Review Article Pathogenesis of Chronic Urticaria: An...

Review ArticlePathogenesis of Chronic Urticaria An Overview

Sanjiv Jain

Skin Care Clinic 108 Darya Ganj New Delhi 110002 India

Correspondence should be addressed to Sanjiv Jain drsanjivjainyahoocom

Received 14 April 2014 Accepted 15 June 2014 Published 10 July 2014

Academic Editor Lajos Kemeny

Copyright copy 2014 Sanjiv Jain This is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Thepathogenesis of chronic urticaria is notwell delineated and the treatment is palliative as it is not tied to the pathomechanismThecentrality ofmast cells and their inappropriate activation and degranulation as the key pathophysiological event are well establishedThe triggering stimuli and the complexity of effector mechanisms remain speculative Autoimmune origin of chronic urticariaalbeit controversial is well documented Numerical and behavioral alterations in basophils accompanied by changes in signalingmolecule expression and function as well as aberrant activation of extrinsic pathway of coagulation are other alternative hypothesesIt is also probable thatmast cells are involved in the pathogenesis throughmechanisms that extend beyond high affinity IgE receptorstimulation An increasing recognition of chronic urticaria as an immune mediated inflammatory disorder related to alteredcytokine-chemokine network consequent to immune dysregulation resulting from disturbed innate immunity is emerging as yetanother pathogenic explanation It is likely that these different pathomechanisms are interlinked rather than independent cascadesacting either synergistically or sequentially to produce clinical expression of chronic urticaria Insights into the complexities ofpathogenesis may provide an impetus to develop safer efficacious and targeted immunomodulators and biological treatment forsevere refractory chronic urticaria

1 Introduction

Chronic urticaria is a distressing disorder that adverselyimpacts the quality of life yet its pathogenesis is not welldelineated and accordingly the treatment is often palliativeand therapeutic outcome is suboptimal This necessitates anunderstanding of the pathogenesis to facilitate developmentof improved therapies In the recent past rapid strides inunderstanding the pathomechanismof chronic urticaria havebeen recorded yet most of the evidence based seeminglyimpregnable and conclusive hypotheses have been counteredby alternative equally authentic convincing and logisticcounter explanations

The knowledge of molecular immunopathogenesis andcomplexities of effector mechanisms in chronic urticariahas been enhanced by immunohistologic studies performedon sequential biopsies of urticarial wheals and focused oninfiltrating cell immunophenotypes and related cytokineschemokineschemokine receptors and adhesion molecules[1]

The urticarial wheal is characterized by dermal edemavasodilatation and perivascular nonnecrotizing infiltrate

comprising primarily of mononuclear cells predominantlyCD4+ lymphocytes with variable numbers of monocytesneutrophils eosinophils and basophils [2ndash4] The dermalneutrophilia is strikingly evident at sixtyminutes of evolutionof wheal with neutrophils representing the main componentof the cellular infiltrate [4] Mast cell numbers remainunaltered and are comparable to those in uninvolved skin andhealthy controls [4 5] The cytokine profile is characterizedby an increase in interleukin-4 (IL-4) interleukin-5 (IL-5)and interferon-gamma RNA (IFN-gamma) suggestive of amixed Th 1Th 2 response Chemokines are upregulated andincreased expression of adhesion molecules is evident Theuninvolved skin is characterized by upregulation of solu-ble mediators and adhesion molecules almost identical tolesional skin and significantly higher T-cell numbers whileaccumulation of neutrophils is an exclusivity of whealing skin[4] (Tables 1 and 2)

Chronic urticaria is initiated by inappropriate activationand degranulation of dermal mast cells This key patho-physiological event is predominant at the very onset andthe released cellular contents prime the immediate phase ofinflammation which progresses to a complex interplay of

Hindawi Publishing CorporationDermatology Research and PracticeVolume 2014 Article ID 674709 10 pageshttpdxdoiorg1011552014674709

2 Dermatology Research and Practice

Table 1 Infiltrating cells pattern in urticarial wheal uninvolved skin and normal healthy control subjects [4]

Cell type Urticarial wheal Uninvolved skin Healthy control subjectsMast cells Normal count Normal count Normal count

Lymphocytes Raised T-lymphocyte count More numerous T-lymphocytes than inlesional skin Low T-lymphocyte counts

Neutrophils Major cellular infiltrate at 60 minutes ofevolution of urticarial wheal

Significantly less infiltration than inlesional skin Insignificant

Eosinophils Significantly higher number Insignificant Insignificant

Basophil Significant number especially at 30 minutesof evolution of urticarial wheal Less but relevant number Insignificant

Table 2 Cytokine chemokine and adhesion molecule expression urticarial wheals uninvolved skin and healthy control subjects [4]

Urticarial wheal Uninvolved skin Normal healthy controlsCytokines

Interferon gamma High expression Significantly low expression Not expressedInterleukin-4 High expression Significantly low expression Not expressedInterleukin-5 High expression Significantly low expression Not expressedInterleukin-8 Moderate expression Moderate expression Not expressed

Chemokines

C X C R 3CC R 3 Expression similar tocontrol skin High expression Expression similar in lesional

and healthy control skinAdhesion molecules

Cellular adhesion molecule High expression Intense expression Significant expression

varied proinflammatory mediators cytokines chemokineschemokine receptors and adhesion molecules that regulatevasoactivity and specific kinetics of cellular infiltration ulti-mately evolving into a lymphocyte and granulocyte medi-ated hypersensitivity reaction evident as urticarial whealsThe incoming inflammatory cells in turn release moreproinflammatory mediators that serve to recruit and acti-vate other cell types thereby amplifying and extending thehost response The upregulation of inflammatory moleculesalmost comparable expression of chemokines and adhesionmolecules and higher T-cell numbers in uninvolved skin isindicative of widespread immunologic activation represent-ing a low level priming of the cutaneous inflammatory andimmunologic response apparatus reconfirming the hypoth-esis of latent minimal persistent inflammation in apparentlyuninvolved skin [4 5] This lowers the reactive threshold ofmast cells to triggering stimuli and facilitates themaintenanceof susceptibility to urticaria during clinical remission

