Hindawi Publishing Corporation

Dermatology Research and Practice

Volume 2014, Article ID 674709, 10 pages
http://dx.doi.org/10.1155/2014/674709

Review Article
Pathogenesis of Chronic Urticaria: An Overview

Sanjiv Jain
Skin Care Clinic, 108 Darya Ganj, New Delhi 110002, India

Correspondence should be addressed to Sanjiv Jain; [email protected]

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

Academic Editor: Lajos Kemeny

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

The pathogenesis of chronic urticaria is not well delineated and the treatment is palliative as it is not tied to the pathomechanism. The
centrality of mast cells and their inappropriate activation and degranulation as the key pathophysiological event are well established.
The triggering stimuli and the complexity of effector mechanisms remain speculative. Autoimmune origin of chronic urticaria,
albeit controversial, is well documented. Numerical and behavioral alterations in basophils accompanied by changes in signaling
molecule expression and function as well as aberrant activation of extrinsic pathway of coagulation are other alternative hypotheses.
It is also probable that mast cells are involved in the pathogenesis through mechanisms that extend beyond high affinity IgE receptor
stimulation. An increasing recognition of chronic urticaria as an immune mediated inflammatory disorder related to altered
cytokine-chemokine network consequent to immune dysregulation resulting from disturbed innate immunity is emerging as yet
another pathogenic explanation. It is likely that these different pathomechanisms are interlinked rather than independent cascades,
acting either synergistically or sequentially to produce clinical expression of chronic urticaria. Insights into the complexities of
pathogenesis may provide an impetus to develop safer, efficacious, and targeted immunomodulators and biological treatment for
severe, refractory chronic urticaria.

1. Introduction comprising primarily of mononuclear cells, predominantly

CD4+ lymphocytes, with variable numbers of monocytes,
Chronic urticaria is a distressing disorder that adversely neutrophils, eosinophils, and basophils [2–4]. The dermal
impacts the quality of life; yet its pathogenesis is not well neutrophilia is strikingly evident at sixty minutes of evolution
delineated and, accordingly, the treatment is often palliative of wheal with neutrophils representing the main component
and therapeutic outcome is suboptimal. This necessitates an of the cellular infiltrate [4]. Mast cell numbers remain
understanding of the pathogenesis to facilitate development unaltered and are comparable to those in uninvolved skin and
of improved therapies. In the recent past rapid strides in healthy controls [4, 5]. The cytokine profile is characterized
understanding the pathomechanism of chronic urticaria have by an increase in interleukin-4 (IL-4), interleukin-5 (IL-5),
been recorded; yet, most of the evidence based, seemingly and interferon-gamma RNA (IFN-gamma), suggestive of a
impregnable and conclusive hypotheses have been countered mixed Th 1/Th 2 response. Chemokines are upregulated and
by alternative, equally authentic, convincing and logistic increased expression of adhesion molecules is evident. The
counter explanations. uninvolved skin is characterized by upregulation of solu-
The knowledge of molecular immunopathogenesis and ble mediators and adhesion molecules, almost identical to
complexities of effector mechanisms in chronic urticaria lesional skin, and significantly higher T-cell numbers, while
has been enhanced by immunohistologic studies performed accumulation of neutrophils is an exclusivity of whealing skin
on sequential biopsies of urticarial wheals and focused on [4] (Tables 1 and 2).
infiltrating cell immunophenotypes and related cytokines, Chronic urticaria is initiated by inappropriate activation
chemokines/chemokine receptors, and adhesion molecules and degranulation of dermal mast cells. This key patho-
[1]. physiological event is predominant at the very onset and
The urticarial wheal is characterized by dermal edema, the released cellular contents prime the immediate phase of
vasodilatation, and perivascular nonnecrotizing infiltrate inflammation, which progresses to a complex interplay of
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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 subjects

Mast cells Normal count Normal count Normal count
More numerous T-lymphocytes than in
Lymphocytes Raised T-lymphocyte count Low T-lymphocyte counts
lesional skin
Major cellular infiltrate at 60 minutes of Significantly less infiltration than in
Neutrophils Insignificant
evolution of urticarial wheal lesional skin
Eosinophils Significantly higher number Insignificant Insignificant
Significant number, especially at 30 minutes
Basophil Less but relevant number Insignificant
of evolution, of urticarial wheal

