Current Opinion in Allergy and Clinical Immunology最新文献

Purpose of review: This review provides the current understanding on primary antibody deficiencies (PAD) in children with chronic rhinosinusitis (CRS).

Recent findings: There is clear evidence that the prevalence of PAD is higher in children with CRS than in the general population. Common disorders include common variable immunoglobulin deficiency (CVID), X-linked agammaglobulinemia (XLA), specific antibody deficiency (SAD), IgG subclass deficiency (IGGSD), selective IgA deficiency (SIGAD), and hyperIgM syndrome. Despite the presence of multiple studies addressing CRS and PAD, the level of evidence supporting different treatment options continues to be lacking. Optimal management requires a multidisciplinary approach through collaboration with clinical immunology.

Summary: This review outlines the current approach for diagnosis and treatment of PAD in children with CRS. While some of the disorders can be asymptomatic, children who present with more severe deficiencies will present with chronic and recurrent rhinosinusitis, as well as recurrent otitis media and pneumonia. Otolaryngologists are often at the forefront of early diagnosis of these disorders.

Purpose of review: Asthma is a mosaic of phenotypes shaped by complex host-environment interactions. Among these, the microbiome has moved to a central determinant of disease expression, and airway and gut microbiome should be seen as active players in asthma pathophysiology. This review critically examines how environmental exposures, including pollution, drugs, diet, and climate, remodel microbial ecosystems, and reprogram immune responses in adults with asthma, with emphasis on clinical translation.

Recent findings: Advances from multiomics, large-scale cohorts, and Mendelian randomization studies reinforce the concept of the gut-lung axis as a decisive modulator of asthma outcomes. Airway dysbiosis, often marked by Proteobacteria dominance, consistently correlates with poor asthma control, exacerbations, and steroid resistance. Environmental determinants of microbiome reshape erode immune tolerance. Microbial metabolites such as short-chain fatty acids act as molecular messengers capable of restoring epithelial and immune balance. These findings challenge the traditional inflammatory-centric view of asthma and demand broader mechanistic frameworks.

Summary: The microbiome should be considered a central piece of the puzzle in asthma research. Precision medicine in adult asthma will remain aspirational unless microbiome-informed biomarkers and interventions are embraced. Robust interventional studies are urgently needed to translate this promise into practice.

Purpose of review: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disorder, with neutrophilic inflammation representing a clinically challenging endotype due to its resistance to corticosteroids and biologics targeting type 2 responses. Single-cell RNA sequencing (scRNA-seq) studies are providing novel insights into the pathogenesis of CRSwNP, particularly the roles of neutrophils and stromal cells. This review discusses how scRNA-seq has inspired a new focus on stromal-immune cell crosstalk as a driver of neutrophilic inflammation. We emphasize the pathogenic contributions of fibroblasts, granzyme K-expressing (GZMK+) CD8+ T cells, and dysregulated cytokine networks such as interleukin (IL)-1β and C-X-C motif chemokine ligand (CXCL). Understanding these interactions is critical for developing endotype-specific therapies for refractory CRSwNP characterized by neutrophilic inflammation.

Recent findings: ScRNA-seq has revealed a significant heterogeneity in neutrophils and stromal cell populations within CRSwNP, with distinct subpopulations exhibiting unique functional profiles. The IL-1β-activated indoleamine 2,3-dioxygenase 1-expressing (IDO1+) fibroblast subset drives neutrophilic inflammation in CRSwNP through secreting a number of CXCL chemokines. Lymphocyte antigen 6 family member D-expressing (LY6D+) club cells in nasal epithelium express high levels of S100 calcium binding protein A (S100A) 8 and S100A9, known as chemoattractants for neutrophils, under IL-1β stimulation. Fibroblast-derived CXCL12 recruits C-X-C motif chemokine receptor (CXCR) 4+GZMK+CD8+ T cells, establishing a feed-forward inflammatory loop. This cycle is driven by GZMK-mediated stromal activation, resulting in the secretion of potent neutrophil chemokines. Therapeutics targeting of IL-1β and CXCL12-CXCR4 signaling show potential for suppressing neutrophilic inflammation in CRSwNP.

Summary: Stromal and immune cell interactions drive neutrophilic inflammation in CRSwNP. Targeting these cells and their signaling networks offers promising avenues for precision therapy, aiming to control neutrophilic inflammation, reduce associated polyp recurrence, and improve long-term disease outcomes.