2 Autoimmunity and Chronic Urticaria

The autoimmune origin is the most accepted hypothesisadvanced to explain inappropriate activation and degranu-lation of mast cells in urticaria Immune tolerance is main-tained by a balance between autoreactive lymphocytes andregulatory mechanisms that counteract them An increase innumber andor function of naturally occurring autoreactiveT-cells or diminished regulator mechanism manifests asautoimmunity Regulatory T-cells (T(REG)) particularly thenaturally occurring CD4(+) CD25(+) subset of T (REG)

provide a substantial component of autoimmune counterbal-ance The identification of forkhead box P3 (FOX P3) as acritical determinant of CD4(+) CD25(+) T(REG) cell devel-opment and function has provided insights into the delicatebalance between autoreactive and regulatory mechanismsin autoimmune disorders including chronic autoimmuneurticaria Functional assays and phenotype analysis haverevealed that T(REG) isolated from patients of autoimmunedisorder exhibit reduced regulatory function as opposed tothose fromhealthy controls Itmay be concluded that reducedpercentage of CD4(+) CD25(+) FOX P3(+) regulator T-cellscontributes to the autoimmune pathogenic process of chronicurticaria [6] The autoimmune pathogenic mechanism hasbeen conceptualized on the following observations thatprovided the initial circumstantial evidence and impetus forfurther clinical and laboratory investigations that reaffirmedthe concept

(i) Higher prevalence of thyroid autoantibodies inchronic urticaria [7]

(ii) A wheal-and-flare reaction on intradermal injectionof autologous serum in a subpopulation of patients(positive autologous serum skin test) and repro-ducibility on passive transfer of serum to normalhealthy control subjects [8]

(iii) Subsequent identification of IgG antibody directedto the alpha subunit of the IgE receptor capableof inducing positive autologous serum skin test aswell as histamine release from basophils [9] Theincidence of such autoantibodies is about 30 percent

Dermatology Research and Practice 3

and an additional 5ndash10 percent of patients have anti-IgE antibodies rather than anti-IgE receptor antibody[10]

(iv) Positive association with HLA subtypes DRBlowast04(DR4) and DQB 1lowast0302 (DQ8) [11]

(v) Therapeutic response to plasmapheresis [12] andintravenous immunoglobulin [13]

The evidence favouring autoimmune pathomechanismalthough persuasively convincing is incomplete Certainissues elucidated below need to be addressed for unequivocalacceptance of the proposed hypothesis

(i) The cutaneous response to intradermal injection ofautologous serum may be due to the presence ofnonimmunoglobulin vasoactive histamine releasingfactors [14] Moreover reactivity to autologous serumhas been observed in subjects with allergic respiratorydiseases and healthy controls [15] ASST identifiessubsets of patients exhibiting autoreactivity ratherthan establishing autoimmunity

(ii) Animal model mandatory to establish autoimmunestatus of the disorder is yet to be developed forchronic urticaria [16]

(iii) The autoantibodies of similar specificity have beendetected in sera of healthy persons and may belongto the natural repertoire Such natural autoantibodiesmay become pathogenic under certain circumstancesand this occurrence is dependent on the state ofoccupancy of the FceRI receptor by its natural ligandIgE The urticaria results from alteration in the tissuebinding of preexisting autoantibody in susceptibleindividuals rather than its production de novo Thusthe concept of conditional autoimmunity has evolved[17] in chronic urticaria

(iv) It has been proposed that anti-FceRI and anti-IgEautoantibodies are not actually pathogenic but aresecondary to the presence of urticaria in individu-als with a predisposition to develop autoimmunity[18]

The complex pathway involved in triggering maintain-ing and controlling autoantibody formation against FceRIandor IgE remains unexplainedThe autoantibodies relevantto chronic urticaria belong to complement fixing subtypesIgG1 and IgG3 [19]The vascular leakage of such autoantibod-ies by local events facilitates their binding to either FceRI orIgE cross-linking of the receptor and complement activationthat generates C5a C5a interacts with the receptor for com-plement anaphylatoxin (C5a receptor) localized on the sur-face ofmast cellMCTC the subtype dominant in the skin andparticipates in mast cell activation [20] This triggers a seriesof intracellular events and the earliest in signal transductioninvolves phosphorylation of tyrosine on the beta and gammachains of FceRI at immunoreceptor tyrosine activationmotifs(ITAM) The ITAMS associate with Src-family protein tyro-sine kinases (PTKs) such as Lyn and Syk which initiatethe activation of downstream effector pathways [21] and the

release of preformed granule contents such as histamineheparin tryptase and tumour necrosis factor-alpha (TNF-alpha) as well as the synthesis of other proinflammatorycytokineschemokines and eicosanoids [22] The downregu-lation of signal transduction andmediator release is regulatedby signal regulatory proteins (SIRP) that contain immuno-tyrosine inhibition motifs (ITIMS) which act by recruitingSH-2 bearing tyrosine phosphatases (SHIP 1 and 2) thatdephosphorylate ITAMonbeta and gamma subunits of FceRI[21]

The autoantibodies to alpha chain of FceRI andor IgEhave been detected in only 35 to 40 percent and 5 to 10percent of patients respectively [23] Moreover the detectionof autoantibodies in the serum does not confirm their func-tionality and may not be always implicated in the inductionof histamine release frommast cellsbasophils It is likely thatother permeabilizing factors are involved in serum mediatedvascular leakage

3 Nonimmunologic Agonists

Nonimmunologic agonists including substance P endor-phins enkephalins endogenous peptides and somatostatinmay induce regulated degranulation and liberation of proin-flammatory molecules from mast cells especially when theproducts of activated immune system lower the cutaneousmast cell release threshold [24]

4 Cellular Abnormalities Basophils

The primary abnormality in some patients of chronicurticaria might be cellularsubcellular rather than immuno-logically mediated autoimmune mechanism

There is increasing evidence of altered number structurefunction and trafficking defects in basophils Basopenia iswell documented and basophil numbers are inversely relatedto urticaria severity [25] Other evidence perhaps moreconvincing is the paradoxical suppression of FceRI medi-ated anti-FceRIanti-IgE antibody induced histamine releasefrom basophils during active disease [26] It is still moreintriguing that these basophils maintain normal responseto monocyte chemotactic protein-1 (MCP-1) and bradykininand are hyperresponsive to serum [27] It had been reasonedthat basophils in chronic autoimmune urticaria are desensi-tized in vivo to further FceRI induced activation Howeverautoantibody mediated desensitization of IgE receptor seemsunlikely as similar response of basophils has been observedin patients lacking autoimmune antibodies [27]

A more complex picture has emerged from insight intothe dysregulated expression of molecules that are criticalto signal propagation or its inhibition after IgE receptoractivation [28] Spleen tyrosine kinase (Syk) is a positiveregulator of signaling through FceRI and its levels are a majordeterminant of basophil histamine release (HR) in normalbasophils [29] Src homology 2 (SH2) containing inositolphosphatases SHIP-1 and SHIP-2 are negative regulators ofsignal propagation [30] In chronic urticaria there is a shiftin the paradigm of Syk dominated regulation of HR and


unlike normal basophils altered levels of SHIP-1 and SHIP-2 correlate with the pattern of anti-IgE stimulated histaminerelease [31 32]

