Pathomechanisms in Physical Urticaria
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Pathomechanisms in Physical Urticaria Ju ¨rgen Grabbe Department of Dermatology, Medical University of Lu ¨beck, Lu ¨ beck, Germany Various exogenous stimuli, e.g., rubbing, pressure, cold, heat, or electromagnetic waves, have been described to elicit whealing reactions, the so-called physical urticarias. They may occur as isolated dis- eases or in association with other types of urticaria. In many cases, the respective physical factors can be defined exactly, e.g., the degree of temperature changes or the range of eliciting ultraviolet wave- lengths. In contrast, the underlying pathomechan- isms are mostly still obscure. In the past, often contradictory results have been reported regarding the role of IgE, complement factors, histamine, or even mast cells. Recently, many investigations have been performed on solar urticaria where subgroups of patients with different clinical and pathophysiolo- gic features could be defined and mechanisms of tol- erance induction have been studied that also offered an efficient treatment modality. Therefore this review will mainly focus on this type of disease as a paradigm of the pathomechanisms of physical urticaria. Key words: mast cells/photoallergen/solar urti- caria/tolerance. Journal of Investigative Dermatology Symposium Proceedings 6:135–136, 2001 T he physical urticarias form a heterogeneous group of diseases due to the wide range of eliciting stimuli or clinical pictures as well as their association with other types of urticaria. Dermographic, cold, and pressure urticaria often occur together with chronic idiopathic, cholinergic, or other physical urticarias. In contrast, solar or heat urticaria mostly appear either as isolated diseases or are associated only with other types of physical urticaria (Henz, 1989). This suggests that in the former types nonspecific mechanisms play a role, e.g., a lowered threshold of mast cell activation or higher reactivity of target cells. This has been observed in patients with dermographic urticaria, who may also suffer from bronchial hyperreactivity to histamine or metacholine. In contrast, more specific mechanisms may be important in solar and heat urticaria; however, many questions concerning the pathomechanisms of physical urticarias remain to be clarified: How is a physical stimulus transformed to the level of molecular and cellular activation? Do IgE molecules and mast cells play a decisive role? Which mediators derived from mast cells or other sources are responsible for the activation of endothial cells, dermal nerve endings, and the influx of inflammatory cells? What is the role of this inflammatory infiltrate? In the past, many functional and biochemical studies led to inconsistent or even contradictory results. All these data on the different types of physical urticaria cannot be discussed in detail here, therefore I will focus on the pathomechanisms of solar urticaria, as many interesting investigations have been performed recently. PHOTOALLERGENS In about 75% of patients from a large survey reported by Japanese authors, photosensitive activity could be observed in the serum that produced a wheal and flare reaction upon intradermal injection following in vitro irradiation using individual eliciting wavelengths (Uetsu et al, 2000). The fact that irradiated patient serum injected into the skin of healthy recipients fails to produce such a reaction argues against a phototoxic mechanism in solar urticaria. The origin of the postulated circulating photoallergen is still unclear. Blocking the arterial blood supply prevented an urticarial reaction upon irradiation in some patients, suggesting an extracutaneous produc- tion of a photoallergen (Ramsay et al, 1970). Leenutaphong et al (1989), however, reported a patient who failed to respond to injection of his irradiated serum, but reacted to eluates from in vivo irradiated skin or irradiated eluates from the epidermis. In addition, stripping off of the horny layer or removal of the suction blister roof abolished urticarial reactions upon irradiation. From this, it may be concluded that in some patients a photoreactive precursor molecule is produced in the epidermis and forms a photoallergen upon activation by UV or visible light. Few attempts have so far been made to characterize the circulating photoallergen. A 25–45 kDa molecule that displayed wheal and flare activity could be demon- strated in patients with an action spectrum