What causes vasodilation in allergic response?

Definition

Systemic anaphylaxis, a form of immediate hypersensitivity, arises when mast cells and possibly basophils are provoked to secrete mediators with potent vasoactive and smooth muscle contractile activities that evoke a systemic response. Although mast cells in any organ system may be involved, depending on the distribution of the instigating stimulus, the principal targets are the cardiovascular, cutaneous, respiratory, and gastrointestinal systems, sites where mast cells are most abundant. Systemic anaphylaxis can occur when these cells are activated by an allergen that binds immunoglobulin (Ig) E, resulting in classic immediate hypersensitivity, or when they are activated by alternative pathways.

Mast Cells in Anaphylaxis

Systemic anaphylaxis is the most striking and immediately life-threatening IgE-dependent reaction. Food allergies are the most common cause, but it also can result from drug allergies, in particular to penicillin, insect venom such as bee stings, or physical stimuli such as exercise, or it may be idiopathic. Reactions that are clinically indistinguishable from anaphylactic reactions but are not IgE-dependent are sometimes termed anaphylactoid reactions.80

Anaphylaxis is a syndrome with varied triggers and clinical presentations that is mediated predominantly by mast cells and perhaps basophils. In exercise-induced anaphylaxis, mast cell degranulation has been demonstrated in the skin using electron microscopy.81 However, the best marker of systemic mast cell activation in anaphylaxis is an acute rise in the concentration of β-tryptase in the peripheral circulation.82 Unlike α-tryptase, which is released by mast cells constitutively, β-tryptase is stored in mast cell granules and released after IgE-dependent activation and therefore constitutes a more specific marker of acute activation than total tryptase. Histamine and β-tryptase are released from mast cells together, but whereas histamine concentrations in blood peak within 5 minutes, the tryptase concentration is maximal between 15 and 120 minutes after the onset of symptoms.83 This is because tryptase is a larger molecule than histamine but also remains bound to heparin longer, delaying its diffusion from the tissue. Tryptase is therefore not only a more specific marker for mast cell activation than histamine, which also is released by basophils, but more convenient to measure after a suspected anaphylactic event. Of interest, patients with systemic mastocytosis are at increased risk for anaphylactic and anaphylactoid reactions and often demonstrate increased baseline serum concentrations of tryptase—predominantly α-tryptase, which is released constitutively and reflects the increased mast cell mass.84

The key difference between anaphylaxis and other mast cell–associated diseases is that anaphylaxis involves the systemic activation of mast cells, leading to gastrointestinal symptoms, urticaria, cardiovascular collapse, and respiratory embarrassment secondary to bronchospasm and/or laryngeal edema. The reason for this widespread mast cell activation has been assumed to relate to systemic diffusion of allergen, but this is perhaps implausible, and amplification mechanisms need to be considered—for example, neurologic reflexes. Recent work also has identified platelet-activating factor (PAF) (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) as a potential amplifier.

PAF is implicated in the pathogenesis of anaphylaxis in humans and can activate human mast cells. In the skin, neural reflexes activate mast cells after the administration of PAF, but isolated human skin mast cells do not degranulate in response to PAF directly. HLMCs and HPBMCs release histamine and PGD2 rapidly in response to concentrations of PAF similar to those measured in human blood during anaphylactic reactions.85 This response is partially dependent on Ca2+ influx. PAF also induces the release of CXCL8 and transiently upregulates mRNA expression for several other chemokines.85 PAF signals via the PAF receptor coupled to Gαi, with activation of the phospholipases (PLCγ1 and PLCβ2), and also enhances IgE-dependent mediator release.

The observations that PAF can directly activate HLMCs and HPBMCs and potentiate IgE-dependent secretion provides a mechanism whereby PAF amplifies the effects of allergen exposure. This biologically plausible mechanism would serve to link elevated PAF concentrations in human anaphylaxis to an amplified airway mast cell response. The source of PAF in human anaphylaxis is uncertain, but in part might come from mast cells.86 Here it is suggested that PAF generated locally by mast cells, and perhaps other cells in response to mast cell activation at the point of allergen contact, may lead to an exaggerated mast cell response at more distal sites, such as the airway. In turn, skin mast cells may be activated indirectly by PAF through neural reflexes.87 Such a PAF amplification loop may be a key factor in the pathogenesis of systemic anaphylaxis.