In addition to these observations based on the pro-file of ex vivo activation of basophils by optimal con-centration of polyclonal anti-IgE it has been confirmedthat distinct basophil degranulation phenotypes exist inchronic urticaria and a bimodal stratification of basophilshas been proposed [32] Fifty percent of chronic urticariasubjects have significant reduction in basophil histaminerelease (HR) with anti-IgE stimulation It is consequent toincreased SHIP-2 levels and such subjects are designated anti-IgE nonresponders (CIU-NR) The remaining subjects havebasophils that release more than 10 percent of histaminecontent after anti-IgE stimulation and are termed anti-IgEresponders (CIU-R) and SHIP-1 levels in such basophils arereduced

This pattern of basophil functional phenotypes (CIU-Rand CIU-NR) appears to be independent of the existenceandor levels of autoantibodies [33] and remains stablein subjects with persistent disease The salient features ofbasophil phenotypes in chronic urticaria are summarized inTable 3 [31ndash33]

The levels andor expression of regulatory proteins isfunctional and normalizes during remission [33] Such shiftin basophil function is independent of the autoimmune statusof urticaria and in thosewith autoimmunity is notedwithouta parallel decrease in antibody titres

This profiling of signal proteins in basophils in conjunc-tion with their stratification into distinct phenotypes hasreaffirmed that abnormal basophil function may be a keyfactor in disease pathogenesis

5 Mast Cells and Chronic Urticaria

A direct role of mast cells in CU is speculated (Table 4)The activating factors derived from inflammatory cell infil-trate surrounding dermal postcapillary venules [34] stimu-late mast cells to secrete vasoactive molecules that activateendothelial cells The expression of adhesion molecules isupregulated [35] and the increased vasopermeability pro-motes extravascular leakage of fluids and proteins leading todevelopment of urticarial wheals

In an in vitro study performed to evaluate permeabilizingactivity of CU serum a similar pattern of mast cell degranu-lation and increased endothelial monolayer permeability wasobserved after exposure of two distinct mast cell lines (LAD-2 and HMC-1) [36 37] to CU serum The CU serum evokedresponse remained unaltered after IgG depletion reaffirmingits nondependence on mast cell IgE receptor activation [38]It was concluded that vasoactive molecules may be releasedfrom mast cells without degranulation [38]

It is likely that varied membrane receptors expressedon mast cells are selectively triggered by ligands suchas IgG peptides microbial derivatives and fragments ofactivated complement [39] and mast cells are stimulatedby activating signals to synthesize vasoactive substancesincluding lipid metabolites cytokines and chemokines [40

41] These newly formed permeabilizing factors includetumour necrosis factor-alpha (TNF-alpha) interleukin-6 (IL-6) vascular endothelial growth factor (VEGF) and plateletactivating factor (PAF) These are secreted from mast cellsindependent of release of preformed mediators stored ingranules such as histamine serotonin proteases and proteo-glycans [40 41] These permeabilizing factors facilitate thedevelopment of urticarial whealsThese observations providean explanation for lack of correlation between detectionof autoantibodies and degranulation of mast cells [42]quality and quantity of released vasoactive factors increasedvasopermeability urticaria severity refractoriness of severeurticaria to standard first line management with antihis-tamines and therapeutic response to immunosuppressiveagents

6 Chronic Urticaria Immune MediatedInflammatory Disorder

The concept of chronic urticaria being an immune mediatedinflammatory disorder evolved from incidental observationthat recommendation of targeted immunomodulator bio-logic therapy directed at a particular cytokinecell receptoradministered for some other inflammatory disorder amelio-rated coexisting chronic urticaria [43] It was indicative thatinflammatory cascade in chronic urticaria may be triggeredby altered chemokine-cytokine network and is attributedto immune dysregulation consequent to disturbed innateimmunity in the disorder

The investigation of early events of innate immunitythrough the study of dendritic cells that link innate andadaptive immune system has provided insights into thedysregulated immune response in chronic urticaria [44]Plasmacytoid dendritic cells (pDC) express toll-like receptors(TLR) that are activated by natural and synthetic ligandstriggering proinflammatory responses that play a key role inthe pathogenesis of several inflammatory disorders includingurticaria [45]

Accordingly a study of early events of the immuneresponse through the activation of pDC by TLR sensingwas undertaken to evaluate immune dysregulation in chronicurticaria [44]

Plasmacytoid dendritic cells are unremarkably scatteredamongst cellular infiltrate in the cutaneous lesion and theirpercentage in the peripheral blood mononuclear cells isunaltered and is similar to healthy controls A normal degreeof activation of pDC by the expression of costimulatorymolecules and an increased constitutive STAT 1 phosphoryla-tion on nonstimulated lymphocytes was observed HoweverIFN-alpha secretion by pDC upon stimulation by CpGAwas impaired and it was associated with altered IRF-7 anddownregulation of TLR 9 expression indicating a functionalimpairment of pDC and was supportive of immune dysreg-ulation in CU [44]

Several hypotheses have been proposed to explain thedownregulation of TLR9 in pDC after CpGA stimulationIt is probable that IgE or anti-FceRI autoantibodies cross-link FceRI on immature pDC impairing immune function


Table 3 Basophil phenotypes profile in chronic urticaria [31ndash33]

Feature Chronic urticarial (autoimmunenonautoimmune)CIU-R CIU-NR

(1) Anti-IgE stimulationcross-linkingHR in active disease gt10 percent of cellular content lt10 percent of cellular content

(2) Regulatory proteins Paradigm shift Paradigm shift

(a) KinaseHR not determined by kinaselevel HR not determined by kinase level

Normal Syk levels Normal Syk levels

(b) Phosphatase Regulates HR reduced SHIP-1levels

Regulates HR increased SHIP-2levels

(3) Sensitivity to anti-IgE stimulationin remission Heightened sensitivity Sensitivity restored to levels as in

normal healthy subjectsHR histamine releaseCIU-R chronic idiopathic urticariamdashrespondersCIU-NR chronic idiopathic urticariamdashnonrespondersSyk serum tyrosine kinaseSHIP-1 Src homology 2 (SH2) containing inositol phosphatase 1SHIP-2 Src homology 2 (SH2) containing inositol phosphatase 2

Table 4 Mast cell mediators relevant to chronic urticaria

Mediator Effect in chronic urticariaPreformed mediators

Histamine Direct potent vasoactive and smooth muscle spasmogenic effectsPrincipal mediator of vascular changes [70 71]

Newly synthesised mediatorsLipid mediators

LTC4LT B4PGD2

Actions similar to histaminePotentiate vasodilatation vascular permeability and smooth muscle contractionChemotactic for neutrophils and eosinophils [72]

Cytokines and chemokines

Tumour necrosis factor-alpha Newly synthesised as well as preformedUpregulates expression of adhesion molecules on endothelial cellsPromotes leukocyte rolling and adhesionChemotactic for neutrophils [73]

Interleukin-1Proinflammatory cytokineLymphocyte activator [74]Activates mast cells after release from leukocyte [75]

