Speaker- Domingo Barber

Pan allergens are responsible for many false positive reactions in both in vitro and in vivo diagnostic tests. Profilins, present in various plant tissues from infancy, contribute significantly to these reactions. True food allergies, primarily early-onset syndromes, are usually caused by primary sensitizers such as milk, eggs, fish, and other proteins. High doses of allergens, often in the gram range, including casein, RH2, and storage proteins, can lead to significant immune responses, though typically underlying inflammation is minimal and stable when ingested via the gastric route. Conversely, food allergies associated with pan allergens generally follow respiratory sensitization, involve lower doses, and rarely pose life-threatening risks, but they can cause significant inflammation primarily through the oral cavity route. Examples of true food allergens include casein, egg white, fish, and peanut proteins, while pan allergens like profilin and PR-10 (Bet v 1-like proteins) are often linked to pollen-food syndromes. Between these categories are non-specific lipid transfer proteins (nsLTPs).

Specific IgE (sIgE) levels are crucial for assessing the risk in individual patients, particularly for allergens such as peanut proteins, profilin, PR-10, and storage proteins, which range from unstable to stable forms. The underlying mechanism of reactivity to pan allergens, such as profilin, is strongly associated with pollenosis, particularly grass pollen allergy, progressing to other major grass allergens like Phl p 5. Profilin's role in controlling the stability and polymerization of actin filaments, its binding to protein-rich domains, and its biological functions are notable, with more than 70% sequence identity within the plant kingdom and low homology (22%) with animals. Its lack of disulfide bridges results in poor thermal and pH stability.

An epidemiological study conducted several years ago identified a clear association between profilin sensitization and grass pollen gradients in Spain. The regions of Spain with extremely high pollen gradients are those with grasses and olive trees. Initially, it was hypothesized that profilin sensitization would correlate with overall pollen counts, but it was specifically linked to grass pollen counts, not olive pollen counts. The grass pollen gradient is particularly pronounced in the Cáceres area in western Spain, where sensitization rates are highest. The association with IgE levels to Lipi 5 further supported that sensitization to profilin was linked to grass pollen, which has the highest profilin content among all analyzed pollens. The relevance of these areas in Spain is due to the moist ground during spring coupled with scarce rainfall, leading to continuous and exceptionally high grass pollen counts, sometimes reaching thousands of pollen grains. Such high pollen levels can cause severe reactions even at doses as low as one microgram. 

A 2019 study highlighted that patients with severe profilin sensitization were predominantly grass-allergic individuals who did not respond to grass immunotherapy. These patients not only developed severe profilin reactions but also failed to develop tolerance through immunotherapy. Examination of oral biopsies from these patients revealed severe epithelial damage, cellular infiltration of presenting and effector T cells, and elevated levels of IL-33 and periostin in the oral mucosa. Profilin sensitization is more closely related to respiratory diseases. According to a study, two additional models were used to investigate this. One model involved severe respiratory conditions linked to olive allergy, associated with sensitization to the pollen LTP of olive, without concurrent food allergy. The other model involved severe respiratory allergy associated with mites in the Canary Islands, where patients developed severe reactions to flour contaminated with mites. In both models, severe epithelial impairment was observed, but unlike profilin sensitization, there were no immunological infiltrates, suggesting a systemic signature.

A study published by Obeso et al. in Allergy (2018) used omics analyses to identify previously undescribed inflammatory actions. Signatures of energy metabolism connected to proliferation, known as Warburg metabolism, sphingolipid metabolism stress, and multiple augmented lysophospholipids were observed. Altered platelet functions were also noted. Profilin induces strong T cell proliferation in Spanish sensitized patients compared to Nordic patients. In contrast to the Danish cohort, T cells from Spanish patients responded vigorously to profilin, comparable to the major allergen Phl p1 in both prevalence and strength of response.

Severe respiratory allergy involves high exposure to inhalant allergens, associated food allergies, and poor response to allergen immunotherapy (AIT), leading to uncontrolled inflammation and failed regulatory responses. This condition explains why patients may react to profilin and develop severe reactions. Understanding the mechanisms of severity and the balance between inflammation and repair is crucial. Identifying patients with severe profilin sensitization requires determining whether it is genetic, epigenetic, or mediated by other factors. Omics approaches are essential for understanding the underlying mechanisms of effector cell activation.

A study revealed different metabolic changes in anaphylaxis depending on severity and triggers, identifying patient clusters through multiomic analysis, particularly proteomics. Based on IgE-driven food allergies, this model was used to classify drug-mediated reactions. Effector cell activation in food allergy without systemic inflammation suggests a mixed IgE/IgG1 mechanism, as seen in animal models. Severe respiratory allergies linked to pan allergens can cause chronic, out-of-season T cell-driven immunological stimulation. Non-specific lipid transfer protein (ns-LTP) allergies are not associated with remodelling or inflammation in the oral mucosa. LTPs, primarily driven by Pru p 3, can induce severe respiratory allergies, indicating multiple phenotypes.

Patients with profilin allergy may develop eosinophilic esophagitis. Immunotherapy desensitizes patients, but underlying inflammation increases if regulation is not achieved. About 30% of patients do not develop regulation during immunotherapy, which might explain why some develop systemic inflammation or eosinophilic esophagitis.

European Academy of Allergy and Clinical Immunology (EAACI), 2024 31st May-3rd June, Valencia.