Physiopathology of urticaria

ARTICLE

Fifteen to 20% of the general population has had or will have urticaria and/or angioedema in their lifetime. This goes to show the frequency of this disease, secondary to many causes and which can last months or even years, its precise cause being sometimes never found. If the clinical presentation is monomorphous, resembling nettle sting, the pathogenesis, be it immunological, pharmacological, or physical, is complex and not well known [1].

Quite often clinical presentation is evident...

The diagnosis of urticaria is made by the patient himself, in view of an erythematous eruption made of very pruritic, transient wheals. Certain aspects are more peculiar: vast polycyclic rings in marginated urticaria, vesiculo-bullous forms, punctiform papules in cholinergic urticaria.

Angioedema corresponds to subcutaneous urticaria and presents as local swelling, firm to the touch, white or pink colored, possibly with an interesting skin surface, particularly on the face, genital region and the mucous membranes.

In acute urticaria, the eruption lasts a few days or a few weeks. Bouts which recur every so often are called recurrent urticaria. Chronic urticaria concerns lesions present almost daily for more than 6 weeks.

... due to multiple causes...

Numerous physical agents can trigger the onset of urticaria, be it cold, heat, the sun, vibrations, rubbing (dermographism) or pressure. Diverse substances (vegetal, animal, or chemical) can also be responsible by direct contact. Urticaria can also be caused by drugs, food, infections (viral, bacterial, parasitic or fungal), more rarely to pneumoallergens. It can sometimes reveal or accompany a general disease, collagenosis, hematological diseases, dysthyroidia... When systemic manifestations, biological abnormalities (inflammatory syndrome, hypocomplementemia) and fibrinoid necrosis of small vessel walls of the skin accompany an urticarial eruption the entity is called urticarial vasculitis.

The responsibility of psychosomatic phenomena is diversely appreciated. Nonetheless stress is indisputably a worsening factor.

If one or more triggering factors are often discovered in acute urticaria, this is not so in the chronic forms which are called idiopathic in almost 70% of individuals.

... explained by histopathology...

Histology reveals dermal and/or hypodermal edema dissociating collagen bundles, vascular dilatation and perivascular infiltrates, most often mononuclear cells, but depending on evolution and intensity, its composition varies associating eosinophils, neutrophils, T lymphocytes, mainly CD4 [2, 3]. The number of perivascular mast cells is diversely appreciated, high for some, normal for others [4]. Under electron microscopy, the mast cells are degranulated and clusters of platelets are noted in the vascular lumen.

In some cases, leukocytoclastic vasculitis is seen, associating an infiltrate composed of pycnotic neutrophils and fibrinoid necrosis of the vascular walls. In fact, depending on the case, the infiltrate is more or less important and necrosis of the endothelial cells more or less intense [5].

... itself due to the action of various mediators...

This brutal vasodilatation which increases vascular permeability is due to different vasoactive substances:

Histamine, one of the most important mediators and the best known, is mainly stocked in the intracytoplasmic granulations of perivascular mast cells but also in circulating basophils. It acts through the H1 receptors present on the endothelial cells, thus creating vasodilatation and increase in vascular leakage and plasma exsudation. Histamine also contracts bronchial and gastrointestinal smooth muscles. Feedback limits its release but also that of other mediators. During urticaria a transient elevation of the histamine rate is noted in the serum (but it is metabolized within minutes following excretion) and in skin blister fluids [6].

Other mediators also intervene:

­ Serotonin, synthesized by platelets.

­ Proteoglycans which, by creating metachromasis, permit the identification of mast cells (heparin, chondroitin sulfate).

­ Enzymes, among which proteolytic ones like carboxypeptidase, chymase and most of all tryptase, the principal protease of mast cell granules and an important witness of anaphylactic reactions, released with histamine. Acidic hydrolases, a superoxyde dismutase and a myeloperoxydase also exist.