Immunology and Pathophysiology

Systemic anaphylaxis results from the release of mast cell and basophil mediators in sufficient quantity to evoke a systemic response involving multiple end organs. Anaphylaxis begins when antigen cross-linking of receptor-bound IgE causes mast cell mediator release. The exact mechanisms and thresholds required to initiate anaphylaxis after sensitizing antigen exposure are uncertain. This IgE-mediated mechanism of anaphylaxis requires systemic distribution of the offending agent, hence parenteral or enteral exposures are common routes for anaphylactic reactions. The signs and symptoms elicited by mast cell mediator release depend on the organ system in which those mast cells reside: skin, gastrointestinal tract, respiratory tract, and cardiovascular system. Mast cells in perivascular locations can have a significant effect on hemodynamics. Other cell types, including basophils, monocytes, eosinophils, antigen presenting cells, and epithelial cells, may participate in this process and affect the duration and intensity of the reaction with their interactions and secreted products.

One of the most important mediators is histamine, which causes vasodilation, increased vascular permeability, mucous hypersecretion, smooth muscle spasm, and eosinophil chemotaxis and activation. Serum histamine levels correlate with the severity of cardiopulmonary manifestations and GI manifestations in anaphylaxis episodes.16 Histamine mediates its effects through H1 and H2 receptors. Histamine causes extravasation of blood volume and decreased peripheral vascular resistance. Tryptase, chymase, heparin, and other chemokines and chemotactic factors are also involved. These above mediators activate other inflammatory systems, but may also have an attenuating role in the chain reaction of inflammatory events in an anaphylactic episode.11

Mast cell degranulation products can activate other important biochemical pathways that contribute to an anaphylactic episode, like the kininogen–kallikrein system, coagulation cascade, and the complement cascade through the actions of tryptase.11 Tryptase, which is stored in mast cell secretory granules, can activate the kinin system, clotting cascade, and complement cascade.17 Levels of C4 and C3 decrease in anaphylaxis, and increases in C3a have been measured, suggesting that complement activation plays a role in the process. Factors V, XIII, and fibrinogen decrease with anaphylaxis, suggesting involvement of these systems in anaphylactic episodes.16 Nitric oxide production is dramatically increased in anaphylactic episodes. The net effect of nitric oxide production is vasodilation and increased vascular permeability.11 In addition to preformed mediator release from mast cells, newly generated lipid mediators, including leukotrienes (LT) B4, C4, D4, E4, platelet activating factor, prostaglandin D2, and others, are involved. LT B4 is chemotactic and may play a role in the late manifestations of anaphylaxis. Recurrent or biphasic anaphylaxis may be secondary to inflammatory cell activation and recruitment (like eosinophils) and may occur 12 hours after the initial attack.16

Anaphylaxis is primarily an IgE-mediated phenomenon, but can involve IgG or IgM antibodies.3 In mouse models of anaphylaxis, there is an IgG-dependent pathway that depends on the involvement of macrophages, which secrete platelet activating factor.18 Antigen–antibody complexes may activate complement and trigger “immune aggregate anaphylaxis,” and this mechanism is implicated in anaphylactoid reactions to protamine, dextran, and albumin.17

Some anaphylactoid reactions due to drugs, exercise, or physical factors may be due to direct release of mediators from mast cells. Aspirin- and NSAID-induced anaphylactoid reactions are due to altered arachidonic acid metabolism. It is thought that inhibited production of prostaglandin E (which prevents mast cell degranulation) and excess production of leukotriene C (which stimulates degranulation) is responsible for mediator release in NSAID-induced anaphylactoid reactions. Radiocontrast material may provoke anaphylactoid reactions by activating multiple systems, including the kallikrein–kinin, clotting system, and complement system.17 Non-IgE-mediated complement activation can occur from exposure to radiocontrast media, liposomal drug preparations, NSAIDs, and other drugs in a reaction now called CARPA (C activation-related pseudo-allergy). A CARPA reaction can occur on first exposure to an agent. In the case of radiocontrast media, the classical and alternative complement pathways are activated.19

