Clinical Reviews in Allergy & Immunology最新文献

Self-DNA sensing by the immune system was discovered more than half a century ago. It has emerged as a key factor in the development of cancer, autoimmune diseases and many inflammatory diseases. While the innate immune response has been extensively studied, how self-DNA drives adaptive immune responses, particularly those mediated by T cells, has only been gradually unraveled over the past decade. In fact, adaptive DNA immunity plays a role in key cellular activities relevant to physiology and disease, containing cell functional activation, proliferation, differentiation, senescence and apoptosis. Herein, we review the latest research of self-DNA induced T cell immune response from the point of the origin of self-DNA, the mechanism of T cell responses to self-DNA and the fate of T cells. We also summarize how these cellular maneuvers influence disease outcome in mammalian cells, providing an overview of the expanding landscape of self-DNA-evoked T cell immunity.

The emergence of SARS-CoV-2 has not only reshaped our understanding of viral pathogenesis but also highlighted its capacity to trigger autoimmune and inflammatory diseases. Accumulating evidence indicates that SARS-CoV-2 infection can lead to a broad spectrum of immune-mediated complications, ranging from well-defined conditions such as Guillain-Barré syndrome, multisystem inflammatory syndrome in children (MIS-C), and systemic lupus erythematosus, to the development of diverse autoantibodies and atypical inflammatory phenotypes. This review synthesizes the current clinical and experimental evidence linking COVID-19 to autoimmune and inflammatory sequelae. We have provided a structured overview on the multifactorial mechanisms underpinning this immune dysregulation, including molecular mimicry, epitope spreading, bystander activation, cytokine storm, host genetic predisposition, and viral genomic variability. Additionally, we discussed the contribution of gut dysbiosis and metabolic reprogramming in shaping aberrant immune responses following infection. Special attention is given to the therapeutic potential of intravenous immunoglobulin (IVIG), which has shown promise in mitigating hyperinflammation and modulating autoimmunity in affected individuals. IVIG can provide therapeutic benefits by diverse mutually nonexclusive mechanisms. By integrating emerging insights across clinical immunology, virology, and host-pathogen interactions, this review aims to advance our understanding of COVID-19-induced immune complications and therapeutic strategies to manage post-COVID autoimmune and inflammatory syndromes.

Myopia represents a growing global public health challenge, characterized by increasing prevalence and associated complications such as myopic macular degeneration and retinal detachment. Although genetic and environmental factors are well-recognized contributors, emerging evidence supports a pathological link between inflammation and myopia progression. Epidemiological studies indicate a higher incidence of myopia among individuals with systemic or ocular inflammatory conditions. Inflammation perturbs the ocular immune microenvironment by upregulating pro-inflammatory cytokines and matrix metalloproteinase-2, thereby accelerating extracellular matrix (ECM) degradation and scleral remodeling, which culminates in axial elongation. Conversely, excessive axial elongation in high myopia triggers choroidal microvascular dysfunction, tissue hypoxia, and disruption of the blood-retinal barrier, leading to elevated inflammatory cytokines in the aqueous humor and vitreous, thereby raising the possibility of a self-perpetuating loop. Anti-inflammatory agents, including diacerein, resveratrol, and lactoferrin, have demonstrated therapeutic potential in experimental models by modulating inflammatory pathways, reducing pro-inflammatory cytokines, and preserving ECM integrity. However, their clinical efficacy and long-term safety require further validation. Elucidating the complex interplay between inflammation and myopia is pivotal for the development of targeted interventions, moving the focus of myopia management beyond optical correction towards disease-modifying strategies.

In recent years, the prevalence of obesity and asthma has risen steadily, emerging as two major chronic diseases threatening public health. These conditions exert mutual promotion and may induce pathological superposition effects in obesity-related asthma. Obesity-related asthma represents a distinct asthma phenotype, with pathogenesis involving chronic low-grade inflammation, metabolic dysregulation, mechanical constraints, and genetic predispositions. Critically, four core components, including adipose dysfunction with metabolic dysregulation, gut microbiota dysbiosis with intestinal barrier impairment, systemic chronic inflammation, and pulmonary inflammation with airway hyperresponsiveness, interlock into a self-reinforcing cycle that synergistically amplifies disease progression. Accordingly, obesity-related asthma exhibits a greater clinical burden than classical asthma, including more severe symptoms, higher exacerbation rates, and poorer therapeutic responsiveness. As key metabolites derived from gut microbiota, short-chain fatty acids (SCFAs) demonstrate potential to disrupt this pathological cycle in obesity-related asthma through anti-inflammatory actions, immune-metabolic modulation, and epithelial barrier protection. Furthermore, SCFA levels can be effectively modulated through dietary interventions, microbial preparation supplementation, and fecal microbiota transplantation, positioning them as promising translational targets for obesity-related asthma.

