Platelet‐activating factor as an endogenous cofactor of food anaphylaxis

Anaphylaxis is a severe, acute, life‐threatening generalized or systemic hypersensitivity reaction. The incidence of anaphylaxis is increasing worldwide, with medications and food contributing to most cases. Physical exercise, acute infections, drugs, alcohol, and menstruation are the external cofactors associated with more severe systemic reaction. The aim of this review is to show that platelet‐activating factor contributes to the development of severe anaphylactic reaction, and even to anaphylactic shock.


| FOOD ANAPHYLAXIS
Food allergy is a pathological immune reaction triggered by food in sensitized individuals.The term related to gastrointestinal disturbances caused by certain foods is food intolerance.Food intolerance is defined as non-immune reactions in which the most significant mechanisms are associated with toxicity, metabolism, pharmacology, and idiopathic effects. 1,2he global prevalence of food allergy is estimated to be approximately 220 million, and epidemiological studies comparing the recent decades show an increasing trend. 3The greatest increase has been observed in infants and children with food allergies. 4ood allergens, alongside medicines and the Hymenoptera venom, are the most common cause of anaphylaxis. 5,6e World Health Organization defines anaphylaxis as "a severe, life-threatening systemic hypersensitivity reaction characterized by being rapid in onset with potentially lifethreatening airway, breathing, or circulatory problems and is usually, although not always, associated with skin and mucosal changes." 7According to the Codex Alimentarius data, the following food groups are important in the induction of food allergies: cereals containing gluten, crustaceans, egg, fish, peanut and soybean, milk, and tree nuts.Among the foods that cause severe anaphylaxis are peanuts, tree nuts, cow milk, and crustaceans. 8However, it should be remembered that sometimes it is not possible to detect the cause of anaphylaxis.In such cases, the reactions are called idiopathic anaphylaxis. 9In Europe, cow milk is the most common cause of anaphylaxis in children. 10Studies of the epidemiology of food allergy are difficult to conduct, because symptoms may vary in type and timing.Based on molecular allergology, Lisik et al. 11 summarized the prevalence of sensitization to food allergens in the general population in Europe.The studies indicates on cross reactive PR10 proteins, as the important and highest allergenic proteins particularly in atopic individuals.The lipid transfer protein (LTP) is the frequent cause of primary food allergy in the Mediterranean European Countries.LTPs, widespread distributed in the plant kingdom and also are responsible for number of food-induced anaphylactic reactions.The proteins have cross-reacting nature. 12,13he impressive study by Baseggio et al. 8 also showed that anaphylaxis is caused by different foods in the different regions of the world.Recent epidemiological data indicate that Black children have higher rates of food allergy relative to other racial/ethnic groups. 14enetic and environmental factors are considered in the etiology of food allergy. 15Recently, the importance of diet in women during pregnancy and breastfeeding, as well as early inclusion of particular foods in children during their development, have been emphasized. 16he clinical manifestations of generalized anaphylaxis may vary.Approximately 90% of patients are affected by skin and mucosa symptoms, with respiratory and circulatory symptoms being the most dangerous and estimated at approximately 50%. 17naphylaxis research shows predisposing factors that stimulate anaphylaxis.In general, they can be divided into endogenous and exogenous.Endogenous predispositions include mastocytosis, 18 hereditary α-tryptasemia, 19 uncontrolled and severe asthma, as well as pre-menstrual period in women. 20Exogenous factors include physical exercise, alcohol intake, on-going infections, psychological burden, sleep deprivation, and medications (the most common triggers are beta-lactam antibiotics, general anesthetic agents, radio contrast injections; Figure 1). 21,22