between 400 and 500 nm. In one case, reactivity to UVA and short-wave visible light from 330 to 520 nm was associated with an additional high molecular weight activity of 300–1000 kDa, and in patients showing a broad spectrum of activity from UVB to visible light multiple photoallergens seemed to be present (Kojima et al, 1986). This relationship between the individual action spectrum and the nature of the photoallergen is also interesting with regard to the different action spectra prevailing in different groups of patients: among 24 Belgium patients, most reacted to UVA alone or to UVA together with UVB or visible light (Ryckaert and Roelandts, 1998). In a series of 40 Japanese patients the majority (n = 24) was only responsive to visible light. This indicates that the nature of the responsible photoallergen may be dependent on either racial or enviromental factors. Among patients with solar urticaria, two groups (types I and II) could be classified based on their skin reaction to in vitro irradiated serum (Leenutaphong et al, 1989). Type I patients only responded to their own serum, in the type II group a reaction also developed with irradiated serum from normal subjects. Therefore, in the first group, Manuscript received June 19, 2001; accepted for publication June 19, 2001. Reprint requests to: Dr. Ju ¨ rgen Grabbe, Department of Dermatology, Medical University of Lu ¨beck, Ratzeburger Allee 160, D-23538 Lu ¨beck, Germany. Email: [email protected] 1087-0024/01/$15.00 · Copyright # 2001 by The Society for Investigative Dermatology, Inc. 135
Transcript of Pathomechanisms in Physical Urticaria
Pathomechanisms in Physical Urticaria
JuÈrgen GrabbeDepartment of Dermatology, Medical University of LuÈbeck, LuÈbeck, Germany
Various exogenous stimuli, e.g., rubbing, pressure,cold, heat, or electromagnetic waves, have beendescribed to elicit whealing reactions, the so-calledphysical urticarias. They may occur as isolated dis-eases or in association with other types of urticaria.In many cases, the respective physical factors can bede®ned exactly, e.g., the degree of temperaturechanges or the range of eliciting ultraviolet wave-lengths. In contrast, the underlying pathomechan-isms are mostly still obscure. In the past, oftencontradictory results have been reported regardingthe role of IgE, complement factors, histamine, or
even mast cells. Recently, many investigations havebeen performed on solar urticaria where subgroupsof patients with different clinical and pathophysiolo-gic features could be de®ned and mechanisms of tol-erance induction have been studied that also offeredan ef®cient treatment modality. Therefore thisreview will mainly focus on this type of disease as aparadigm of the pathomechanisms of physicalurticaria. Key words: mast cells/photoallergen/solar urti-caria/tolerance. Journal of Investigative DermatologySymposium Proceedings 6:135±136, 2001
The physical urticarias form a heterogeneous group ofdiseases due to the wide range of eliciting stimuli orclinical pictures as well as their association with othertypes of urticaria. Dermographic, cold, and pressureurticaria often occur together with chronic idiopathic,
cholinergic, or other physical urticarias. In contrast, solar or heaturticaria mostly appear either as isolated diseases or are associatedonly with other types of physical urticaria (Henz, 1989). Thissuggests that in the former types nonspeci®c mechanisms play arole, e.g., a lowered threshold of mast cell activation or higherreactivity of target cells. This has been observed in patients withdermographic urticaria, who may also suffer from bronchialhyperreactivity to histamine or metacholine. In contrast, morespeci®c mechanisms may be important in solar and heat urticaria;however, many questions concerning the pathomechanisms ofphysical urticarias remain to be clari®ed: How is a physical stimulustransformed to the level of molecular and cellular activation? DoIgE molecules and mast cells play a decisive role? Which mediatorsderived from mast cells or other sources are responsible for theactivation of endothial cells, dermal nerve endings, and the in¯ux ofin¯ammatory cells? What is the role of this in¯ammatory in®ltrate?
In the past, many functional and biochemical studies led toinconsistent or even contradictory results. All these data on thedifferent types of physical urticaria cannot be discussed in detailhere, therefore I will focus on the pathomechanisms of solarurticaria, as many interesting investigations have been performedrecently.