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

Urticarial wheal Uninvolved skin Normal healthy controls

Cytokines
Interferon gamma High expression Significantly low expression Not expressed
Interleukin-4 High expression Significantly low expression Not expressed
Interleukin-5 High expression Significantly low expression Not expressed
Interleukin-8 Moderate expression Moderate expression Not expressed
Chemokines
Expression similar to Expression similar in lesional
C X C R 3/CC R 3 High expression
control skin and healthy control skin
Adhesion molecules
Cellular adhesion molecule High expression Intense expression Significant expression

varied proinflammatory mediators, cytokines, chemokines, provide a substantial component of autoimmune counterbal-
chemokine receptors, and adhesion molecules that regulate ance. The identification of forkhead box P3 (FOX P3) as a
vasoactivity and specific kinetics of cellular infiltration, ulti- critical determinant of CD4(+) CD25(+) T(REG) cell devel-
mately evolving into a lymphocyte and granulocyte medi- opment and function has provided insights into the delicate
ated hypersensitivity reaction, evident as urticarial wheals. balance between autoreactive and regulatory mechanisms
The incoming inflammatory cells, in turn, release more in autoimmune disorders including chronic autoimmune
proinflammatory mediators that serve to recruit and acti- urticaria. Functional assays and phenotype analysis have
vate other cell types, thereby amplifying and extending the revealed that T(REG) isolated from patients of autoimmune
host response. The upregulation of inflammatory molecules, disorder exhibit reduced regulatory function as opposed to
almost comparable expression of chemokines and adhesion those from healthy controls. It may be concluded that reduced
molecules, and higher T-cell numbers in uninvolved skin is percentage of CD4(+) CD25(+) FOX P3(+) regulator T-cells
indicative of widespread immunologic activation, represent- contributes to the autoimmune pathogenic process of chronic
ing a low level priming of the cutaneous inflammatory and urticaria [6]. The autoimmune pathogenic mechanism has
immunologic response apparatus, reconfirming the hypoth- been conceptualized on the following observations that
esis of latent, minimal persistent inflammation in apparently provided the initial circumstantial evidence and impetus for
uninvolved skin [4, 5]. This lowers the reactive threshold of further clinical and laboratory investigations that reaffirmed
mast cells to triggering stimuli and facilitates the maintenance the concept.
of susceptibility to urticaria during clinical remission.
(i) Higher prevalence of thyroid autoantibodies in
chronic urticaria [7].
2. Autoimmunity and Chronic Urticaria (ii) A wheal-and-flare reaction on intradermal injection
of autologous serum in a subpopulation of patients
The autoimmune origin is the most accepted hypothesis
(positive autologous serum skin test) and repro-
advanced to explain inappropriate activation and degranu-
ducibility on passive transfer of serum to normal
lation of mast cells in urticaria. Immune tolerance is main-
healthy control subjects [8].
tained by a balance between autoreactive lymphocytes and
regulatory mechanisms that counteract them. An increase in (iii) Subsequent identification of IgG antibody directed
number and/or function of naturally occurring autoreactive to the alpha subunit of the IgE receptor, capable
T-cells or diminished regulator mechanism manifests as of inducing positive autologous serum skin test as
autoimmunity. Regulatory T-cells (T(REG)), particularly the well as histamine release from basophils [9]. The
naturally occurring CD4(+) CD25(+) subset of T (REG), incidence of such autoantibodies is about 30 percent
 3029, 2014, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/2014/674709 by Nat Prov Indonesia, Wiley Online Library on [03/12/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Dermatology Research and Practice 3