| MECHANISMS OF FOOD ANAPHYLAXIS
Food allergy can be classified into IgE-and non-IgEmediated depending on the involvement of IgE in its pathogenesis. 23he key mechanism of anaphylaxis is the activation of mast cells and basophils by the IgE-allergen complex.Subsequently, interaction with FcεRI on their surfaces leads to degranulation and release mediators such as vasoactive agents (histamine, bradykinin, nitric oxide, endothelin-1), proteases (tryptase, carboxypeptidase, chymase, plasminogen activator, cathepsin G, elastase), lipid mediators (leukotriene B4 [LTB4], LTC4, LTD4, LTE4, PGD2, TXA2, prostacyclin, platelet-activation factor [PAF]), cytokines, and chemokines (tumor necrosis factor [TNF]-α, TGF-β, IFN-Υ, G-CSF, M-CSF, granulocyte macrophage colony-stimulating factor [GM-CSF], interleukins-1β, -3, -4, -5, -6, -8, -10, -13, -16, -18, -22, -33). 24Mast cells reside virtually in all tissues that have a blood vessel network. 25In the pathogenesis of anaphylaxis caused by food, recent studies have highlighted the role of basophils.Both mast cells and basophils have a high-affinity IgE receptor-FcϵRI.In sensitized individuals, both cell populations can play an important role in the development of anaphylaxis. 26The simultaneous activation of mast cells and basophils releases large quantities of anaphylaxis mediators.Additional evidence for the role of basophils in anaphylaxis are clinical signs which, following the definition of anaphylaxis, may occur within seconds after exposure to the sensitizing food.Additional evidence is provided by the basophil activation test, which has a particularly high diagnostic value in allergies to peanuts and tree nuts. 27,28he literature on anaphylaxis also highlights other cells that can play an important role in the pathogenesis of this condition.Particular attention is paid to eosinophils, macrophages, neutrophils, endothelial cells, and platelets. 29,30owever, the role of these cells, especially the mechanisms through which they participate in anaphylaxis, have not yet been fully understood.Most of the studies that discuss the importance of specific cells were conducted in animals. 31n-going studies of anaphylaxis are aimed at identifying endogenous factors responsible for severe anaphylaxis. 32any studies have shown that PAF is an important factor in the development of severe anaphylaxis. 33,34

| PAF AND FOOD ANAPHYLAXIS
PAF (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) was identified in 1972. 35Seven years latter, in 1972, Demopoulos et al. determined the structure and physical characteristic of PAF. 36Later articles demonstrated traverses, that PAF is a highly potent biologic mediator.][39][40][41][42] A recent research has investigated the role of PAF in COVID-19 pathogenesis.Interestingly, the coronavirus spike protein modulates the PAF production.Subsequently PAF is implicated in platelet aggregation and microthromboses and thrombosis formation in nonvaccination subjects. 43,44AF can be produced by many cells, but the most important producers of this factor are: platelets, macrophages, monocytes, eosinophils, basophils, endothelial cells, and renal cells. 45Endothelial cells produce PAF in response to thrombin, vesopressin, IL-1 and anti-factor VIII.Researches have shown that the eosinophils and neutrophils can be stimulated to produce PAF through anaphylatoxine C5a and chemotaxis. 42,46he factor is quickly eliminated (halftime, 3-13 min). 31It is associated with the LDL fraction of lipoproteins.In healthy individuals, the concentration of this agent does not exceed 400 pg/mL.It targets cells through specific receptors (PAF receptor).Initially, it was believed that the main function of PAF was limited to the stimulation of platelet aggregation and expansion (dilation) of blood vessels. 47It is currently apparent that PAF, through receptors located on numerous cells of the immune system, affects the course of inflammation.It has been established that this factor can modulate the production of mediators such as prostaglandins, cytokines, and other inflammatory factors. 48A B L E 1 PAF in food anaphylaxis.

PAF activity
PAF-acetylhydrolase gene Val279P mutation decreases the enzyme activity.The severity of food anaphylaxis correlates with a higher level of PAF, particularly in patients with bronchial asthma.PAF and airway Induces long-lasting bronchial hyperresponsiveness, contributes to the obstruction lower, upper, or both airway, and increases bronchial vascular permeability.Is a potent chemotactic factor for eosinophils.