PHOTOALLERGENS
In about 75% of patients from a large survey reported by Japaneseauthors, photosensitive activity could be observed in the serum thatproduced a wheal and ¯are reaction upon intradermal injection
following in vitro irradiation using individual eliciting wavelengths(Uetsu et al, 2000). The fact that irradiated patient serum injectedinto the skin of healthy recipients fails to produce such a reactionargues against a phototoxic mechanism in solar urticaria. The originof the postulated circulating photoallergen is still unclear. Blockingthe arterial blood supply prevented an urticarial reaction uponirradiation in some patients, suggesting an extracutaneous produc-tion of a photoallergen (Ramsay et al, 1970). Leenutaphong et al(1989), however, reported a patient who failed to respond toinjection of his irradiated serum, but reacted to eluates from in vivoirradiated skin or irradiated eluates from the epidermis. In addition,stripping off of the horny layer or removal of the suction blister roofabolished urticarial reactions upon irradiation. From this, it may beconcluded that in some patients a photoreactive precursor moleculeis produced in the epidermis and forms a photoallergen uponactivation by UV or visible light. Few attempts have so far beenmade to characterize the circulating photoallergen. A 25±45 kDamolecule that displayed wheal and ¯are activity could be demon-strated in patients with an action spectrum between 400 and500 nm. In one case, reactivity to UVA and short-wave visiblelight from 330 to 520 nm was associated with an additional highmolecular weight activity of 300±1000 kDa, and in patientsshowing a broad spectrum of activity from UVB to visible lightmultiple photoallergens seemed to be present (Kojima et al, 1986).This relationship between the individual action spectrum and thenature of the photoallergen is also interesting with regard to thedifferent action spectra prevailing in different groups of patients:among 24 Belgium patients, most reacted to UVA alone or to UVAtogether with UVB or visible light (Ryckaert and Roelandts,1998). In a series of 40 Japanese patients the majority (n = 24) wasonly responsive to visible light. This indicates that the nature of theresponsible photoallergen may be dependent on either racial orenviromental factors.
Among patients with solar urticaria, two groups (types I and II)could be classi®ed based on their skin reaction to in vitro irradiatedserum (Leenutaphong et al, 1989). Type I patients only responded totheir own serum, in the type II group a reaction also developed withirradiated serum from normal subjects. Therefore, in the ®rst group,
Manuscript received June 19, 2001; accepted for publication June 19,2001.
Reprint requests to: Dr. JuÈrgen Grabbe, Department of Dermatology,Medical University of LuÈbeck, Ratzeburger Allee 160, D-23538 LuÈbeck,Germany. Email: [email protected]
1087-0024/01/$15.00 ´ Copyright # 2001 by The Society for Investigative Dermatology, Inc.
135
an abnormal photoreactive factor seems to be produced that can leadto an allergic reaction, but in the type II patients a physiologicprecursor molecule forms an allergen upon activation by irradiation.As a consequence, passive transfer experiments, i.e., injection ofpatient serum in healthy recipients and subsequent irradiation, willonly occasionally give positive results with type I serum if speci®cIgE as well as the abnormal precursor molecule are transferred. Incontrast, type II serum transfer usually gives a positive reaction as thephotoreactive precursor is also produced by normal subjects. Type Ipatients are mostly responsive to visible light, whereas no predom-inant action spectrum is observed in the type II patients, furtherindicating molecular heterogeneity of photoallergens. Due to ethicalreasons investigations based on injection of foreign sera are dif®cultto perform, but in vitro histamine release from blood basophils mayreplace such in vivo tests. For example, we could observe markedhistamine release in a patient with extreme sensitivity to UVA andUVB by stimulation with his own and also normal irradiated serum.Nonirradiated serum from neither the patient nor healthy controlsshowed this activity. Accordingly, the patient could be assigned tothe type II group.
IGE, MAST CELLS, AND INFLAMMATION
A pathophysiologic role of IgE in physical urticaria is mainlyinferred from passive transfer experiments, but de®nite proof is stilllacking. Positive results in demographic urticaria have beendoubted, whereas cold and solar urticaria reactions could bereproduced. The role of mast cells in the pathogenesis of solarurticaria has also to be clari®ed: an increase of histamine in theef¯uent blood after local irradiation has been observed togetherwith histologic signs of mast cell degranulation in lesional skin(Keahey et al, 1984). Induction of unresponsiveness by repeatedinjection of histamine liberators like polymyxin B, however, didnot prevent a urticarial response to irradiation in all patients(Torinuki et al, 1983). In addition, antihistamines often produce anunsatisfactory clinical effect. Interestingly, in cases of heat, cold, andsolar urticaria terfenadine may suppress whealing and itch, whereasthe development of erythema still occurs (Cox et al, 1989). Theseobservations correspond with data from a sequential ultrastructuralanalysis in solar urticaria: within 3 min of UV irradiation, whenonly erythema had developed, signs of increased endothelialpermeability, platelet activation, and swelling of nerve ®berscould be observed. Only 10 min later, mast cell degranulationand accumulation of eosinophils accompanied cutaneous whealing.Thus non mast cell dependant mechanisms may be involved in theearly phases of solar urticaria. At the time of 4 h, erythema andwhealing had almost disappeared, but signs of mast cell degranula-tion were still present together with the extravasation of eosinophilsand neutrophils (Leenutaphong et al, 1990). This in¯ux of in¯am-matory cells has been investigated in detail by Norris et al (1988):in®ltration by neutrophils and eosinophils peaked at approximately2 h and mononuclear cells were only observed after highconcentrations of UV irradiation with a delay of up to 24 h. Thefact that leukocyte in¯ux is prominent when clinical signs havealmost disappeared may suggest a downregulatory effect possibly bydegradation of mast cell mediators.