­ Phospholipidic metabolites of activated cell membranes (mast cells but also neutrophils and eosinophils, macrophages, endothelial cells, platelets...). Eicosanoids are oxygenated metabolites of arachidonic acid through the cyclooxygenase pathway (prostaglandins, mainly type PGD2) and the lipooxygenase pathway (leukotriens, LTC4 and LTB4 in particular). The platelet activating factor (PAF) induces secretion of vasoactive amines and is chemoattractant for neutrophils.

Diverse seric factors can also have a physiopathological role in the different types of urticaria:

­ Certain components of complement, liberated through the classic and/or the alternative pathway, namely C3a, C5a and to a lesser degree C4a generate edema, and are chemoattractants and cell activators.

­ Kinins generated from precursors or kininogens synthesized by the liver, are activated by plasmatic kininogenases or kallikreins. Bradykinin and kallidin induce vasodilatation and increased vascular permeability through receptors. They liberate histamine and induce arachidonic acid metabolism.

­ Among the neurotransmittors synthesized in the skin by nerve fibers but also by numerous cells when stimulated physically or chemically, adrenaline is responsible for certain "stress urticaria". Acetylcholine, liberated by the cutaneous cholinergic nervous system actually acts by permitting the release of histamine. Neuropeptides like substance P, VIP (vasoactive intestinal peptide) and CGRP (calcitonin related peptide) are vasodilators by direct action on vessel walls, but they also activate mast cells, thus causing their degranulation. Histamine is then released and stimulates nerve fibers [7-9].

... synthesized by different cells namely mast cells and basophils...

Mast cells do have a primary role in urticaria [10]. Medullar in origin, the native cell migrates to the different tissues and is transformed into a mature cell thanks to environmental factors and IL-3. Two main types of mast cells exist:

­ Mucosal or atypical mast cells, present in the lungs, nasal and intestinal mucous membranes, which secrete tryptase but no chymase.

­ Conjunctive or typical mast cells found in the skin and the digestive submucosa, which secrete both tryptase and chymase. They are distinguished by their metachromatic granules, violet after Toluidine coloration and red after Alcian blue coloration.

Mast cells are found in the dermis, around blood vessels (7,000/mm³), but also in the peripheral and autonomic nervous systems and in the sympathetic pre- and paravertabral ganglia [11].

In urticaria, the number of dermal mast cells is diversely appreciated, increased for some, normal for others. Sometimes these cells present with qualitative or functional abnormalities: disorganized intracytoplasmic granules, increased intragranular histamine, and early release of mediators after stimulation compared to controls [12].

Basophils derive from myeloid medullar precursors which differentiate under the influence of diverse cytokines (IL-3, GMCSF) [13]. They are mainly circulating cells but their migration in tissues is possible, thanks to adhesion molecules present on their surface (ß1 and ß2 integrines) [14].

Their cytoplasmic granules contain mediators like mast cells do, but they differ in that they contain less histamine, and they have neither tryptase nor chymase. They do not synthesize prostaglandins nor PAF, but small quantities of leukotrienes [15].

But most of all, these two types of cells have high affinity receptors on their surface, specifically for IgE [16]. The FcepsilonRI is formed by 4 polypeptidic transmembranary chains, an alpha chain, a ß chain and 2 gamma chains bound by disulfur links (alphaßgamma2). The second domain of the extracellular part of the alpha chain binds with the C epsilon 3 central domain of the Fc region of the IgE [14]. These receptors also exist on other cells, eosinophils, monocytes, dendritic cells, but they are of the alpha gamma 2 type, the ß chain belonging to basophils and mast cells; this latter chain is the one that permits transmission of cell activation signals.

The IgE-receptor link is reversible but dissociation is very slow. It induces increased expression of receptors but does not induce cell activation. Cell activation only occurs when fixation of the multivalent antigen creates aggregation of the receptors. Within seconds, phosphorylation by associated tyrosine-kinase proteins (PTK) of the ß and gamma chains on the tyrosine residues of the ITAM (immunoreceptor tyrosine based activation motif) sequence occurs. These phosphorylated substrates will propagate the activation signals, thus inducing liberation of the different cellular mediators [17].