and an additional 5–10 percent of patients have anti- release of preformed granule contents such as histamine,
IgE antibodies rather than anti-IgE receptor antibody heparin, tryptase, and tumour necrosis factor-alpha (TNF-
[10]. alpha), as well as the synthesis of other proinflammatory
(iv) Positive association with HLA subtypes DRB∗ 04 cytokines/chemokines and eicosanoids [22]. The downregu-
(DR4) and DQB 1∗ 0302 (DQ8) [11]. lation of signal transduction and mediator release is regulated
by signal regulatory proteins (SIRP) that contain immuno-
(v) Therapeutic response to plasmapheresis [12] and tyrosine inhibition motifs (ITIMS) which act by recruiting
intravenous immunoglobulin [13]. SH-2 bearing tyrosine phosphatases (SHIP 1 and 2) that
dephosphorylate ITAM on beta and gamma subunits of FceRI
The evidence favouring autoimmune pathomechanism,
[21].
although persuasively convincing, is incomplete. Certain
issues, elucidated below, need to be addressed for unequivocal The autoantibodies to alpha chain of FceRI and/or IgE
acceptance of the proposed hypothesis. have been detected in only 35 to 40 percent and 5 to 10
percent of patients, respectively [23]. Moreover the detection
(i) The cutaneous response to intradermal injection of of autoantibodies in the serum does not confirm their func-
autologous serum may be due to the presence of tionality and may not be always implicated in the induction
nonimmunoglobulin vasoactive histamine releasing of histamine release from mast cells/basophils. It is likely that
factors [14]. Moreover reactivity to autologous serum other permeabilizing factors are involved in serum mediated
has been observed in subjects with allergic respiratory vascular leakage.
diseases and healthy controls [15]. ASST identifies
subsets of patients exhibiting autoreactivity rather
than establishing autoimmunity. 3. Nonimmunologic Agonists
(ii) Animal model, mandatory to establish autoimmune Nonimmunologic agonists including substance P, endor-
status of the disorder, is yet to be developed for phins, enkephalins, endogenous peptides, and somatostatin
chronic urticaria [16]. may induce regulated degranulation and liberation of proin-
(iii) The autoantibodies of similar specificity have been flammatory molecules from mast cells especially when the
detected in sera of healthy persons and may belong products of activated immune system lower the cutaneous
to the natural repertoire. Such natural autoantibodies mast cell release threshold [24].
may become pathogenic under certain circumstances
and this occurrence is dependent on the state of 4. Cellular Abnormalities: Basophils
occupancy of the FceRI receptor by its natural ligand
IgE. The urticaria results from alteration in the tissue The primary abnormality in some patients of chronic
binding of preexisting autoantibody in susceptible urticaria might be cellular/subcellular rather than immuno-
individuals rather than its production de novo. Thus logically mediated autoimmune mechanism.
the concept of conditional autoimmunity has evolved There is increasing evidence of altered number, structure,
[17] in chronic urticaria. function, and trafficking defects in basophils. Basopenia is
(iv) It has been proposed that anti-FceRI and anti-IgE well documented and basophil numbers are inversely related
autoantibodies are not actually pathogenic but are to urticaria severity [25]. Other evidence, perhaps more
secondary to the presence of urticaria in individu- convincing, is the paradoxical suppression of FceRI medi-
als with a predisposition to develop autoimmunity ated, anti-FceRI/anti-IgE antibody induced histamine release
[18]. from basophils during active disease [26]. It is still more
intriguing that these basophils maintain normal response
The complex pathway involved in triggering, maintain- to monocyte chemotactic protein-1 (MCP-1) and bradykinin
ing, and controlling autoantibody formation against FceRI and are hyperresponsive to serum [27]. It had been reasoned
and/or IgE remains unexplained. The autoantibodies relevant that basophils in chronic autoimmune urticaria are desensi-
to chronic urticaria belong to complement fixing subtypes tized in vivo to further FceRI induced activation. However,
IgG1 and IgG3 [19]. The vascular leakage of such autoantibod- autoantibody mediated desensitization of IgE receptor seems
ies by local events facilitates their binding to either FceRI or unlikely as similar response of basophils has been observed
IgE, cross-linking of the receptor, and complement activation in patients lacking autoimmune antibodies [27].
that generates C5a. C5a interacts with the receptor for com- A more complex picture has emerged from insight into
plement anaphylatoxin (C5a receptor) localized on the sur- the dysregulated expression of molecules that are critical
face of mast cell MCTC , the subtype dominant in the skin, and to signal propagation or its inhibition after IgE receptor
participates in mast cell activation [20]. This triggers a series activation [28]. Spleen tyrosine kinase (Syk) is a positive
of intracellular events and the earliest in signal transduction regulator of signaling through FceRI and its levels are a major
involves phosphorylation of tyrosine on the beta and gamma determinant of basophil histamine release (HR) in normal
chains of FceRI at immunoreceptor tyrosine activation motifs basophils [29]. Src homology 2 (SH2) containing inositol
(ITAM). The ITAMS associate with Src-family protein tyro- phosphatases, SHIP-1 and SHIP-2, are negative regulators of
sine kinases (PTKs), such as Lyn and Syk, which initiate signal propagation [30]. In chronic urticaria there is a shift
the activation of downstream effector pathways [21] and the in the paradigm of Syk dominated regulation of HR and
 3029, 2014, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/2014/674709 by Nat Prov Indonesia, Wiley Online Library on [03/12/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
4 Dermatology Research and Practice