Prevention

Patients with a history of systemic anaphylaxis provoked by a sting and detectable venom-specific IgE should be considered for desensitization with purified venoms. This treatment proved significantly more effective than placebo or whole-body extracts of Hymenoptera in preventing anaphylactic reactions to sting challenge.5,6 Desensitization involves a series of visits to the clinic for administration of gradually increasing doses of venom followed by 5 years of maintenance therapy. Systemic reactions (anaphylaxis) occur in 5% to 15% of courses and local reactions in 50%.

Wasps are attracted by sweet things and meat in homes, greengrocers, orchards, and vineyards. At night, hornets are attracted by light. Some species, such as the Asian Vespa mandarina, are so aggressively territorial that their nests must be eradicated before the area can be farmed. Vespid nests may be destroyed by fumigation with insecticides. In aggressive bee colonies, the queens should be replaced.

Death from anaphylaxis can be prevented by self-administered first aid with epinephrine (adrenaline).

Anaphylaxis

Complement activation does not occur in systemic anaphylaxis because IgE immune complexes do not activate complement. In this immediate hypersensitivity reaction, the antigen binds to an IgE antibody on mast cells or basophils, causing release of mediators that produce life-threatening symptoms. However, studies with mice that lack IgE suggest that generation of C3a and C5a via complement activation contributes to the bronchoconstriction and hypotension of anaphylaxis. Indeed, additional animal studies implicate C3a and C5a as putative mediators of anaphylactic shock. Both C3a and C5a peptides contract airway smooth muscle in the guinea pig independent of histamine, and treatment with soluble CR1 (sCR1), which inhibits complement activation, eliminates the antigen-induced hypotensive response in these animals.

Epinephrine

A cornerstone in the management of systemic anaphylaxis is the administration of intramuscular (IM) epinephrine to mitigate vasodilation and bronchoconstriction. A 21-year-old previously health male presented with an urticarial rash and difficulty in breathing after ingestion of prawns which was a known allergen to the patient [46c]. The patient received epinephrine 0.5 mg IM, hydrocortisone 200 mg IV, and chlorpheniramine10 mg IV. Ten minutes after administration of epinephrine the patient developed palpitations and chest pain. The initial ECG revealed ST segment depressions in leads III, aVF and V1–V5. Subsequent ECG had persistent T wave inversions and troponin I 6 h after the event was 0.69 ng/mL. The authors concluded the patient likely developed a type II myocardial infarction (supply–demand mismatch) due to coronary vasospasm and was successfully treated with sublingual nitroglycerin. After anaphylaxis there are two possible reasons for a myocardial infarction to occur: (1) the allergen resulting in anaphylaxis results in an allergic myocardial infarction or (2) use of epinephrine and a supply–demand mismatch [46c].

5.20.4.1 Mechanisms of Anaphylaxis

Some of the problems associated with studying systemic anaphylaxis stem from the fact that multiple mechanisms may produce similar clinical pictures. The most common mechanism for anaphylaxis involves IgE cross-linking of the FcϵRI on the surface membranes of mast cells and basophils causing the immediate release of mediators of inflammation including histamine, cytokines, and chemokines (classical pathway). Less common (alternative pathways), non-IgE mediated mechanisms include activating the low affinity IgG receptor FcγRIII and macrophages. In this case, PAF has been implicated in the development of shock. Basophils may also be involved. Activation of the complement or coagulation systems, formation of immune aggregates (which may contain IgG, IgM, platelets, and T cells and cause leukotriene formation), or cross-linking of the FcϵRI through autoimmune mechanisms can also lead to anaphylactic reactions. In some cases factors such as exercise, cold air, radiation, or ethanol may trigger release of mediators from mast cells and basophils by mechanisms that are not clearly understood but do not appear to be immune mediated (Simons et al. 2007).