Interleukin-4 Chemotactic for neutrophilsRecruits eosinophils [76]

Interleukin-5 Recruits eosinophils [77]

Interleukin-6 Proinflammatory cytokineActivates lymphocytes [78]

Interleukin-8CXCL2Member of C X C chemokinesPotent neutrophil chemoattractantInvolved in neutrophil degranulation respiratory burst and adhesion to endothelial cells [79]

MCP-1CCL2 Chemoattractant for eosinophilsMIP-1 alphaCCL3 Chemoattractant for eosinophilsInterleukin-16 Chemoattractant for T-lymphocytesRANTESCCL5 Chemoattractant for eosinophils [79]

LTC4 leukotrieneC4 LTB4 leukotriene B4 PGD2 prostaglandinD2MCP-1monocyte chemotactic protein-1MIP-1 alphamonocyte inflammatory peptide-1 RANTES regulated upon activation normal T-cell expressed and secreted


by suppressing IFN-alpha production [46] Alternativelyregulatory receptors including BDCA-2 ILT-7 and NKp44downmodulate IFN production [47ndash49] It is also likelythat histamine released into circulation from degranulatingmast cellsbasophils may regulate several cell types throughstimulation of histamine receptors andpDCactivated byCpGrespond to histamine through H2 receptors with downregu-lation of IFN-alpha production [50]

The dysfunctional innate immune response in CU conse-quent to functional impairment of pDC to TLR9 activationdisturbs the cytokine production by T-cells mainly of IL-17Aand IL-10 [51] Besides elevated serum levels of IL-1 IL-4 IL-13 IL-18 tumour necrosis factor-alpha (TNF-alpha) [52 53]B-cell activating factor (BAFF) [54] and factors related toinflammatory process such as neopterin [55] and C-reactiveprotein have been documented These observations suggestthat there is an ongoing inflammatory process creating aproinflammatory environment in chronic urticaria that inturn is responsible for an altered pattern of secretion ofchemokines

Significantly higher serum levels of chemokines (C-Cand C-X-C) including CXCL8 CXCL9 CXCL10 and CCL2have been observed in CU and are not correlated witheither the clinical parameters of the disorder or the outcomeof basophil histamine release (BHR) andor ASST assays[56] These proinflammatory chemotactic cytokines interactwith chemokine receptors on the surface of inflammatorycells to trigger chemotaxis and transendothelial migration ofleukocytes to the site of inflammation

CXCL8IL-8 is chemotactic for neutrophils T-lympho-cytes and monocytes [56]

CXCL9Mig a monokine induced by interferon- (IFN-)gamma induced protein 1 (IP-10) is a type 1 C-X-Cchemokine and displays strong chemoattraction for T-helpertype 1 (Th 1) lymphocytes [57 58]

C-C ligand 2 (CCL2) (monocyte chemoattractant protein1) prototype of C-C chemokine is secreted mainly bymonocytes as evidenced by increased mRNA expression inCD14 + cells in CU CCL2 activates a variety of cells includ-ing monocytes macrophages lymphocytes eosinophils andbasophils and is a crucial factor for the development of Th 2responses [59]

The upregulation of chemokines in CU contributes tothe maintenance of activated status of inflammatory cellsubsets Basophils in CU display an upregulation of activa-tiondegranulation markers CD203c and CD63 and highresponsiveness to interleukin-3 (IL-3) stimulation It is likelythat activated profile of basophils is triggered by in vivopriming with potent basophil activating factor such as CCL2[60]

CCL2 induces degranulation of mast cell and has a potentbasophil histamine releasing activity Furthermore it hasbeen documented that an assembly of circulating chemokinesCCL2 CCL5 and CXCL8 play an important role in mast cellactivation and generation of histamine and serotonin [61]

It may be inferred that immunologic dysregulation con-sequent to disturbed innate immune response alters thecytokine-chemokine network that triggers the inflammatorystatus contributing to the pathogenesis of CU

7 Chronic Urticaria and Coagulation System

It has been observed that autologous plasma anticoagu-lated with substances other than heparin generates positiveautoreactive responses in a higher percentage of patientsthan autologous serum skin test (ASST) [62 63] As serumand plasma do not differ in their autoantibody content thisobservation points to a possible role of clotting factors inwheal-and-flare reaction It has been reasoned that plasmacontains more coagulation factors and complement whileconsumption of such factors in serum during formation ofclot is responsible for the discrepant reactivity of autologousplasma and serum It has thus been inferred that clottingcascademay be involved in pathogenesis of urticaria [64] andthis may provide an explanation for therapeutic effects notedin some patients with drugs active on coagulation system[65 66]

The extrinsic pathway of coagulation is activated andthrombin is generated from prothrombin by activated factorX in the presence of activated factor V and calcium ions[64] In vitro studies have confirmed that plasma of urticariapatients has significantly higher levels of prothrombin frag-ment F

1+2 a polypeptide of 34 kDa that is released into

circulation during the activation of prothrombin to thrombinby factor X [67] and severe exacerbations of urticaria areassociatedwith a strong activation of coagulation cascade thatleads to fibrin formation and fibrinolysis as shown by elevatedD-dimer plasma levels

Thrombin is a serine protease that enhances vascular per-meability activates and degranulates mast cells and inducesgeneration of anaphylatoxin C5a The activation of extrinsicpathway of coagulation is thus proposed as yet anotherexplanation

It is likely that different pathomechanistic pathwaysnamely seroimmunologic autoimmune inflammatory cellu-lar defects coagulative and complement system are inter-linked rather than separate independent cascades and thereis extensive cross talk amongst them with mutual regulationof activationThey act synergistically or sequentially as eitherindependent or interlinked pathomechanisms to activatemast cells with release of preformed mediators andor secre-tion of newly synthesized vasoactive molecules to producefinal clinical expression of urticaria [68 69] (Figure 1)

The various mast cell mediators preformed and newlysynthesized relevant to chronic urticaria are summarized inTable 4

Histamine is the principal vasoactive mediator and com-bined histamine-1 and -2 receptor responses are required forthe full expression of histamine vasoactivity including imme-diate vasodilation alteration in vasopermeability plasmaextravasation and dermal sensory nerve stimulation [69ndash71]Its role in the pathogenesis of wheal is less certain and it isprobable that nonhistamine mast cell mediators regulate cellrecruitment The leukotrienes cytokines and chemokinesupregulate adhesionmolecule expression on endothelial cellspromoting rolling and adhesion of leukocytes followedby chemotaxis and transendothelial migration and cellularinflux into whealing skin These infiltrating cells in turnrelease proinflammatory cytokines and chemokines that