77,83
In addition to the modulation of PAF has a pleiotropic effect on various organs.A summary of PAF actions in anaphylaxis has been described in Table 1.
The action of PAF in food allergy and anaphylaxis can be direct and indirect.Its direct biological actions are mediated via a specific receptors coupled with G-protein, which activates a phosphatidylinozitol specific phospholipase C on target cells and tissues.The PAF binds to the receptors on endothelial cells, bronchial smooth muscle, platelet, monocytes, macrophages, and neutrophils. 39mportantly, PAF indirectly induces synthesis of arachidonic acid and its metabolites triggers production and effects of various cytokines and eucosanoids.PAF has been identified as the most efficient chemotactic agent for eosinophils. 36oreover, PAF induces vascular permeability far more potently than histamine.The vascular hyperpermeability has been recognized as a major causative factor of anaphylaxis.Rapid and marked vascular leaks lead to a decrease in the volume of circulating blood and subsequent hypotension and anaphylactic shock. 49Studies in vitro have also demonstrated that PAF in endothelial cells promotes eNOS translocation from the plasma membrane to the cytosol and induces vascular hyperpermeability. 50n the respiratory system, it is capable of causing massive bronchoconstriction and regulates surfactant in Type II alveolar cells. 51In the circulatory system, PAF has a hypotensive effect, may cause coronary artery spasm, decrease cardiac output, and lead to cardiac arrhythmia. 52The effect of PAF on the kidneys results in reduced blood flow and glomerular filtration rate, and increased resistance of the renal vessels. 53PAF has also been proven to have an effect on the reproductive system.It stimulates oocyte maturation and promotes the progression of pregnancy.It also increases sperm motility. 54he biological effect of PAF is associated with its degradation by PAF acetylhydrolase (PAF-AH).This enzyme causes detachment of the acetyl group in the sn-2 position, thus producing lyso-PAF and acetate. 55n the case of anaphylaxis, it is hypothesized that mutations in the acetylhydrolase-coding genes lead to a reduction in the activity of this enzyme, which results in an increased concentration of PAF in blood.The lower level of PAF-AH activity and a higher level of PAF predispose to the occurrence of severe anaphylaxis. 55,56linical trials provide evidence of PAF involvement in the occurrence of severe food anaphylactic reactions.Upton et al. 56 claimed that elevated levels of PAF in serum could be considered as an important marker of severe anaphylaxis in children.The study showed that reduced PAF-AH activity promotes severe anaphylactic reactions.Similar observations were made by Zhu et al. 57 who studied the course of anaphylaxis in patients allergic to wheat allergens (glyceraldehyde-3-phosphate dehydrogenase [GAPDH] and omega-5 gliadin).PAF is an endogenous cofactor of anaphylaxis in addition to physical effort, which is a wellknown cofactor in allergies mentioned above. 58Vadas et al. 59 reported that PAF-AH activity in patients with fatal anaphylaxis in peanut allergy and compared it with controls-PAF-AH was significantly reduced.
PAF enhances the effect of histamine on blood vessels.It has been shown to increase the permeability of vascular endothelium.In this way, it contributes to hypotonia, which can lead to anaphylactic shock.Animal studies have shown that PAF increases the permeability of intestinal blood vessels, as well as causes edema in the intestinal segment in which allergic inflammation is taking place. 60

| TREATMENT OF FOOD ANAPHYLAXIS AND PAF
The treatment of food allergies relies on the strict elimination of the offending allergens.][63] The EAACI recommends using intramuscular adrenaline as soon as anaphylaxis is recognized.Prompt use of adrenaline reduce the risk of biphasic reactions. 64Epinephrine increases blood pressure by inotropic and chronotropic cardiac effects and increases peripheral vascular resistance.It causes via beta-2 adrenergic receptors bronchodilation and decreased mucosal edema. 65Studies suggest also that adrenaline inhibits the effect of PAF.Epinephrine was most effective when administered before stimulation with PAF but was progressively less effective with time after PAF stimulation. 66,67][70] The World Allergy Organization recommends the administration of glucocorticoids, however, are not firstline treatment for anaphylaxis.Recent studies have demonstrated that glucocorticoids induce a rapid antiinflammatory effect by a non-genomic mechanism, acting through membrane-bound or cytosolic receptors. 6,70he H 1 and H 2 antihistamines are the next step during treatment anaphylaxis.Blocking the H 1 and H 2 receptors can inhibit histamine and PAF release from mast cells and improve the vasculature integrity and maintenance of the blood pressure and heart rate. 2,56,71umerous clinical studies indicate on a rupatadine as a potent the H 1 antagonist and also PAF inhibitor. 72xperiments in vitro have shown that the rupatadin inhibit release allergic mediators (histamine, interleukin-5, interleukin-6, interleukin-8, TNF, and GM-CSF) from mast cells. 73Furthermore, several studies observed also inhibitory effect on eosinophil and LTB4-induced human neutrophil chemotaxis. 74

| CONCLUSIONS
Anaphylaxis is one of the most serious types of allergic reactions.Its drivers, cellular mechanisms, and mediators are gradually being elucidated.In addition to the wellknown endogenous factors that are responsible for the signs of anaphylaxis, PAF should be taken into account in the light of this study.This factor can certainly be considered as an important endogenous cofactor of anaphylaxis.
U R E 1 Effects of PAF after activation of the mast cells and basophils.Production of newly generated lipid-derived PAF contributing to the amplification and prolongation of anaphylaxis.