The exact conditions that lead to systemic anaphylaxis as opposed to more localized reactions are poorly understood. Some, but not all patients, presenting with anaphylaxis have elevated blood histamine and/or serum tryptase levels. Significantly higher serum PAF levels were demonstrated in patients with anaphylaxis versus controls and the level correlated with severity of the anaphylactic reaction. PAF acetylhydrolase, the enzyme responsible for inactivating PAF, activity was significantly lower in these patients (Vadas et al. 2008). In patients allergic to bee stings and challenged with insect venom, broader shifts in expression of basophil-activation markers (CD69 and CD203c) after in vivo challenge occurred among subjects with a history of in vivo systemic anaphylaxis (as opposed to large local responses) despite venom immunotherapy suggesting that basophil activation markers may be potential biomarkers for anaphylaxis (Gober et al. 2007). However, despite recent research efforts, biomarkers that robustly distinguish between sensitized individuals at risk of anaphylaxis and sensitized individuals who are not at risk are currently unavailable.

Mast Cells in Allergic Disease: Anaphylaxis, Allergic Disease, and Asthma

Mast cells are the primary mediator of systemic anaphylaxis. This is demonstrated in mast cell–deficient mice, in which resistance to IgE-mediated anaphylaxis may be restored by engraftment with mast cells.98 In humans, participation of mast cells in anaphylaxis has been documented through the detection of elevated serum levels of β-tryptase, a specific marker of mast cell degranulation.70 Mast cells accumulate in atopic mucosal tissues, where they degranulate upon exposure to antigen and contribute prominently to tissue edema and the overproduction of mucus.41 Mast cells also accumulate in the asthmatic airway, including within the smooth muscle lining the airways, and have been implicated by human and animal data in airway hyperreactivity and mucosal changes.99,100

4.2 Induction of anaphylactic shock by SLPs-specific antibodies

One recent paper reported the occurrence of systemic anaphylaxis after application of SLPs (Smith et al., 2011). Analysis of the vaccine-induced immune response revealed the efficient generation of CD4 T helper cells and the generation of peptide-specific IgG and IgE antibodies. Serum titers were high at time of the booster vaccination and mice responded within minutes with anaphylaxis, accompanied with quick increase of blood histamine levels (Smith et al., 2011). These detrimental effects were only observed when strong underlying CD4 T-cell responses were present and most peptides were coupled to KLH, a strong hapten that elicits strong CD4 T-cell immunity and is often coupled to proteins with the intention to evoke strong antibody responses (Ragupathi et al., 2005). One peptide displayed similar features even without the KLH coupling, and moreover, we recently identified several other free long peptides with this allergenic capacity able to induce anaphylaxis within minutes (E. Quakkelaar and C. Melief, unpublished observations). Again, no adverse reactions were found when the booster vaccination was performed in slow release IFA depots. Finally, vaccine-induced antibodies to long peptides were detected in blood of patients who were treated with the HPV long peptide vaccine (our own unpublished data), whereas we never observed anaphylaxis in our patients, suggesting that it is not the presence of SLPs-specific antibodies per se that is associated with adverse events.

Treatment of emergencies

Patients with food allergy and a history of systemic anaphylaxis, or sensitization against dangerous allergens such as peanuts, tree nuts, or lipid transfer proteins found in peaches and other fruits should be equipped with emergency medications including adrenaline [automatic syringe for intramuscular or subcutaneous injection (0.3 mg for patients >25–30 kg; 0.15 mg for patients >10–25 kg)], H1 blockers, such as clemastine (2 mg), cetirizine (10 mg) or diphenhydramine (1.25 mg/kg up to 50–75 mg), and prednisolone (1–2 mg/kg up to 100 mg). In children, half the adult doses indicated here should be used. These drugs must be prescribed every year and usage of the drugs must be carefully explained to the patient and his relatives.