Allergy & Immunology — Weekly Evidence Brief

Asthma continues to be a complex disease, with recent research shedding light on its diverse molecular and clinical presentations. For instance, exacerbation-prone pediatric asthma patients exhibit greater rhinovirus replication and exaggerated interferon and inflammatory responses post-infection, with pre-infection IFN tone identified as a modifiable factor and IFN-" as a potential prophylactic 1. Furthermore, cough-variant asthma (CVA) has been stratified into two molecular endotypes: mixed-inflammatory and pauci-inflammatory CVA, which differ in their inflammatory profiles and cough persistence, potentially guiding personalized treatment approaches, especially for those resistant to corticosteroids 2. Quantitative computed tomography (qCT) has also identified four distinct clusters of asthma patients, each linked to specific airway remodeling, air trapping, and sputum proteomic profiles, further emphasizing the heterogeneity of severe asthma 3. The coexistence of asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP) shares genetic components, implicating immunological pathways like type 2 inflammation and JAK-STAT signaling 4.

Understanding immune dysregulation is crucial for several autoimmune and rare diseases. Hyper-IgE syndromes (HIES), a heterogeneous group characterized by eczema, recurrent infections, and high IgE, involve significant genetic and clinical diversity, with non-immunological comorbidities posing diagnostic and management challenges 5. Specifically, STAT3 mutations in HIES lead to increased terminally differentiated and exhausted NK and NKT cells and a Th2 cell differentiation trend, offering molecular explanations for elevated IgE 6. In antisynthetase syndrome-associated interstitial lung disease (ASS-ILD), monocyte-specific interferon-stimulated gene activity is central, with a specific monocyte subset (mono2) driving inflammatory and profibrotic signatures via type II interferon and TNF signaling 7. Primary Sjögren's Syndrome (pSS) patients show a selective reduction in MAIT cells, particularly in DN and CD8+CD4- subsets, which correlates negatively with inflammatory markers, suggesting MAIT cell levels as a potential diagnostic biomarker 8.

Highly effective modulator therapies (HEMTs) are transforming cystic fibrosis (CF) care, though ongoing research reveals nuanced long-term effects. While ETI therapy significantly downregulates neutrophilic inflammatory gene expression within six months and improves pulmonary function, a resurgence of baseline inflammatory programs is observed transcriptionally between six months and two years, despite stable clinical outcomes 9. Additionally, cystic fibrosis-related diabetes (CFRD) is associated with worse lung function and distinct inflammatory and proteomic changes, including higher neutrophil elastase, IL-8, and IL-1", offering insights into its pathophysiology 10. The pIgR/IgA system, crucial for respiratory epithelial protection, remains hyperactivated even after several months of HEMT, suggesting persistent local IgA immunity impairment in CF 11.

Broader immune mechanisms and their modulation are also under investigation. Oxygen sensing and hypoxia-inducible factors (HIFs) critically orchestrate innate immune responses, with hypoxia playing dual roles depending on the physiological context and offering potential therapeutic targets to restore immune competence 12. Beyond specific diseases, the innate immune system is impacted by high-fat diets, which activate innate immune cells and alter the gut microbiome, leading to chronic inflammation, obesity, and worsened asthma risk through mechanisms like lipid-associated macrophages and innate immune memory 13. Furthermore, a probiotic, Weizmannia coagulans BC99, has shown promise in improving allergic rhinitis symptoms by modulating oxidative stress, reducing serum IgA and eosinophils, and affecting metabolic pathways, suggesting a novel adjunct therapy 14. The identification of genetic and transcriptional biomarkers for predicting sintilimab-induced thyroid immune-related adverse events (irAEs), particularly involving a "C3 complement-matrix axis," could pave the way for precision risk prediction and targeted interventions 15.