unlike normal basophils altered levels of SHIP-1 and SHIP- 41]. These newly formed permeabilizing factors include
2 correlate with the pattern of anti-IgE stimulated histamine tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-
release [31, 32]. 6), vascular endothelial growth factor (VEGF), and platelet
In addition to these observations, based on the pro- activating factor (PAF). These are secreted from mast cells
file of ex vivo activation of basophils by optimal con- independent of release of preformed mediators stored in
centration of polyclonal anti-IgE, it has been confirmed granules such as histamine, serotonin, proteases, and proteo-
that distinct basophil degranulation phenotypes exist in glycans [40, 41]. These permeabilizing factors facilitate the
chronic urticaria and a bimodal stratification of basophils development of urticarial wheals. These observations provide
has been proposed [32]. Fifty percent of chronic urticaria an explanation for lack of correlation between detection
subjects have significant reduction in basophil histamine of autoantibodies and degranulation of mast cells [42],
release (HR) with anti-IgE stimulation. It is consequent to quality and quantity of released vasoactive factors, increased
increased SHIP-2 levels and such subjects are designated anti- vasopermeability, urticaria severity refractoriness of severe
IgE nonresponders (CIU-NR). The remaining subjects have urticaria to standard first line management with antihis-
basophils that release more than 10 percent of histamine tamines, and therapeutic response to immunosuppressive
content after anti-IgE stimulation and are termed anti-IgE agents.
responders (CIU-R) and SHIP-1 levels in such basophils are
reduced.
This pattern of basophil functional phenotypes (CIU-R 6. Chronic Urticaria: Immune Mediated
and CIU-NR) appears to be independent of the existence Inflammatory Disorder
and/or levels of autoantibodies [33] and remains stable
in subjects with persistent disease. The salient features of The concept of chronic urticaria being an immune mediated
basophil phenotypes in chronic urticaria are summarized in inflammatory disorder evolved from incidental observation
Table 3 [31–33]. that recommendation of targeted immunomodulator bio-
logic therapy, directed at a particular cytokine/cell receptor,
The levels and/or expression of regulatory proteins is
administered for some other inflammatory disorder amelio-
functional and normalizes during remission [33]. Such shift
rated coexisting chronic urticaria [43]. It was indicative that
in basophil function is independent of the autoimmune status
inflammatory cascade in chronic urticaria may be triggered
of urticaria and, in those with autoimmunity, is noted without
by altered chemokine-cytokine network and is attributed
a parallel decrease in antibody titres.
to immune dysregulation consequent to disturbed innate
This profiling of signal proteins in basophils in conjunc- immunity in the disorder.
tion with their stratification into distinct phenotypes has The investigation of early events of innate immunity
reaffirmed that abnormal basophil function may be a key through the study of dendritic cells that link innate and
factor in disease pathogenesis. adaptive immune system has provided insights into the
dysregulated immune response in chronic urticaria [44].
5. Mast Cells and Chronic Urticaria Plasmacytoid dendritic cells (pDC) express toll-like receptors
(TLR) that are activated by natural and synthetic ligands
A direct role of mast cells in CU is speculated (Table 4). triggering proinflammatory responses that play a key role in
The activating factors derived from inflammatory cell infil- the pathogenesis of several inflammatory disorders including
trate surrounding dermal postcapillary venules [34] stimu- urticaria [45].
late mast cells to secrete vasoactive molecules that activate Accordingly, a study of early events of the immune
endothelial cells. The expression of adhesion molecules is response, through the activation of pDC by TLR sensing,
upregulated [35] and the increased vasopermeability pro- was undertaken to evaluate immune dysregulation in chronic
motes extravascular leakage of fluids and proteins leading to urticaria [44].
development of urticarial wheals. Plasmacytoid dendritic cells are unremarkably scattered
In an in vitro study performed to evaluate permeabilizing amongst cellular infiltrate in the cutaneous lesion and their
activity of CU serum, a similar pattern of mast cell degranu- percentage in the peripheral blood mononuclear cells is
lation and increased endothelial monolayer permeability was unaltered and is similar to healthy controls. A normal degree
observed after exposure of two distinct mast cell lines (LAD- of activation of pDC by the expression of costimulatory
2 and HMC-1) [36, 37] to CU serum. The CU serum evoked molecules and an increased constitutive STAT 1 phosphoryla-
response remained unaltered after IgG depletion, reaffirming tion on nonstimulated lymphocytes was observed. However,
its nondependence on mast cell IgE receptor activation [38]. IFN-alpha secretion by pDC upon stimulation by CpGA
It was concluded that vasoactive molecules may be released was impaired and it was associated with altered IRF-7 and
from mast cells without degranulation [38]. downregulation of TLR 9 expression, indicating a functional
It is likely that varied membrane receptors expressed impairment of pDC, and was supportive of immune dysreg-
on mast cells are selectively triggered by ligands such ulation in CU [44].
as IgG, peptides, microbial derivatives, and fragments of Several hypotheses have been proposed to explain the
activated complement [39] and mast cells are stimulated downregulation of TLR9 in pDC after CpGA stimulation.
by activating signals to synthesize vasoactive substances It is probable that IgE or anti-FceRI autoantibodies cross-
including lipid metabolites, cytokines, and chemokines [40, link FceRI on immature pDC impairing immune function
 3029, 2014, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/2014/674709 by Nat Prov Indonesia, Wiley Online Library on [03/12/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Dermatology Research and Practice 5