ETS1 and FLI1 exhibit distinct roles in immunoregulation and autoimmune pathogenesis. Previous transethnic genome-wide meta-analyses incorporating our Han Chinese population established significant associations between ETS1 single-nucleotide polymorphisms (SNPs) and susceptibility to primary biliary cholangitis (PBC). In our earlier genome-wide association study (GWAS), ten SNPs within the ETS1 and FLI1 loci demonstrated modest yet suggestive associations with PBC susceptibility in the Han Chinese population. To validate these putative risk loci, we conducted an independent replication study of rs10893900 and rs2246290 using a separate Han Chinese PBC cohort. A meta-analysis combining data from two stages identified rs10893900 as a genome-wide significant variant (P = 4.55 × 10^-8, OR = 1.19, 95% CI = 1.12-1.27). Subsequent functional characterization identified rs10893900 as a susceptibility-associated functional variant. Based on the literature review, we summarized ETS1 variants' susceptibility to human autoimmune diseases, including SLE, RA, and PBC, and evaluated these variants in silico analysis. Importantly, our research implicates the importance of ETS1 involving JAK-STAT signaling pathway, expanding the understanding of pathological mechanisms of PBC.

T cell metabolism constitutes a pivotal regulator of cellular states and disease progression. At the cellular level, the metabolic status of T cells directly governs their function and fate determination. Senescent T cells, for instance, exhibit fundamentally distinct metabolic signatures compared to effector T subsets, underscoring metabolic reprogramming as a critical mechanistic driver of T cell senescence. In pathological contexts, aberrant metabolic rewiring in T cells disrupts differentiation, function, and cellular survival, thereby contributing to disease onset and progression. Notably, the pathological accumulation of senescent T cells observed across chronic inflammatory and autoimmune diseases positions metabolism-driven T cell senescence as a key nexus linking metabolic dysregulation to clinical manifestations. Consequently, targeted modulation of T cell metabolism offers a dual therapeutic potential: direct intervention in cellular states (e.g., delaying senescent phenotypes) and synergistic amelioration of disease pathology through functional immune restoration. This Review summarizes the fundamental principles of T cell metabolic reprogramming, its causative role in propelling T cell senescence, and the dynamic interplay between metabolic dysfunction, T cell senescence, and disease pathogenesis. We specifically dissect these relationships in two immunologically divergent conditions-systemic lupus erythematosus (SLE, exemplifying hyperactive autoimmunity) and chronic infection (Chronic HIV infection, reflecting immune exhaustion)-to establish a mechanistic framework for developing metabolism-targeted immunotherapeutics that precisely restore T cell efficacy.

Allergen-specific immunotherapy (AIT) is currently the only disease-modifying treatment for food allergies. The most extensively studied form of AIT is oral immunotherapy, in which an increasing dose of specific food allergen is gradually introduced to allergic patients for immune system "re-education." It has been demonstrated to effectively achieve desensitization, raising the threshold for inducing allergic reactions after allergen ingestion. However, lengthy dosing schedules and the occurrence of severe adverse events have impeded the adoption and compliance of oral immunotherapy. In recent years, extensive efforts in developing novel platforms have been directed to heighten the immunogenicity and lower the allergenicity of AIT, in hopes of increasing its efficacy and safety. Certain vaccine candidates have been investigated in preclinical and clinical trials. In this review, we aim to summarize the state-of-the-art technology of next-generation AIT vaccines for food allergy and explore research gaps in the field that warrant further investigation. We adopted a 'Cargo-Truck-Lubricant' analogy to illustrate the components of AIT, corresponding to modified allergens, carriers delivering the allergens, and the immunomodulators fostering the delivery. While most studies focused mainly on peanut allergy, novel AITs for other food allergies were still in preclinical stages. Future directions point towards optimization and the clinical translation of next-generation AIT vaccines to maximize the therapeutic outcome and minimize risks.