Other cells also take part in these reactions:

­ Eosinophils come from a medullar precursor which differentiates under the influence of diverse cytokines (GMCSF, IL-3, and mainly IL-5). They are ubiquitous, both tissular and circulating cells.

After stimulation, eosinophils release two types of mediators:

­ Neoformed mediators generated from arachidonic acid: prostaglandins, leukotrienes (LTC4) and PAF, which is a chemoattractant and an activator for the eosinophils themselves.

­ Granular proteins: MBP (major basic protein), ECP (eosinophil cationic protein), EDN (eosinophil derived neurotoxin) and EPO (eosinophil peroxydase). These proteins have a very powerful cytolytic activity versus foreign target cells but also normal tissue cells.

On their surface, eosinophils have receptors for different immunoglobulins: IgA, IgG, and IgE (FcepsilonRII of poor affinity).

For quite a while, the eosinophil was considered a cell which could limit allergic reactions by blocking histamine liberation, by phagocyting mast cell granules, by neutralizing mediators. Actually these in vitro studies have not been confirmed in vivo. On the contrary, we now know that the eosinophil amplifies these phenomena: some of these components ease histamine liberation, others increase the inflammatory processes (LTC4, PAF...).

­ Lymphocytes, some of which also present with poor affinity receptors for IgE (FcepsilonRII), can also step in by secreting diverse cytokines which can influence the allergic reaction.

­ Platelets activated by PAF, release cytotoxic substances, lipidic mediators and cytokines.

­ Neutrophils activated by chemoattractant factors liberated by mast cells also produce by-products of arachidonic acid, namely LTB4.

­ Macrophages, with their FcepsilonRII receptors can maintain the inflammatory reaction by secreting PAF and different cytokines, namely IL-1.

­ Endothelial cells participate by producing cytokines and by expressing adhesion molecules on their surface which help adherence of mononuclear and polynuclear cells. In fact, endothelial cell-leukocyte adhesion is stimulated by different cytokines (IL-1, IL-4, TNFalpha, interferon gamma) but also by leukotriene B4 and P substance [18].

But the main question is "what activates these cells in urticaria ?"

Sometimes immunological phenomena are concerned,
but this is infrequently the case

In type I immediate hypersensitivity, allergens introduced orally (food, drugs), parenterally or transcutaneously (insect bites), induce specific IgE synthesis. The next time contact occurs, these allergens bind to the IgE which in turn links to mast cells and basophils thanks to their surface receptors. If they are polyvalent, these antigens can "cross-link" on cell surfaces, thus creating intercellular activation signals, inducing liberation of neoformed mediators present in granules and de novo synthesis of lipidic cell membrane substances. Urticaria appears within minutes following contact with the antigen, and recedes in 30 to 60 min.

In certain types of urticaria, those of infectious origin for example, the antigen forms with its IgG or IgM type antibody an immune complex which binds to vascular walls and activates complement. Different factors are thus released, namely C3a and C5a which induce vasodilatation and increased vascular permeability either by direct action on the vessels, or by activating mast cells or basophils; they are also chemoattractant for neutrophils.

Most often, the mechanism is not immune

­ Certain chemical substances, food, drugs, or different physical factors like cold, heat, vibrations, directly stimulate the mast cell membrane, thus releasing mediators.

­ Others act by changing arachidonic acid metabolism; Thus acetylsalicylic acid inhibits the cyclooxygenase pathway and favors the lipooxygenase pathway. More leukotrienes are thus synthesized, some of which are vasodilators.

­ In cholinergic urticaria, acetylcholine is released by sensitive nerve endings through a neuroreflex activated by perception by the central nervous system of increased local temperatures, thus liberating histamine.