C1 C1 C2C5 C6 C7 C8 C9

C4 C4b C2a C5aC5b C5b C5b6 C5b67 C5b679 MAC

C3 C3bFibrin Fibrinogen

Thrombin Prothrombin

XVII

Tissue factorExtrinsic pathway of

coagulation

+

+

Histamine chemokinesand cytokines

IgGanti-FceRI

ITAMLyn Syk

PKCGTP Ca2+

Mast cell

Interleukin-1

Interleukin-5Interleukin-6Interleukin-4

Eosinophil

GammaSubstance P

C5a receptor

Lymphocyte

ITAM immunotyrosine activation motifGTP guanosine triphosphateLyn Syk cytoplasmic tyrosine kinase

PKC protein kinase CMAC membrane attack complex

FceRI alpha

Beta

alpha

Figure 1 Pathogenesis of chronic urticaria molecular intercommunication between autoimmune complement and coagulation cascade

serve to recruit and activatemore inflammatory cells therebysustaining amplifying and extending the host responseThe signals for resolution of urticaria are also not wellcharacterized It involves downregulation of the histaminereceptor reconstitution of integrity of the endothelial celllining apoptosis of the inflammatory cells clearance ofcellular debris by macrophages and drainage of edema fluidinto the vascular circulation [22]

It may be concluded that the pathogenesis of chronicurticaria is as perplexing as the disorder is intriguing anda concise pathomechanism has as yet not been identifiedthat may provide a rational explanation for all cases Anincomplete understanding has hampered the search fornovel efficacious low toxicity drugs that may be offered asalternatives in severe unremitting urticaria unresponsiveto standard first line of management It is however likelythat newer insights into the complexities of pathogenesismay pave the way for evolving therapies that are morespecifically tied to the pathomechanics of the disorder andprovide an impetus to develop targeted immunomodulatorsand biological therapies that may be favorably included intherapeutic armamentarium

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

References

[1] R A Sabroe and M W Greaves ldquoWhat is urticaria Anatom-ical physiological and histologic consideration and classifica-tionrdquo in Urticaria and Angioedema A P Kaplan Ed pp 1ndash14Informo Health Care New York NY USA 2nd edition 2009

[2] J Elias E Boss and A P Kaplan ldquoStudies of the cellularinfiltrate of chronic idiopathic urticaria Prominence of T-lymphocytes monocytes andmast cellsrdquo Journal of Allergy andClinical Immunology vol 78 no 5 pp 914ndash918 1986

[3] Y AMekori R C Giorno P Anderson and P F Kohler ldquoLym-phocyte subpopulations in the skin of patients with chronicurticariardquo Journal of Allergy and Clinical Immunology vol 72no 6 pp 681ndash684 1983

[4] M Caproni B Giomi W Volpi et al ldquoChronic idiopathicurticaria infiltrating cells and related cytokines in autologousserum-induced whealsrdquoClinical Immunology vol 114 no 3 pp284ndash292 2005

[5] C H Smith C Kepley L B Schwartz and T H Lee ldquoMast cellnumber and phenotype in chronic idiopathic urticariardquo Journalof Allergy and Clinical Immunology vol 96 no 3 pp 360ndash3641995

[6] X Valencia and P E Lipsky ldquoCD4+CD25+FoxP3+ regulatory Tcells in autoimmune diseasesrdquoNature Clinical Practice Rheuma-tology vol 3 no 11 pp 619ndash626 2007

[7] A Leznoff R G Josse J Denburg and J Dolovich ldquoAssociationof chronic urticaria and angioedema with thyroid autoimmu-nityrdquo Archives of Dermatology vol 119 no 8 pp 636ndash640 1983

[8] C E H Grattan T B Wallington R P Warin C T Kennedyand J W Bradfield ldquoA serological mediator in chronic idio-pathic urticariamdasha clinical immunological and histologicalevaluationrdquo British Journal of Dermatology vol 114 no 5 pp583ndash590 1986

[9] MHide DM Francis C E H Grattan J Hakimi J P Kochanand M W Greaves ldquoAutoantibodies against the high-affinityIgE receptor as a cause of histamine release in chronic urticariardquoTheNew England Journal of Medicine vol 328 no 22 pp 1599ndash1604 1993

[10] C E H Grattan D M Francis M Hide and M W GreavesldquoDetection of circulating histamine releasing autoantibodieswith functional properties of anti-IgE in chronic urticariardquo


Clinical and Experimental Allergy vol 21 no 6 pp 695ndash7041991

[11] B F OrsquoDonnell C M OrsquoNeill D M Francis et al ldquoHumanleucocyte antigen class II associations in chronic idiopathicurticariardquo British Journal of Dermatology vol 140 no 5 pp853ndash858 1999

[12] C E H Grattan D M Francis N G P Slater R J Barlowand M W Greaves ldquoPlasmapheresis for severe unremittingchronic urticariardquoThe Lancet vol 339 no 8801 pp 1078ndash10801992

[13] B F OrsquoDonnell R M Barr A K Black et al ldquoIntravenousimmunoglobulin in autoimmune chronic urticariardquo BritishJournal of Dermatology vol 138 no 1 pp 101ndash106 1998

[14] U Fagiolo F Kricek C Rufb A Peserico A Amadori and MCancian ldquoEffects of complement inactivation and IgGdepletionon skin reactivity to autologous serum in chronic idiopathicurticariardquo Journal of Allergy and Clinical Immunology vol 106no 3 pp 567ndash572 2000

[15] E Guttman-yassky R Bergman C Maor M Mamorsky SPollack and E Shahar ldquoThe autologous serum skin test ina cohort of chronic idiopathic urticaria patients compared torespiratory allergy patients and healthy controlsrdquo Journal of theEuropean Academy of Dermatology and Venereology vol 21 no1 pp 35ndash39 2007

[16] N R Rose and C Bona ldquoDefining criteria for autoimmunediseases (Witebskyrsquos postulates revisited)rdquo Immunology Todayvol 14 no 9 pp 426ndash430 1993

[17] M P Horn J M Pachlopnik M Vogel et al ldquoConditionalautoimmunitymediated by human natural anti-Fc120576RI120572 autoan-tibodiesrdquo FASEB Journal vol 15 no 12 pp 2268ndash2274 2001

[18] E Novembre A Cianferoni F Mori et al ldquoUrticaria andurticaria related skin conditiondisease in childrenrdquo EuropeanAnnals of Allergy and Clinical Immunology vol 39 no 8 pp253ndash258 2007

[19] E Fiebiger F Hammerschmid G Stingl and D Maurer ldquoAnti-Fc120576RI120572 autoantibodies in autoimmune-mediated disordersidentification of a structure-function relationshiprdquo Journal ofClinical Investigation vol 101 no 1 pp 243ndash251 1998

[20] Y Kikuchi and A P Kaplan ldquoA role for C5a in augmentingIgG-dependent histamine release from basophils in chronicurticariardquo Journal of Allergy and Clinical Immunology vol 109no 1 pp 114ndash118 2002