Non-celiac wheat sensitivity (NCWS) is a clinical entity characterized by gastrointestinal and extraintestinal symptoms triggered by wheat ingestion, distinct from celiac disease and wheat allergy. Its pathophysiology is complex and multifactorial, involving alterations in intestinal barrier integrity, gut microbiota dysbiosis, activation of innate and adaptive immune responses, and neuroimmune interactions. These alterations, however, are not specific to NCWS and may also be observed in other conditions. Emerging evidence highlights the role of non-gluten wheat components, gut dysbiosis, and neuro-immune interactions exacerbating immune responses and visceral hypersensitivity. Clinically, NCWS patients present with a wide spectrum of gastrointestinal symptoms and extraintestinal manifestations including fatigue and neuropsychiatric disorders, underscoring the need for a multidisciplinary approach. Diagnosis remains challenging due to the absence of validated biomarkers. It is predominantly based on the exclusion of celiac disease and wheat allergy, symptom resolution upon wheat withdrawal, and symptom recurrence after blinded wheat exposure, as recommended by the Salerno Experts' Criteria. Current management primarily involves dietary interventions, such as gluten-free or wheat-free diets, often complemented by low-FODMAP diets and strategies targeting microbiome modulation. However, restrictive diets may lead to nutritional deficiencies and impact quality of life, highlighting the necessity for personalized dietary interventions. This comprehensive review synthesizes recent advances in understanding the pathophysiology of NCWS, emphasizing their clinical implications for diagnosis and management, and identifies critical areas for future research.

Immunodeficiencies in adults are increasingly recognized yet often remain underdiagnosed, leading to significant morbidity from recurrent infections, autoimmunity, and malignancy. Both primary immunodeficiencies (PIDs), now known as inborn errors of immunity (IEI), and secondary immunodeficiencies (SIDs) contribute to immune dysfunction in adults. Although SIDs are more common in adults due to factors like medications, malignancies, metabolic disorders, chronic conditions, and protein-losing conditions, IEI-particularly common variable immunodeficiency (CVID)-can also manifest in adulthood with diverse clinical features. Early recognition is crucial, with key warning signs including recurrent sinopulmonary infections, unexplained autoimmunity, poor vaccine responses, chronic diarrhea, bronchiectasis, and persistent lymphadenopathy. The diagnostic approach should be systematic. It begins with a detailed patient history and status followed by the evaluation of immunoglobulin levels, lymphocyte subsets, vaccine-specific antibody responses, and exclusion of secondary causes. Genetic testing, increasingly accessible, plays an important role in confirming the diagnosis of IEI and guiding prognosis and treatment. Management strategies focus on treating the underlying condition in SIDs. Preventive measures, including antimicrobial prophylaxis, vaccination, and immunoglobulin replacement therapy (IGRT) in patients with significant antibody deficiencies, are essential for reducing infections and complications in high-risk patients. Given the growing recognition of adult-onset immunodeficiency, clinicians should maintain a high index of suspicion and adopt a structured diagnostic and management approach to improve patient outcomes and quality of life.

PD-1 (Programmed cell death protein 1) located on T cells, binds to PD-L1 (Programmed cell death ligand 1) on cancer cells, to suppress T cell activation and enable immune evasion. Hitherto, reviews have mainly highlighted the role of PD-1/PD-L1 in anti-cancer immunomodulation, anti-cancer therapy resistance, and immune-related adverse events. However, there are critical modes of enhancement of therapeutic efficacy, which remain underappreciated. This review provides a holistic perspective on: (a) a comprehensive analysis of recent clinical trials targeting PD-1/PD-L1, specifically on the use of immune checkpoint inhibitors (ICIs); (b) the underlying molecular mechanisms of immune surveillance; (c) the role of ubiquitin-mediated post-translational modifications (PTMs, viz the ubiquitin machinery); and (d) the gut microbiome crosstalk with the PD-1/PD-L1 axis, which influences the tumor microenvironment (TME). Clarity gained from opinions exerted from these four factors, in this review, will provide insights on improving cancer prevention, diagnosis, and treatment, thus bridging translational research to the clinic. These standpoints will be presented with a view to advocating the integration of precision medicine with AI, to accelerate the discovery of more effective ICIs and enhance mono-/combinatorial drug strategies for PD-1/PD-L1-targeted therapy. Altogether, this review opines that AI-driven analytics will provoke an innovative impact on promoting clinical outcomes beneficial for cancer patients.