­ Complement can be activated directly, without antibody participation, by bacterial endotoxins, radiocontrast media, certain venoms, thus liberating C3a and C5a factors. These two by-products as well as a C2 kinin factor are synthesized in excessive amounts in the case of C1-esterase inhibitor deficiency, which explains the edematous manifestations occurring in angioneurotic edema, be it acquired or hereditary.

­ Urticaria and angioedema can also be secondary to excessive intake of histamine-rich substances which can be found in food in particular.

But all cases of urticaria cannot be explained by the same physiopathological mechanisms

Indeed, its seems that according to the mechanism which activates mast cells and basophils, be it immune or not, the mediators are released in different quantities. If histamine is produced the same way, PGD2 and LTC4 would be synthesized in greater amounts by mast cells in IgE-dependant phenomena than in those not using antibodies, these mediators being most likely released through different transduction signals [19]. It has also been proven that some basophils do not release mediators when stimulated by IgE whereas these same cells do when stimulated by other stimuli [20, 21]. Depending on which type of urticaria is concerned, the mediators released may differ. Thus, in delated pressure urticaria, histamine does not interfere or barely does (besides antihistamines are ineffective), whereas kinins, prostaglandins and cytokines, namely IL-1 and IL-6, are concerned [22]. In cold-related urticaria, PAF seems to be particularly important.

Actually, if this classic theory is still valid, some aspects are better known today

* Recently, the concept of "cell-releasability" asserted itself: each cell can release a more or less important quantity of mediators in response to a same stimulus. This means that mast cells and basophils in different individuals are not equally sensitive to the activating factors and that they will respond in various ways.

* If urticaria is always considered as an immediate hypersensitivity reaction which appears within minutes following antigen introduction, it is well known that a delayed phase exists. It consists in a sustained inflammatory reaction which appears three or four hours after allergen contact. It is major between 6 and 12 hrs, and consists in erythema, edema and pressure sensitiveness on a much larger scale than in the immediate reaction, and disappears in 24 to 72 hrs. Biopsy of these lesions reveals basophils, neutrophils, eosinophils, T lymphocytes, macrophages and mast cells whose role is essential in this reaction. These cells can release a great deal of mediators. However, when they are stimulated by an IgE-related mechanism, mainly neoformed substances, like histamine, are liberated. But histamine cannot induce a delayed reaction. This goes to show that other cells must intervene, particularly basophils and eosinophils, and to a lesser degree neutrophils and lymphocytes [23-26]. These cells can synthesize various pro-inflammatory substances noted in the cutaneous lesions themselves: MBP and EDN, LTC4, PAF... [27, 28].

In this delayed reaction, cytokines are particularly involved. They are produced by different cell types: lymphocytes, macrophages, but also mast cells [29].

Indeed, in vitro, mast cells can synthesize different cytokines, namely TNFalpha, IL-3, IL-6 and IL-8 but also GMCSF, TGFß, IL-1ß, IL-4, IL-5, IL-10, IL-13... In humans, it has been proven that these cells could release IL-3, IL-4, IL-5, IL-8... As for TNFalpha, it not only can be liberated by mast cells activated through IgE, but it also exists preformed, constitutively, in the cells themselves [30]. It can participate in systemic manifestations observed in certain cases of urticaria [31].

These cytokines have an inflammatory action in the early and delayed phases: they are chemoattractant for certain cells and increase adhesion molecule expression on endothelial cells, leukocytes and mast cells [32]. They regulate cell migration to the inflammatory site. "Couples" particularly step in, in these phenomena: E selectine (ELAM 1) on activated endothelial cells and carbohydrated determinants on leukocytes, namely neutrophils; ICAM1 and VCAM1, belonging to the immunoglobulin superfamily, bind respectively to ß2 integrins (LFA1) on leukocytes and ß1 integrins (VLA4) on eosinophils. They will thus permit leukocyte rolling on the vascular walls, their activation and firm adhesion to endothelial cells, and finally transendothelial migration.