[21] W Zhao and L B Schwartz ldquoMast cells and basophilsrdquo inUrticaria and Angioedema M W Greaves and A P KaplanEds pp 19ndash50 Marcel Dekker New York NY USA 2004

[22] C E H Grattan ldquoAutoimmune urticariardquo Immunology andAllergy Clinics of North America vol 24 no 2 pp 163ndash181 2004

[23] A P Kaplan and M Greaves ldquoPathogenesis of chronicurticariardquo Clinical and Experimental Allergy vol 39 no 6 pp777ndash787 2009

[24] A L Schocket ldquoChronic urticaria pathophysiology and etiol-ogy or the what and whyrdquo Allergy and Asthma Proceedings vol27 no 2 pp 90ndash95 2006

[25] C E H Grattan G Dawn S Gibbs and D M FrancisldquoBlood basophil numbers in chronic ordinary urticaria andhealthy controls diurnal variation influence of loratadine andprednisolone and relationship to disease activityrdquo Clinical ampExperimental Allergy vol 33 no 3 pp 337ndash341 2003

[26] R A Sabroe D M Francis R M Barr A K Black and MW Greaves ldquoAnti-Fc120576RI autoantibodies and basophil histaminereleasability in chronic idiopathic urticariardquo Journal of Allergyand Clinical Immunology vol 102 no 4 I pp 651ndash658 1998

[27] E Luquin A P Kaplan and M Ferrer ldquoIncreased respon-siveness of basophils of patients with chronic urticaria tosera but hypo-responsiveness to other stimulirdquo Clinical andExperimental Allergy vol 35 no 4 pp 456ndash460 2005

[28] B M Vonakis and S S Saini ldquoNew concepts in chronicurticariardquo Current Opinion in Immunology vol 20 no 6 pp709ndash716 2008

[29] D W MacGlashan Jr ldquoRelationship between spleen tyrosinekinase and phosphatidylinositol 51015840 phosphatase expression andsecretion from human basophils in the general populationrdquoJournal of Allergy and Clinical Immunology vol 119 no 3 pp626ndash633 2007

[30] W Leung and S Bolland ldquoThe inositol 51015840-phosphatase SHIP-2 negatively regulates IgE-induced mast cell degranulation andcytokine productionrdquo Journal of Immunology vol 179 no 1 pp95ndash102 2007

[31] B M Vonakis and S S Saini ldquoSyk-deficient basophils fromdonors with chronic idiopathic urticaria exhibit a spectrum ofreleasabilityrdquo Journal of Allergy and Clinical Immunology vol121 no 1 pp 262ndash264 2008

[32] B M Vonakis K Vasagar S P Gibbons Jr et al ldquoBasophilFc120576RI histamine release parallels expression of Src-homology2-containing inositol phosphatases in chronic idiopathicurticariardquo Journal of Allergy and Clinical Immunology vol 119no 2 pp 441ndash448 2007

[33] J A Eckman R G Hamilton L M Gober P M Sterba and SS Saini ldquoBasophil phenotypes in chronic idiopathic urticariain relation to disease activity and autoantibodiesrdquo Journal ofInvestigative Dermatology vol 128 no 8 pp 1956ndash1963 2008

[34] A Tedeschi R Asero A V Marzano et al ldquoPlasma levelsand skin-eosinophil-expression of vascular endothelial growthfactor in patients with chronic urticariardquo Allergy vol 64 no 11pp 1616ndash1622 2009

[35] H L Kwang Y K Ji D Kang J C Yoo W Lee andY R Jai ldquoIncreased expression of endothelial cell adhesionmolecules due to mediator release from human foreskin mastcells stimulated by autoantibodies in chronic urticaria serardquoJournal of Investigative Dermatology vol 118 no 4 pp 658ndash6632002

[36] A S Kirshenbaum C Akin Y Wu et al ldquoCharacterizationof novel stem cell factor responsive human mast cell linesLAD 1 and 2 established from a patient with mast cell sar-comaleukemia Activation following aggregation of Fc120576RI orFc120574RIrdquo Leukemia Research vol 27 no 8 pp 677ndash682 2003

[37] G Nilsson T Blom M Kusche-Gullberg et al ldquoPhenotypiccharacterization of the human mast-cell line HMC-1rdquo Scandi-navian Journal of Immunology vol 39 no 5 pp 489ndash498 1994

[38] F Bossi B Frossi O Radillo et al ldquoMast cells are criticallyinvolved in serum-mediated vascular leakage in chronicurticaria beyond high-affinity IgE receptor stimulationrdquoAllergy vol 66 no 12 pp 1538ndash1545 2011

[39] B Frossi G Gri C Tripodo and C Pucillo ldquoExploring aregulatory role for mast cells MCregsrdquo Trends in Immunologyvol 31 no 3 pp 97ndash102 2010

[40] F Levi-Schaffer and J PersquoEr ldquoMast cells and angiogenesisrdquoClinical and Experimental Allergy vol 31 no 4 pp 521ndash5242001

[41] A Hennino F Berard I Guillot N Saad A Rozieres andJ Nicolas ldquoPathophysiology of urticariardquo Clinical Reviews inAllergy and Immunology vol 30 no 1 pp 3ndash11 2006

[42] J A Eckman R G Hamilton and S S Saini ldquoIndependentevaluation of a commercial test for autoimmune urticaria in


normal and chronic urticaria subjectsrdquo Journal of InvestigativeDermatology vol 129 no 6 pp 1584ndash1586 2009

[43] F Habal and V Huang ldquoAngioedema associated with Crohnrsquosdisease response to biologicsrdquo World Journal of Gastroenterol-ogy vol 18 no 34 pp 4787ndash4790 2012

[44] E Futata M Azor J Dos Santos et al ldquoImpaired IFN-120572secretion by plasmacytoid dendritic cells induced by TLR9activation in chronic idiopathic urticariardquo British Journal ofDermatology vol 164 no 6 pp 1271ndash1279 2011

[45] G Hartmann J Battiany H Poeck et al ldquoRational designof new CpG oligonucleotides that combine B cell activationwith high IFN-120572 induction in plasmacytoid dendritic cellsrdquoEuropean Journal of Immunology vol 33 no 6 pp 1633ndash16412003

[46] J R Tversky T V Le A P Bieneman K L Chichester RG Hamilton and J T Schroeder ldquoHuman blood dendriticcells from allergic subjects have impaired capacity to produceinterferon-120572 via toll-like receptor 9rdquo Clinical and ExperimentalAllergy vol 38 no 5 pp 781ndash788 2008

[47] A Dzionek Y Sohma J Nagafune et al ldquoBDCA-2 a novelplasmacytoid dendritic cell-specific type II C-type lectin medi-ates antigen capture and is a potent inhibitor of interferon 120572120573inductionrdquo Journal of Experimental Medicine vol 194 no 12pp 1823ndash1834 2001

