammatory changes and no neuroinvasion. Animals infected two days after immunization showed milder lesions than unvaccinated control groups.

Objective: Immune checkpoint inhibitors (ICIs) can induce immune system activation and cause immune-related adverse events (irAEs). This study aimed to assess the incidence and management of irAEs in thymoma patients with preexisting MG who received ICI therapy.

Methods: This was a retrospective observational cohort study. From September 2018 to May 2024, 12,916 patients received ICI therapy at our hospital. Among them, six patients with preexisting MG and thymoma (MGT) received ICI treatment, and ten thymoma patients without MG (TOMA) served as controls. irAEs, MG flares, and treatment outcomes were primarily assessed through retrospective review of medical records. Anti-acetylcholine receptor antibody (AChR-Ab) levels and pathological thymoma tissue features were analyzed to explore the potential mechanisms underlying the irAEs.

Results: Compared with TOMA patients (n=10), all MGT patients (n=6) had grade 3 or higher irAEs (p=0.034) and experienced ICI-induced myocarditis (p=0.011). All MGT patients experienced symptom exacerbation, including a myasthenic crisis. MGT patients who received immunosuppressive agents before ICI therapy and those who received both steroids and intravenous immunoglobulin (IVIG) during irAE occurrence had better outcomes. AChR-Ab levels markedly increased one month after the onset of irAEs. Furthermore, two TOMA patients with germinal centers (GCs) in their thymus tissues had severe irAEs, whereas two without GCs had no irAEs.

Conclusion: In this study, irAEs were common and severe in patients with preexisting MG and thymoma following ICI therapy. Pretreatment immunosuppressive therapy was associated with better clinical outcomes. The presence of GCs in thymoma patients without MG may serve as a predictive biomarker for the occurrence of irAEs.

Introduction: Autoimmune hepatitis is a chronic inflammatory liver disease in which the immune system attacks liver tissue. While genetic predisposition plays a role, environmental factors are increasingly recognized as contributors to disease onset and progression. This study aimed to examine the association between environmental exposures and autoimmune hepatitis in a Yemeni population.

Methodology: A case-control study was conducted, including 93 patients with clinically diagnosed autoimmune hepatitis and 280 age- and sex-matched healthy controls. Data was collected through structured interviews and laboratory analyses. Environmental exposures assessed included residence in different temperature zones, history of viral infections, medication use, pesticide exposure, and the habit of chewing Khat. Liver biopsy findings and vitamin D levels were evaluated to assess disease severity. Statistical comparisons were performed using odds ratios and confidence intervals to determine associations.

Results: Khat chewing was significantly more common in autoimmune hepatitis patients than in controls (65.6% versus 42.1%, OR: 2.6; 95% CI: 1.6-4.3, p < 0.001). Exposure to medications known to induce autoimmune reactions, such as nitrofurantoin and minocycline, was also higher among patients (27.9% versus 1.8%, OR: 21.3; 95% CI: 7.9-57.7, p < 0.001). Living in warm temperature zones and exposure to pesticides (OR: 13.1; 95% CI: 2.7-62.8, p < 0.001) were both significantly associated with increased disease risk. Patients with these exposures also demonstrated higher liver enzyme levels and more advanced fibrosis on biopsy. Vitamin D deficiency was associated with greater disease severity.

Conclusions: These findings highlight the important role of environmental factors, particularly Khat chewing and pesticide exposure, in the development and progression of autoimmune hepatitis in Yemen. Public health interventions addressing these exposures may help reduce disease burden.

With global population aging, senescence has emerged as a key driver of tumorigenesis. Aging-associated molecular changes, including DNA damage, telomere shortening, and epigenetic dysregulation, increase malignancy, while immunosenescence and the senescence-associated secretory phenotype (SASP), reshape the tumor microenvironment to favor immune suppression and tumor escape. Aging also impairs antigen presentation, disrupts ligand-receptor signaling, and compromises tumor suppressive pathways. In the era of immunotherapy, elderly patients face reduced efficacy and increased resistance due to age-related immune remodeling. This review summarizes mechanisms of tumor immune escape in aging and discusses strategies to improve outcomes, such as senescent cell clearance, SASP modulation, immune potentiation, and combination therapies.

Axial Spondyloarthritis (AS) is a chronic immune-mediated disease of the axial skeleton characterized by persistent inflammation and pathological bone formation driven by reciprocal signaling between immune and stromal cells. Central to this interplay is adenosine-a key metabolic regulator of immune tolerance and tissue remodeling. In AS, purinergic homeostasis is profoundly disrupted: the ectonucleotidases CD39 and CD73, responsible for adenosine synthesis, are downregulated, while adenosine-degrading enzymes ADA and its surface anchor CD26 are upregulated. This enzymatic disequilibrium depletes adenosine in inflamed tissues, impairs FOXP3⁺ regulatory T cell induction, and amplifies Th17-driven inflammation and fibroblast activation. We propose a stage-specific therapeutic framework for restoring adenosine balance in AS encompassing: (1) reconstitution of CD39/CD73 enzymatic activity, (2) receptor-selective modulation of A₂A and A₂B signaling pathways, and (3) exosome-mediated delivery of adenosine-regulating enzymes and microRNAs to reestablish immune homeostasis with cellular precision. The dual nature of adenosine-anti-inflammatory through A₂A receptor activation and pro-fibrotic via A₂B receptor engagement-necessitates context-aware targeting to suppress immune dysregulation without promoting ossification. This synthesis integrates molecular, cellular, and translational insights into a unified model of AS pathogenesis. By aligning mechanistic disruption with stage-specific and exosome-enabled interventions, it establishes a conceptual foundation for precision therapies aimed at recalibrating immune-stromal interactions and halting structural progression. This review synthesizes published mechanistic and translational evidence and includes hypothesis-generating therapeutic concepts that remain to be formally validated in AS.