These cytokines also have characteristics which permit them to intervene directly in the allergic reaction; thus IL-4 plays a key role in IgE production, IL-5 with IL-3 and GMCSF stimulate eosinophil proliferation and migration and activate them...

Certain chemokines can also act without cell recruitment at all. Such is the case for RANTES and MCP1 (macrophage chemoattractant protein 1) which induce basophil and mast cell degranulation and histamine release [33].

Thus inflammatory cells present in tissues have their own role and potentiate the reaction by synthesizing other cytokines and lipidic mediators [34]. At the end of the delayed phase, apoptosis of eosinophils and neutrophils and phagocytosis of the apoptotic bodies by macrophages could exist [35].

Histological results and physiopathological mechanisms involved in this delayed phase match those observed in delayed pressure urticaria. The latter consists in a particular type of urticaria in which edematous manifestations occur hours after pressure has been applied, without an acute phase or identifiable IgE [36].

In the past few years, various seric factors inducing histamine liberation, other than allergens, have been identified.

Indeed, injection of autologous serum in patients presenting with chronic urticaria induces an erythematous and papulous reaction whose intensity would be proportional to urticaria severity, in 30 to 60% of cases. This serum can also induce histamine liberation by circulating basophils and cutaneous mast cells in healthy controls. The seric factors in question still have to be identified.

In 1993, Greaves et al., proved that seric IgE capable of releasing histamine from basophils can be blocked by soluble FcepsilonRI. The authors deduced that FcepsilonRI represented the target for IgG1 and/or IgG3 type auto-antibodies [37]; further studies showed that the epitope was found on the alpha chain of the receptor [38].

These auto-antibodies have also been found in other dermatological diseases (pemphigus, dermatomyositis, systemic lupus erythematosus...) but they are then more often of the IgG2 and/or IgG4 type and do not induce release of histamine [39, 40]. These antibodies, present in 20 to 40% cases of chronic urticaria, can be biologically active, inducing histamine release from circulating basophils and cutaneous mast cells, but not all of them are. This certainly depends on numerous factors: antibody affinity, epitope specificity, IgG subtypes which can fix complement or not [41].

Some chronic cases of urticaria could thus be a model for an auto-immune disease by receptor activation [42, 43]. It has been well known for a long time that auto-immune manifestations often exist, namely of the thyroid type, in urticaria [44]. In some patients anti-IgE antibodies are observed but their specificity is diminished; they are also present in atopic dermatitis and even in controls [45].

Other factors inducing histamine liberation are also noted but their exact nature is still unknown [46]. Thus, for Kermani et al., the substance is not an IgG, does not interfere with the FcepsilonRI alpha chain, does not act through neuropeptides, and is active on mast cells but not on basophils [47].

If understanding the physiopathology of urticaria is interesting on an immunological basis, the pharmacological aspect is also important, so as to propose efficient treatment to patients presenting with this sometimes severe, always bothersome disease [48, 49].

If anti-H1 anti-histamines associated or not to anti-H2 are often effective, this is not always true. This is easily understood, since histamine is not the only mediator concerned. Nonetheless, certain anti-H1 could also act through their anti-inflammatory properties in the delayed reaction.

Corticosteroids are also effective, by decreasing eicosanoid and cytokine production, thus altering eosinophil and mononuclear cell migration, but they do not hinder histamine release. Furthermore, their side effects cannot be disregarded.

Cytokines synthesized by the different cells present in the cutaneous infiltrate, and particularly mast cells, could also constitute a therapeutic target. Indeed, in studies on mice, cyclosporine and FK506 inhibit their production.

Finally, the auto-immune feature of certain cases of urticaria with anti-receptor or anti-IgE auto-antibodies, has led to the prescription of therapies such as plasmapheresis [50], cyclosporine [51] or intravenous immunoglobulins [52] with unquestionable results; it might also be possible to use soluble FcepsilonRI which neutralizes the histamine-releasing activity of these auto-antibodies in in vitro and animal studies [53].

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