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Review
. 2024 Feb 19;3(2):100230.
doi: 10.1016/j.jacig.2024.100230. eCollection 2024 May.

A systematic review of allergen cross-reactivity: Translating basic concepts into clinical relevance

Ekansh Sharma  1 , Joana Vitte  2   3   4
Affiliations
Review

A systematic review of allergen cross-reactivity: Translating basic concepts into clinical relevance

Ekansh Sharma et al. J Allergy Clin Immunol Glob. .

Abstract

Access to the molecular culprits of allergic reactions allows for the leveraging of molecular allergology as a new precision medicine approach-one built on interdisciplinary, basic, and clinical knowledge. Molecular allergology relies on the use of allergen molecules as in vitro tools for the diagnosis and management of allergic patients. It complements the conventional approach based on skin and in vitro allergen extract testing. Major applications of molecular allergology comprise accurate identification of the offending allergen thanks to discrimination between genuine sensitization and allergen cross-reactivity, evaluation of potential severity, patient-tailored choice of the adequate allergen immunotherapy, and prediction of its expected efficacy and safety. Allergen cross-reactivity, defined as the recognition of 2 or more allergen molecules by antibodies or T cells of the same specificity, frequently interferes with allergen extract testing. At the mechanistic level, allergen cross-reactivity depends on the allergen, the host's immune response, and the context of their interaction. The multiplicity of allergen molecules and families adds further difficulty. Understanding allergen cross-reactivity at the immunologic level and translating it into a daily tool for the management of allergic patients is further complicated by the ever-increasing number of characterized allergenic molecules, the lack of dedicated resources, and the need for a personalized, patient-centered approach. Conversely, knowledge sharing paves the way for improved clinical use, innovative diagnostic tools, and further interdisciplinary research. Here, we aimed to provide a comprehensive and unbiased state-of-the art systematic review on allergen cross-reactivity. To optimize learning, we enhanced the review with basic, translational, and clinical definitions, clinical vignettes, and an overview of online allergen databases.

Keywords: Allergen; cross-reactivity; immunoglobulin E; molecular allergology; precision medicine; translational medicine.

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Conflict of interest statement

Funded by 10.13039/100011033Thermo Fisher Scientific. Disclosure of potential conflict of interest: E. Sharma is an employee of Thermo Fisher Scientific. J. Vitte reports speaker and consultancy fees and travel support in the past 5 years from Astra Zeneca, HpVac, Novartis, L’Oréal, Sanofi, Stallergènes-Greer, and Thermo Fisher Scientific.

Figures

Fig 1
Fig 1
Allergic and nonallergic hypersensitivity reactions. Definitions of hypersensitivity versus allergy and main mechanisms of immediate and delayed hypersensitivity reactions are presented with selected examples. Gell and Coombs classification (type I to IV hypersensitivity) is shown. AD, Atopic dermatitis; Ba, basophil; MC, mast cell; MPS, mononuclear phagocyte system (monocyte, macrophage); Neu, neutrophil; TEN, toxic epidermal necrolysis. References , , , , , , , .
Fig 2
Fig 2
Clinical vignette illustrating HDM, edible insects, and shrimp cross-reactivity. Consider assessing IgE to corresponding allergen extracts for accurate interpretation of IgE to MA. Tropomyosins from arthropods (HDM, insects, and crustaceans), mollusks, and gastropods exhibit extensive cross-reactivity. OFC, Oral food challenge. References , , , .
Fig 3
Fig 3
Clinical vignette illustrating pollen and food cross-reactivity. Consider assessing IgE to corresponding allergen extracts for accurate interpretation of IgE to MA. Here, molecular assessment of birch pollen is not useful because it does not contain nsLTP or GRP. Profilin, a plant panallergen family, exhibits extensive pollen–fruit cross-reactivity. Lack of sensitization to grass and weed pollens excludes profilin involvement. PR-10, a cross-reactive family of plant allergens comprising major birch allergen Bet v 1, is heat sensitive. Cupressaceae pollen and bell pepper lack characterized PR-10 homologs. nsLTP, Nonspecific LTP. References , , , .
Fig 4
Fig 4
Pollen marker and cross-reactive allergens. Selected examples are shown for marker and cross-reactive pollen allergen families. Genuine sensitization to major taxonomic groups of trees, weeds, and grasses can be identified using marker allergens. Examples include PR-10 allergens from Fagales trees (birch Bet v 1, alder Aln g 1, oak Que a 1), invertase inhibitors from Proteales (London plane Pla a 1), pectate lyases from Pinales (Arizona cypress Cup a 1, Japanese cedar Cry j 1, juniper Jun a 1), Ole e 1–related allergens from Lamiales (olive tree Ole e 1, ash tree Fra e 1, lilac Syr v 1), and Ole e 1–like allergens from tropical trees (sweet acacia Aca f 1, Prosopis juliflora Pro j 1). Allergen families comprising cross-reactive homologs across unrelated taxonomic groups are denoted as shared allergens. Profilins and polcalcins are ubiquitous in grass, weed, and tree pollen. Profilins, but not polcalcins, are also found in plant foods. Profilins and polcalcins display extensive cross-reactivity (pollen panallergens), while variable cross-reactivity is found with most other families of shared allergens. For example, nsLTP Par j 2 does not cross-react with other pollen nsLTP, while clinically relevant cross-reactivity has been described among other pollen and food nsLTP, such as plane pollen Pla a 3, mugwort pollen Art v 3, and peach (fruit) Pru p 3. Cross-reactivity of olive pollen Ole e 1 with Ole e 1–like allergens is also variable: high cross-reactivity between Ole e 1 and ash tree Fra e 1, moderate cross-reactivity of Ole e 1 with other marker allergens from Lamiales order (lilac, privet), and no clinically relevant cross-reactivity with Ole e 1–like allergens from grass or weed pollen. While marker pollen allergens are typically major allergens—that is, sensitization is detected in >50% of allergic patients—shared allergens can present as either major or minor allergens depending on biochemical family and individual exposure. Marker allergens exhibit climate preferences in relationship to plants they are derived from. IFR, Isoflavone reductase; nsLTP, nonspecific LTP; PR-1, pathogenesis-related family 1; OAS, oral allergy syndrome; TLP, thaumatin-like protein. References , , , , , , .
Fig 5
Fig 5
Flowchart of systematic review. A systematic review of allergen cross-reactivity following the PRISMA-P guidelines (Basic concepts and clinical relevance of allergen cross-reactivity: a systematic review, PROSPERO Registry CRD42022312363) identified 134 PubMed articles. The full-text of original articles, position papers, consensus publications, guidelines, and official recommendations was searched for relevant information on allergen cross-reactivity. Exclusion of 72 nonrelevant publications and manual adjunction of 17 relevant original articles resulted in a final set of 79 relevant publications.
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