[48] A Fuchs M Cella T Kondo and M Colonna ldquoParadoxicinhibition of human natural interferon-producing cells by theactivating receptor NKp44rdquo Blood vol 106 no 6 pp 2076ndash2082 2005

[49] W Cao D B Rosen T Ito et al ldquoPlasmacytoid den-dritic cell-specific receptor ILT7-Fc120576RI120574 inhibits Toll-likereceptor-induced interferon productionrdquo Journal of Experimen-tal Medicine vol 203 no 6 pp 1399ndash1405 2006

[50] A Mazzoni C A Leifer G E Mullen M N Kennedy D MKlinman and D M Segal ldquoCutting edge histamine inhibitsIFN-120572 release from plasmacytoid dendritic cellsrdquo The Journalof Immunology vol 170 no 5 pp 2269ndash2273 2003

[51] J C dos SantosMHAzor V YNojima et al ldquoIncreased circu-lating pro-inflammatory cytokines and imbalanced regulatoryT-cell cytokines production in chronic idiopathic urticariardquoInternational Immunopharmacology vol 8 no 10 pp 1433ndash1440 2008

[52] M Caproni C Cardinali B Giomi et al ldquoSerological detec-tion of eotaxin IL-4 IL-13 IFN-120574 MIP-1120572 TARC and IP-10 in chronic autoimmune urticaria and chronic idiopathicurticariardquo Journal of Dermatological Science vol 36 no 1 pp57ndash59 2004

[53] A Tedeschi M Lorini C Suli and R Asero ldquoSeruminterleukin-18 in patients with chronic ordinary urticariaassociation with disease activityrdquo Clinical and ExperimentalDermatology vol 32 no 5 pp 568ndash570 2007

[54] FMelchers ldquoActions of BAFF inB-cellmaturation and its effectson the development of autoimmune diseaserdquo Annals of theRheumatic Diseases vol 62 supplement 2 pp 1125ndash1127 2013

[55] G Ciprandi M de Amici L Berardi et al ldquoSerum neopterinlevels in spontaneous urticaria and atopic dermatitisrdquo Clinicaland Experimental Dermatology vol 36 no 1 pp 85ndash87 2011

[56] J C Santos C A de Brito E A Futata et al ldquoUp-regulationof chemokine C-C ligand 2 (CCL2) and C-X-C chemokine8 (CXCL8) expression by monocytes in chronic idiopathicurticariardquo Clinical and Experimental Immunology vol 167 no1 pp 129ndash136 2012

[57] R Bonecchi G Bianchi P P Bordignon et al ldquoDifferentialexpression of chemokine receptors and chemotactic respon-siveness of type 1 T helper cells (Th1s) and Th2srdquo Journal ofExperimental Medicine vol 187 no 1 pp 129ndash134 1998

[58] M Rotondi A Rosati A Buonamano et al ldquoHigh pretrans-plant serum levels of CXCL10IP-10 are related to increased riskof renal allograft failurerdquo American Journal of Transplantationvol 4 no 9 pp 1466ndash1474 2004

[59] W J Karpus N W Lukacs K J Kennedy et al ldquoDifferentialCC chemokine-induced enhancement of T helper cell cytokineproductionrdquo The Journal of Immunology vol 158 no 9 pp4129ndash4136 1997

[60] F D Lourenco M H Azor J C Santos et al ldquoActivated statusof basophils in chronic urticaria leads to interleukin-3 hyper-responsiveness and enhancement of histamine release inducedby anti-IgE stimulusrdquo British Journal of Dermatology vol 158no 5 pp 979ndash986 2008

[61] M L Castellani M A De Lutiis E Toniato et al ldquoImpact ofRANTES MCP-1 and IL-8 in mast cellsrdquo Journal of BiologicalRegulators amp Homeostatic Agents vol 24 no 1 pp 1ndash6 2010

[62] R Asero A Tedeschi P Riboldi and M Cugno ldquoPlasmaof patients with chronic urticaria shows signs of thrombingeneration and its intradermal injection causes wheal-and-flare reactions much more frequently than autologous serumrdquoJournal of Allergy and Clinical Immunology vol 117 no 5 pp1113ndash1117 2006

[63] V Safedi M Morahedi A Aghamohammed et al ldquoCom-parison between sensitivity of autologous skin serum test andautologous plasma skin test in patients with Chronic IdiopathicUrticaria for detection of antibody against IgE or IgE receptor(Fc120576RI120572)rdquo Iranian Journal of Allergy Asthma and Immunologyvol 10 no 2 pp 111ndash117 2011

[64] R Asero A Tedeschi R Coppola et al ldquoActivation of the tissuefactor pathway of blood coagulation in patients with chronicurticariardquo Journal of Allergy and Clinical Immunology vol 119no 3 pp 705ndash710 2007

[65] R Parslew D Pryce J Ashworth and P S FriedmannldquoWarfarin treatment of chronic idiopathic urticaria and angio-oedemardquo Clinical amp Experimental Allergy vol 30 no 8 pp1161ndash1165 2000

[66] R J Barlow and M W Greaves ldquoWarfarin in the treatment ofchronic urticariaangio-oedemardquo British Journal of Dermatol-ogy vol 126 no 4 pp 415ndash416 1992

[67] M Metz A Gimenez-Arnau E Borzova C E Grattan MMagerl and M Maurer ldquoFrequency and clinical implicationsof skin autoreactivity to serum versus plasma in patients withchronic urticariardquo Journal of Allergy and Clinical Immunologyvol 123 no 3 pp 705ndash706 2009

[68] S S Saini ldquoChronic spontaneous urticaria etiology and patho-genesisrdquo Immunology and Allergy Clinics of North America vol34 pp 33ndash52 2014

[69] U Amara M A Flierl D Rittirsch et al ldquoMolecular intercom-munication between the complement and coagulation systemsrdquoThe Journal of Immunology vol 185 no 9 pp 5628ndash5636 2010

[70] M Kaliner J H Shelhamer and E A Ottesen ldquoEffects ofinfused histamine correlation of plasma histamine levels andsymptomsrdquo Journal of Allergy and Clinical Immunology vol 69no 3 pp 283ndash289 1982

[71] W Lorenz and A Doenicke ldquoHistamine release in clinicalconditionsrdquoMount Sinai Journal of Medicine vol 45 no 3 pp357ndash386 1978


[72] R J Flower E A Harvey and W P Kingston ldquoInflammatoryeffects of prostaglandin D

2in rat and human skinrdquo British

Journal of Pharmacology vol 56 no 2 pp 229ndash233 1976[73] C Grunfeld and M A Palladino Jr ldquoTumor necrosis factor

immunologic antitumor metabolic and cardiovascular activi-tiesrdquo Advances in Internal Medicine vol 35 pp 45ndash71 1990