Purpose of review: Asthma management is ongoing a paradigm shift from symptom control and exacerbation prevention toward the more comprehensive goal of clinical remission. This review is timely because biologic therapies, precision medicine, and improved understanding of immunopathological mechanisms have made remission a realistic therapeutic goal. By integrating clinical, functional, and biological outcomes, remission offers a more comprehensive framework for assessing long-term disease control.

Recent findings: Recent evidence demonstrate that biologic drugs, such as Mepolizumab, Omalizumab, Dupilumab, Benralizumab, and Tezepelumab, allow clinical remission to be achieved in many patients affected by severe asthma particularly those who show a phenotyping polarized toward T2-High. Lifestyle change, particularly weight loss and smoking cessation, early intervention, and the use of allergen immunotherapy may increase the chances of achieving remission. Real-world data confirm that remission rates vary depending on the definition applied, going from clinical to complete remission, highlighting the lack of a universally shared definition of remission and the need for standardized criteria.

Summary: Clinical remission in asthma is now a feasible target. Achieving this goal requires a multidimensional approach that integrates biologics, early treatment, comorbidity management, and lifestyle interventions. Standardized definitions and biomarkers are essential to guide therapeutic decisions and predict long-term outcomes.

Purpose of review: Immediate hypersensitivity disorders, such as asthma, food intolerance, and anaphylaxis, have risen dramatically since the 20th century, marking a shift in the global disease burden. While mast cells have been associated with IgE-mediated disorders, they also play important roles in homeostasis. To prevent chronic inflammation and aberrant tissue remodeling, tight regulation of mast cells is essential in response to microorganisms, autoantigens, and environmental changes.

Recent findings: The surge in mast cell-mediated disorders and evidence of mast cell interactions with epithelial and neural networks have led to the epithelial barrier hypothesis. This hypothesis extends the protective role of the epithelium by highlighting its integrated communication with both the nervous and immune systems, proposing that dysregulated nerve-mast cell signaling at epithelial barriers contributes to the development of immediate hypersensitivity disorders - both allergic and nonallergic phenotypes. In turn, it offers new strategies for prevention and treatment, focusing on restoring barrier integrity and modulating neuroimmune pathways.

Summary: Clinical populations including hypermobility syndromes, such as certain Ehlers-Danlos syndrome variants and Job syndrome, exemplify the systemic consequences of disrupted epithelial barriers and chronic nerve-mast cell dysregulation. Accordingly, this review discusses the co-emergence of hypersensitivity and hypermobility syndromes as manifestations of immune-neuro-epithelial dysfunction in the context of modern environmental change.

Purpose of review: Alpha-gal syndrome (AGS) is a unique allergy to the carbohydrate galactose-alpha-1,3-galactose, which is found in mammalian products, excluding humans and Old World primates. As its prevalence increases, we are learning that AGS has broader geographical range and wider medical impact than initially recognized.

Recent findings: Time to diagnosis has improved in recent years, but AGS still presents challenges for diagnosis and management, AGS may be found in a larger geographic distribution than originally supposed, and new potential arthropod triggers have been identified. Recent research demonstrates some of the immunologic changes that occur after arthropod bites that can lead to the production of alpha-gal IgE, but we still do not understand why certain individuals become allergic while others are only sensitized. Presentation can vary widely, and reactions may be inconsistent. The list of foods and medical products recognized to have potential for causing reactions continues to expand, which has implications for management of other conditions in patients with AGS.

Summary: With the growing prevalence of AGS, it is increasingly important for clinicians to recognize the syndrome and understand its management.

Purpose of review: This review examines how environmental injustice contributes to disparities in allergic diseases, including asthma, allergic rhinitis, and atopic dermatitis. It focuses on the role of social, geographic, and economic inequities in shaping disease prevalence, severity, and access to care among underrepresented racial and ethnic communities.

Recent findings: Recent studies emphasize the persistent exposure of low-income and racially marginalized populations to environmental hazards such as air pollution, substandard housing, and climate-related changes, factors that are linked to increased prevalence and severity of allergic diseases. While environmental policies have led to overall improvements in air quality, disparities in exposure and outcomes persist. Emerging policies show promise in reducing these gaps through more equitable and inclusive approaches.

