Clinical Reviews in Allergy & Immunology最新文献

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.

Glandular involvement of the head and neck is an extremely rare feature in ANCA-associated vasculitis (AAV). The objective was to describe glandular involvement in AAV by analysing data from a national cohort and comparing the findings to those from a systematic literature review. A multicentric retrospective study was conducted through a survey promoted by the French Vasculitis Study Group and included patients aged ≥ 16 years who met the ACR/EULAR classification criteria for AAV and had lachrymal and/or salivary involvement. Demographic, clinical and biological findings were analysed and pooled with data from a MEDLINE review of the literature since inception until June 5, 2024. The study population included 20 patients with a median age of 52 years (IQR, 44.5-57.5 years). Granulomatosis with polyangiitis (n = 17) and PR3-ANCA (n = 10) were the most represented. Parotitis (n = 9) and dacryoadenitis (n = 8) were found to precede and/or were present at AAV onset and recurrences. All patients received glucocorticoids, usually in combination with immunosuppressants. The systematic review identified another 67 cases. Pooled analysis of all cases (n = 87) showed that salivary gland involvement was not only frequently associated with ENT features (OR = 4.01 (95% CI, 1.30-13.06; p < 0.01)), but also with PR3-ANCA positivity (OR = 3.34 (95% CI, 1.09-11.34; p = 0.02)). Lachrymal involvement was associated with concomitant ophthalmological signs (OR = 3.93 (95% CI, 1.31-12.14; p < 0.01)). Glandular involvement of the head and neck is a rare but identifiable manifestation of active AAV. Knowledge of this uncommon presentation refines clinical assessment for optimal management of patients with AAV.

Food allergies affect 6-8% of children worldwide and can significantly impact quality of life, with potentially severe reactions including anaphylaxis. Over recent decades, oral immunotherapy (OIT) has emerged as a treatment option for food allergies, but safety concerns with conventional high-dose protocols have limited its broader adoption. Low-dose OIT protocols have been developed to address these safety issues while maintaining therapeutic efficacy. This review focuses specifically on low-dose OIT protocols, their clinical outcomes, and evidence-based patient selection strategies. Low-dose OIT has demonstrated efficacy for several food allergens via successful desensitization and sustained unresponsiveness (SU). Clinical trials have reported SU achievements of 33-50% for milk, up to 71% for eggs, 25-37.5% for wheat, and 33-74% for peanut allergies after treatment. Notably, these protocols have shown improved safety profiles compared to conventional higher dose approaches, with substantially reduced rates of severe adverse reactions. Long-term follow-up studies of up to 6 years have shown progressively improving SU rates and a decrease in adverse events over time, supporting the durability of low-dose approaches. Critical factors for successful low-dose OIT implementation include appropriate patient selection based on age, risk stratification, and individual clinical characteristics. Integration with biological agents such as omalizumab may further enhance safety and efficacy in selected high-risk patients. While low-dose OIT offers a safer therapeutic option for persistent food allergies, careful patient selection remains essential to optimize treatment outcomes and minimize risks.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently identified late-onset, X-linked autoinflammatory disorder caused by somatic mutations in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene, which impair ubiquitination and protein degradation pathways. VEXAS is characterized by multisystem involvement, overlapping clinical features with other inflammatory conditions and high mortality. Despite growing attention, our understanding of its pathophysiology, immune dysregulation, and optimal treatments remains limited. This report aims to explore the molecular pathogenesis, diagnostic criteria, and therapeutic approaches for VEXAS syndrome in the context of chronic hepatitis B virus (HBV) infection. A 68-year-old Chinese male patient presented with persistent fever, fatigue, arthritis, weight loss, and hematologic abnormalities (severe macrocytic anemia and thrombocytopenia). Genetic testing revealed a somatic UBA1 mutation (p.Met41Val, c.121A > G, 67.84%) in myeloid cells, confirming VEXAS syndrome. The patient also had chronic HBV infection with active viral replication. Treatment included antiviral therapy (entecavir) for HBV and a combination of corticosteroids and immunosuppressants for VEXAS syndrome. After a follow-up of 6 months, significant improvements were observed in clinical symptoms, hematologic parameters, and inflammatory markers. This case highlights the interplay between chronic HBV infection and VEXAS syndrome-mediated immune dysregulation. Integrated antiviral and immunosuppressive strategies are essential to manage VEXAS syndrome with chronic hepatitis B virus comorbidity. Future studies should focus on targeted therapies, such as JAK-STAT inhibitors and IL-6 blockade, to improve outcomes in patients with chronic viral infections and VEXAS syndrome.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common upper airway inflammatory disorder, characterized by persistent inflammation of the sinonasal mucosa and nasal polyp formation. The pivotal roles of interleukin (IL)-4/IL-13 signaling in CRSwNP pathogenesis is increasingly recognized, evidenced by the remarkable clinical success of biologics targeting this pathway. This review provides a concise overview of the IL-4/IL-13 pathway in CRSwNP, encompassing its molecular architecture, pathogenic mechanisms, current targeted therapies, and emerging therapeutic strategies.

The ubiquitin-proteasome system (UPS) plays a crucial role in asthma by regulating protein stability And activity through post-translational modifications. This review provides a comprehensive Analysis of 42 UPS components in asthma, including one E2 ubiquitin-conjugating enzyme, 27 E3 ubiquitin ligases, eight deubiquitinating enzymes (DUBs), one dual-function (both E3 and DUB) enzyme, And five components of the 26S proteasome. Our Analysis focuses on four key pathological features, including airway inflammation, hyperresponsiveness, mucus hypersecretion, And remodeling. We identify 25 E3 ligase-substrate pairs and seven DUB-substrate pairs, detailing their ubiquitination and deubiquitination mechanisms. Additionally, a Literature review combined with GWAS data reveals 20 single-nucleotide polymorphisms (SNPs) across nine UPS Genes associated with asthma susceptibility. Therapeutic evaluations highlight 24 druggable UPS targets. Furthermore, we underscore 24 UPS-related compounds, with ten having established relevance to asthma And 14 exhibiting untapped potential. Emerging treatment strategies such as PROTACs and nanovaccines show promising potential. Overall, these findings provide new insights into UPS-mediated mechanisms and genetics in asthma and highlight its potential as a therapeutic target, paving the way for future research and clinical applications.