[74] L Borish ldquoCytokines in allergic inflammationrdquo in Allergy Principles and Practice E Middleton Jr C E Reed E F EllisN F Adkinson J W Yunginger and W W Busse Eds vol 1pp 108ndash119 Mosby St Louis Mo USA 5th edition 1998

[75] N Subramanian and M A Bray ldquoInterleukin 1 releases his-tamine from human basophils and mast cells in vitrordquo TheJournal of Immunology vol 138 no 1 pp 271ndash275 1987

[76] H Boey R Rosenbaum J Castracane and L BorishldquoInterleukin-4 is a neutrophil activatorrdquo Journal of Allergy andClinical Immunology vol 83 no 5 pp 978ndash984 1989

[77] JMWang A Rambaldi A Biondi Z G Chen C J Sandersonand A Mantovani ldquoRecombinant human interleukin 5 isa selective eosinophil chemoattractantrdquo European Journal ofImmunology vol 19 no 4 pp 701ndash705 1989

[78] J Willems M Joniau S Cinque and J van Damme ldquoHumangranulocyte chemotactic peptide (IL-8) as a specific neutrophildegranulator comparisonwith othermonokinesrdquo Immunologyvol 67 no 4 pp 540ndash542 1989

[79] A D Luster ldquoMechanisms of disease chemokines chemotacticcytokines thatmediate inflammationrdquoTheNewEngland Journalof Medicine vol 338 no 7 pp 436ndash445 1998

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

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Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

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OphthalmologyJournal of


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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Infiltrating cells pattern in urticarial wheal uninvolved skin and normal healthy control subjects [4]

Cell type Urticarial wheal Uninvolved skin Healthy control subjectsMast cells Normal count Normal count Normal count

Lymphocytes Raised T-lymphocyte count More numerous T-lymphocytes than inlesional skin Low T-lymphocyte counts

Neutrophils Major cellular infiltrate at 60 minutes ofevolution of urticarial wheal

Significantly less infiltration than inlesional skin Insignificant

Eosinophils Significantly higher number Insignificant Insignificant

Basophil Significant number especially at 30 minutesof evolution of urticarial wheal Less but relevant number Insignificant

Table 2 Cytokine chemokine and adhesion molecule expression urticarial wheals uninvolved skin and healthy control subjects [4]

Urticarial wheal Uninvolved skin Normal healthy controlsCytokines

Interferon gamma High expression Significantly low expression Not expressedInterleukin-4 High expression Significantly low expression Not expressedInterleukin-5 High expression Significantly low expression Not expressedInterleukin-8 Moderate expression Moderate expression Not expressed

Chemokines

C X C R 3CC R 3 Expression similar tocontrol skin High expression Expression similar in lesional

and healthy control skinAdhesion molecules

Cellular adhesion molecule High expression Intense expression Significant expression

varied proinflammatory mediators cytokines chemokineschemokine receptors and adhesion molecules that regulatevasoactivity and specific kinetics of cellular infiltration ulti-mately evolving into a lymphocyte and granulocyte medi-ated hypersensitivity reaction evident as urticarial whealsThe incoming inflammatory cells in turn release moreproinflammatory mediators that serve to recruit and acti-vate other cell types thereby amplifying and extending thehost response The upregulation of inflammatory moleculesalmost comparable expression of chemokines and adhesionmolecules and higher T-cell numbers in uninvolved skin isindicative of widespread immunologic activation represent-ing a low level priming of the cutaneous inflammatory andimmunologic response apparatus reconfirming the hypoth-esis of latent minimal persistent inflammation in apparentlyuninvolved skin [4 5] This lowers the reactive threshold ofmast cells to triggering stimuli and facilitates themaintenanceof susceptibility to urticaria during clinical remission

2 Autoimmunity and Chronic Urticaria

The autoimmune origin is the most accepted hypothesisadvanced to explain inappropriate activation and degranu-lation of mast cells in urticaria Immune tolerance is main-tained by a balance between autoreactive lymphocytes andregulatory mechanisms that counteract them An increase innumber andor function of naturally occurring autoreactiveT-cells or diminished regulator mechanism manifests asautoimmunity Regulatory T-cells (T(REG)) particularly thenaturally occurring CD4(+) CD25(+) subset of T (REG)

provide a substantial component of autoimmune counterbal-ance The identification of forkhead box P3 (FOX P3) as acritical determinant of CD4(+) CD25(+) T(REG) cell devel-opment and function has provided insights into the delicatebalance between autoreactive and regulatory mechanismsin autoimmune disorders including chronic autoimmuneurticaria Functional assays and phenotype analysis haverevealed that T(REG) isolated from patients of autoimmunedisorder exhibit reduced regulatory function as opposed tothose fromhealthy controls Itmay be concluded that reducedpercentage of CD4(+) CD25(+) FOX P3(+) regulator T-cellscontributes to the autoimmune pathogenic process of chronicurticaria [6] The autoimmune pathogenic mechanism hasbeen conceptualized on the following observations thatprovided the initial circumstantial evidence and impetus forfurther clinical and laboratory investigations that reaffirmedthe concept

(i) Higher prevalence of thyroid autoantibodies inchronic urticaria [7]

(ii) A wheal-and-flare reaction on intradermal injectionof autologous serum in a subpopulation of patients(positive autologous serum skin test) and repro-ducibility on passive transfer of serum to normalhealthy control subjects [8]

(iii) Subsequent identification of IgG antibody directedto the alpha subunit of the IgE receptor capableof inducing positive autologous serum skin test aswell as histamine release from basophils [9] Theincidence of such autoantibodies is about 30 percent



















































LTC4LT B4PGD2































C1 C1 C2C5 C6 C7 C8 C9




XVII


coagulation

+

+


IgGanti-FceRI

ITAMLyn Syk

PKCGTP Ca2+

Mast cell

Interleukin-1


Eosinophil

GammaSubstance P

C5a receptor

Lymphocyte



FceRI alpha

Beta

alpha






References




























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


































































LTC4LT B4PGD2































C1 C1 C2C5 C6 C7 C8 C9




XVII


coagulation

+

+


IgGanti-FceRI

ITAMLyn Syk

PKCGTP Ca2+

Mast cell

Interleukin-1


Eosinophil

GammaSubstance P

C5a receptor

Lymphocyte



FceRI alpha

Beta

alpha






References




























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































C1 C1 C2C5 C6 C7 C8 C9




XVII


coagulation

+

+


IgGanti-FceRI

ITAMLyn Syk

PKCGTP Ca2+

Mast cell

Interleukin-1


Eosinophil

GammaSubstance P

C5a receptor

Lymphocyte



FceRI alpha

Beta

alpha






References




























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Review Article Pathogenesis of Chronic Urticaria: An...

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