Journal of Investigational Allergology and Clinical Immunology最新文献

Background and objectives: Nonspecific lipid transfer proteins (nsLTPs) are frequently cross-reactive allergens that hamper diagnosis and avoidance. It is challenging to distinguish cross-reactivity from cosensitization with polyclonal serum owing to the presence of a few promiscuous antibodies or many highly specific antibodies. Objective: We hypothesized that a robust analysis of more human monoclonal antibodies (mAbs) would enable us to compare crossreactivity with cosensitization.

Methods: Human monoclonal antibodies were cloned from allergic patients via single cell sequencing and screened for affinity to extracts and recombinant allergens. Ara h 9 was expressed and crystallized with the mAb IGX-3103. Affinity for nsLTPs was explored using molecular modeling, site-directed mutagenesis, and ELISA.

Results: A human IgG4 mAb named IGX-3103 was discovered from a type 2-polarized memory B cell expressing CD23, IL-4Ra, and germline IGHE. IGX-3103 bound to 19 different type 1 nsLTP allergens and to extracts from sources without a characterized nsLTP allergen. The structure showed that IGX-3103 induced a conformational change in Ara h 9, enabling a hydrophobic residue from the antibody, Phe104, to enter the lipid binding cavity. Key residues in the epitope were identified to include Leu1, Ser2, Cys3, Lys39, and Asp43 in Ara h 9; these residues are conserved across type 1 nsLTPs, thus explaining the promiscuity of IGX-3103.

Conclusions: IGX-3103 is an example of a human mAb with cross-reactivity to pollen, fruit, and seed type 1 nsLTPs. This observation anecdotally supports the possibility that a few promiscuous mAbs could be driving cross-reactivity.

Background and objectives: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity reactions (HSRs). NSAID-induced HSRs constitute a significant health problem owing to their prevalence, phenotypes, mechanisms of action, and complex diagnosis. However, in around 60% of individuals attending for suggestive NSAID-induced HSRs, this diagnosis is ruled out. Patients labeled as being hypersensitive to NSAIDs unnecessarily avoid NSAIDs, leading to increased waiting lists, diagnostic delay, and associated costs. Objective: To develop a machine learning (ML) based model for discriminating NSAID hypersensitive patients from non-NSAID hypersensitive individuals by assessing populations with suspected NSAID-induced HSRs.

Methods: We recruited a retrospective population and a prospective population of individuals attending the Allergy Unit of Malaga Regional University Hospital, Malaga, Spain for suggestive NSAID-induced HSRs in whom a diagnosis had been confirmed. One logistic regression analysis and 6 ML-based models were developed using retrospective data, and the most efficient was applied to the prospective population. In addition, 3 prospective populations from Madrid, Barcelona, and Salamanca were included for external validation.

Results: All the models classified at least 85% of individuals correctly, and, considering discrimination by chance, agreement was almost perfect for all of them (k>0.81). However, the light gradient-boosting machine (LGBM) model showed the highest sensitivity (99%), accuracy (97%), and k value (0.94). The final validated LGBM model achieved 91.76% accuracy, a 95.19% area under the curve, and a k of 0.83. Accuracy was >95% in all prospective populations.

Conclusion: Our LGBM model efficiently differentiated NSAID-hypersensitive patients from individuals who can safely receive NSAIDs, despite suggestive NSAID-induced HSRs. Such a model could easily be incorporated into clinical settings, thus improving diagnosis, reducing waiting lists, and optimizing health care resources.

Aspirin-exacerbated respiratory disease (AERD) is characterized by chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs). Although high-dose aspirin therapy after desensitization (ATAD) and surgery are effective, adverse effects and high dropout rates limit its use. The emergence of biologics for asthma and/or CRSwNP entails rethinking the management of AERD. There is no consensus on choosing between ATAD and biologics. This systematic review evaluates current evidence on the role of biologics in the management of AERD, focusing on their potential to induce NSAID tolerance and proposing a management algorithm. A systematic literature search was conducted across PubMed, Embase, and Scopus up to March 2025. Studies were selected based on predefined criteria, excluding editorials, reviews, case reports, guidelines, and publications not in English. Data were extracted from clinical trials, real-world studies, and retrospective analyses. The various inflammatory pathways targeted by biologics included immunoglobulin E (omalizumab), subunit alpha of the interleukin 4 receptor (IL-4Ra) (dupilumab), IL-5/IL-5Ra (mepolizumab, benralizumab), and thymic stromal lymphopoietin (tezepelumab). These drugs have demonstrated efficacy in improving asthma and CRSwNP in AERD. The most consistent evidence seems to favor omalizumab and dupilumab for enhancing tolerance to NSAIDs. Although evidence remains inconclusive, the combination of ATAD and biologics may offer additive benefits in selected patients. Biologics represent a promising alternative in the management of AERD, particularly for patients with poor tolerance to aspirin. Further prospective, controlled studies are needed to define optimal treatment algorithms and identify biomarkers predictive of therapeutic response.