INHIBITION SPECTRUM AND INDUCTION OFTOLERANCE
A unique feature of solar urticaria is the so-called inhibitionspectrum that has been particularly reported from Japanese patients:in most cases exposure to wavelengths longer than the actionspectrum immediately after active irradiation suppresses theurticarial response that only develops after cessation of theinhibitory irradiation (Watanabe et al, 1999). Applying the inhib-ition spectrum beforehand or irradiation with shorter wavelengthsis mostly ineffective. This temporary suppression of the urticarialresponse corresponds to a delayed plasma histamine peak. Theunderlying mechanisms of the inhibition spectrum are still unclear:the destruction of the allergen precursor is unlikely as the inhibition
spectrum usually only works if it is applied after the actionspectrum. Even by prolongation of the inhibition spectrum,whealing of the skin cannot be fully suppressed, but is onlydelayed. This argues against a reconversion of the photoallergeninto the inactive precursor. A more probable explanation is atemporary blockade of allergen binding leading to inhibition ofmast cell degranulation (Horio et al, 1984).
The phenomenon of inhibitory spectrum must not be confusedwith clinical tolerance, which can be achieved in solar and othertypes of physical urticaria by repeated exposure to sub- or over-threshold stimuli; however, in cold urticaria maintenance ofunresponsiveness by daily bathing or showering with cold wateris often dif®cult. UV treatment in solar urticaria is used morefrequently. It is not always necessary to apply the respective activewavelengths, i.e., UVB treatment can be used for patients whoreact to UVA or visible light. Epidermal thickening and pigmen-tation may partially explain the induction of tolerance. But thisdoes not account for the rapid effect within a few hours of usingUVA (Beissert et al, 2000). Depletion of mast cell mediators byrepeated stimulation may be considered as a relevant mechanism.This is, however, incompatible with the observation that mast celldegranulation could not be observed by electron microscopyduring the induction of tolerance. In addition, erythema and whealsfollowing the intradermal injection of mast cell degranulators weresimilar before and after induction of tolerance (Keahey et al, 1984).Furthermore, cutaneous tachyphylaxis to histamine seems unlikelyas the response to histamine injection was not altered after toleranceinduction. General exhaustion of the photoallergen or the precur-sor molecule by repeated irradiation can be excluded by the factthat solar urticaria can still be evoced in areas shielded duringtolerance induction. The occupation of allergen binding sites oncutaneous mast cells by repeated irradiation may account for thetolerance phenomenon (Leenutaphong et al, 1990). Additionallyspeci®c inhibition of intracellular IgE-dependent signaling in mastcells is discussed, whereas other mast cell activators such as codeinand polymyxin B are still active.
Although different therapeutic approaches are described forphysical urticarias, an effective treatment often remains a challen-ging task for the physician. A better understanding of relevantpathomechanisms should help us to obtain more satisfying thera-peutic results.
REFERENCES
Beissert S, StaÈnder H, Schwarz T: UVA rush hardening for the treatment of solarurticaria. J Am Acad Dermatol 42:1030±1032, 2000
Cox NH, Higgins EM, Farr PM: Terfenadine inhibits itch and wheal, but notabnormal erythema, in physical urticarias. J Am Acad Dermatol 21:586±587,1989
Henz BM: Physical urticaria. In: Henz BM, Zuberbier T, Grabbe J, Monroe E, eds.Urticaria. Berlin: Springer, 1989: pp 55±85
Horio T, Yoshika A, Okamoto H: Production and inhibition of solar urticaria byvisible light exposure. J Am Acad Dermatol 11:1094±1099, 1984
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136 GRABBE JID SYMPOSIUM PROCEEDINGS