The administration of therapeutic proteins may induce an anti-drug antibody (ADA) response which may impact pharmacokinetics, safety or efficacy. Numerous factors contribute to ADA development, such as patient population, drug sequence, formulation impurities, as well as drug dose and frequency. Here we report data from a natural experiment where ADA incidence for monoclonal antibodies (mAbs) casirivimab (CAS) and imdevimab (IMD), targeting the SARS-CoV-2 spike protein, was more than 3-fold higher in COVID-19 vaccinated participants compared to unvaccinated. Although ADA incidence to the mAbs was elevated in vaccinated participants, there was no increase in the strength or magnitude of the ADA response, despite these participants developing robust immunogenicity directed against the COVID-19 vaccine. In vitro studies using sedimentation velocity analytical ultracentrifugation demonstrated large complexes (ranging from 1.6 to 4 MDa) being formed between CAS+IMD and recombinant spike trimer. In addition, the substantially increased immunogenicity to CAS+IMD was only observed in participants receiving mRNA-LNP-based products, likely due to higher expression of spike protein compared to adenovirus-based products. No increase in ADA was observed in COVID-19 vaccinated participants receiving mAbs to unrelated targets, suggesting COVID-19 vaccination was not a general adjuvant. Taken together, these data suggest in participants vaccinated with mRNA-LNP-based products, the formation of large mAb-target immune complexes likely results in greater surveillance by immune cells and increased ADA development to mAbs against the same target.

Originally reported as an oncogene and currently known to be a major "genome guardian", the p53 protein remains one of the most explored transcription factors, exhibiting variety of functions both within transcription regulation and beyond. Given that p53 dysfunction contributes to the majority of human cancers, understanding its regulatory mechanisms and therapeutic potential remains a primary research focus. This review addresses the key aspects of p53 regulation and functionality, analyses its role in tumor evolution, and provides a comprehensive analysis of current and emerging therapeutic strategies targeting the p53, with particular emphasis on immunotherapy approaches.

Age-related hearing loss is a global public health issue that impacts the quality of life in the elderly population. Macrophages are the main immune cell population in the cochlea, yet the role in the development and progression of age-related hearing loss is still unclear. This study analyzed single-cell sequencing data from cochlear tissues of C57BL/6J mice across different ages and identified notable increase in CD74 expression in macrophages with aging. Validation revealed that CD74 levels were elevated in the aged cochlea, while macrophage migration inhibitory factor (MIF) levels decreased. MIF was significantly reduced in both senescent HEI-OC1 cells and supernatant. Notably, the senescent HEI-OC1 supernatant stimulated BV2 cells CD74 expression increased. rCD74 significantly upregulated apoptosis-related genes expression levels in HEI-OC1 cells, while decreasing MIF levels. In the co-culture system of scrambled/CD74^-BV2 cells and HEI-OC1 cells, CD74^- BV2 cells markedly reduced the apoptosis-related genes expression in senescent HEI-OC1 cells. MIF could improve the mitochondrial membrane potential of both groups of HEI-OC1 cells, and decreased the TUNEL positive cells significantly. Our findings using the HEI-OC1 cell model reveal that macrophages secrete CD74 into the microenvironment, where it interacts with MIF, reducing local MIF levels. This interaction weakens MIF's protective effect on senescent HEI-OC1 cells, promoting apoptosis in these auditory cells. This suggests a potential mechanism whereby elevated CD74 in the aging cochlear microenvironment may contribute to the loss of hair cells in vivo. Targeting macrophage CD74 may offer therapeutic potential for preventing and treating age-related hearing loss.

Our understanding of the mechanisms underlying multiple sclerosis (MS) has advanced substantially over recent decades, yet the primary drivers of disease onset and progression remain unclear. Immune dysregulation, particularly antibody-mediated processes and lymphocyte activation, is widely recognised as central to MS pathogenesis, and immune-targeted therapies have improved the management of relapsing disease. However, neither self-antigens nor self-antibodies have been definitively identified. This leaves open a fundamental question: does immune activation initiate MS, or does it arise in response to earlier pathological events? Most of our current knowledge relies on extrapolating findings from artificially induced models, which are mechanistically informative but may be limited in explaining spontaneous onset and responses to neurodegeneration in MS. Furthermore, the recent reclassification of conditions such as MOGAD and NMOSD, previously considered within the MS spectrum, has prompted renewed reflection on longstanding assumptions regarding MS aetiology. In this review, we refine the definition of autoimmune disease (AD) and apply a systematic, criterion-based evaluation of MS, complemented by direct comparison with well-established autoimmune conditions. Unlike previous reviews, which have largely addressed this question in conceptual terms, this paper explicitly examines whether MS fulfils the defining features of autoimmunity. By doing so, we highlight conceptual and evidentiary gaps that remain unresolved. Clarifying whether MS should be defined as autoimmune is not merely semantic, but has important implications for experimental modelling, biomarker discovery, and therapeutic development. By encouraging exploration beyond the conventional autoimmune framework, this review seeks to support a more integrative understanding of disease mechanisms.