Summary: Environmental injustice is a key driver of health disparities in allergic diseases and asthma. Structural inequities continue to place marginalized communities at higher risk of harmful exposures and adverse health outcomes. Addressing these disparities requires collaboration between policymakers, healthcare workers, researchers, and affected communities.

Purpose of review: In the past, treatment of asthma aimed primarily at "control" of symptoms and a reduction of future risk. Recently, however, the concept of remission has been introduced which is broader than control and includes the concept of disease modification by using disease-modifying antiasthmatic drugs (DMAADs) that exclude the use of systemic corticosteroids. This review highlights the definitions as well as the clinical implications of the concept of remission in asthma.

Recent findings: While in the past remission has been used mainly for the relatively rare event of spontaneous cessation of symptoms of asthma, a new definition has been proposed and included in several national guidelines and most recently also in international guidelines which include absence of symptoms, no exacerbations, stable pulmonary function, no need for systemic corticosteroids. In this review, novel definitions and their clinical implications are being discussed such as remission off treatment (e.g. following allergen immunotherapy) and remission on treatment (e.g. during treatment with a biologic). Furthermore, the concept of partial remission as well as the need to further investigate the interdependence of clinical and biological remission (reduction or normalization of inflammatory biomarkers) is discussed. This concept includes for the majority of patients the continuous use of a personalized treatment with DMAADs with a potentially lower treatment burden, provided patients are properly phenotyped and comorbidities are being recognized and treated.

Summary: In contrast to previous guidelines, applying the concept of remission has the potential to improve asthma care with earlier interventions with DMAADs and broader treatment approaches to improve long-term outcomes.

Purpose of review: To summarize the effects of type 2 (T2) cytokine-targeting therapies on respiratory infection risk in patients with allergic diseases, with a focus on the interplay between epithelial barrier restoration and immune rebalancing.

Recent findings: T2 inflammation, driven by IL-4, IL-13, IL-5, and IgE, disrupts epithelial integrity and impairs mucosal defenses, increasing susceptibility to infections. Biologics targeting these pathways restore barrier function and modulate immune responses, promoting Th1/Th17-mediated antimicrobial activity. Dupilumab improves epithelial integrity and Th1/Th17 activity, with post hoc analyses from QUEST and SINUS-52 showing fewer respiratory infections compared to placebo. IL-13-specific therapies (tralokinumab, lebrikizumab) reduce excessive Th2 signaling and effector T-cell transdifferentiation, supporting mucosal homeostasis and low infection rates. IL-5-targeted biologics (mepolizumab, benralizumab) decrease eosinophil-mediated tissue injury without significantly increasing respiratory infections, despite theoretical concerns regarding antiviral defense. Omalizumab enhances Th1 antiviral pathways while reducing IgE-mediated inflammation, preserving infection control.

Summary: T2-modulating biologics not only control allergic inflammation but also restore epithelial and immune homeostasis, contributing to maintained or reduced respiratory infection risk. These therapies represent a dual benefit of barrier repair and immune rebalancing. Further studies are warranted to evaluate long-term infection outcomes in high-risk populations.

Purpose of review: Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is an autosomal dominant combined immunodeficiency (CID), often caused by increased CXCR4 pathway signaling. Against early-onset hallmark of neutropenia, diagnosis is delayed due to lack of awareness, incomplete penetrance, and requirement for specialized bone marrow evaluation to detect myelokathexis.

Recent findings: Some infants with WHIM are identified via newborn screening for low thymic emigrant T cells. Early pediatric diagnosis is associated with improved outcomes. The genetic spectrum of CXCR4 expands beyond the canonical C-terminal hotspot, with N-terminal p.D84H variant. Recent trials of oral CXCR4 antagonist demonstrated increased circulating mature neutrophils and lymphocytes, reduced infection burden, and, in some cases, wart regression. Mechanistic studies in human and murine models contribute to the understanding of the combined immunodeficiency phenotype and highlight how CXCR4 hyperactivation impairs hematopoietic stem/progenitor cell egress, leukocyte trafficking and disrupts stromal niches critical for lymphocyte development and survival.

Summary: Increased awareness, opportunities for screening at birth, improved pathological and genetic diagnostics, and 2024 FDA approval of the first oral CXCR4 antagonist create practical advance in targeting WHIM syndrome. As a CID with lifetime risk for humoral deficiency, impaired antiviral defense and malignancy, WHIM warrants long-term monitoring and further investigation into broader applications of CXCR4 antagonism.