Table 3: Basophil phenotypes: profile in chronic urticaria [31–33].

Chronic urticarial (autoimmune/nonautoimmune)

Feature
CIU-R CIU-NR
(1) Anti-IgE stimulation/cross-linking:
>10 percent of cellular content <10 percent of cellular content
HR in active disease
(2) Regulatory proteins Paradigm shift Paradigm shift
HR not determined by kinase
HR not determined by kinase level
(a) Kinase level
Normal Syk levels Normal Syk levels
Regulates HR, reduced SHIP-1 Regulates HR, increased SHIP-2
(b) Phosphatase
levels levels
(3) Sensitivity to anti-IgE stimulation Sensitivity restored to levels as in
Heightened sensitivity
in remission normal healthy subjects
HR: histamine release.
CIU-R: chronic idiopathic urticaria—responders.
CIU-NR: chronic idiopathic urticaria—nonresponders.
Syk: serum tyrosine kinase.
SHIP-1: Src homology 2 (SH2) containing inositol phosphatase 1.
SHIP-2: Src homology 2 (SH2) containing inositol phosphatase 2.

Table 4: Mast cell mediators: relevant to chronic urticaria.

Mediator Effect in chronic urticaria
Preformed mediators
Direct potent vasoactive and smooth muscle spasmogenic effects
Histamine
Principal mediator of vascular changes [70, 71]
Newly synthesised mediators
Lipid mediators
LTC4 Actions similar to histamine
LT B4 Potentiate vasodilatation, vascular permeability, and smooth muscle contraction
PGD2 Chemotactic for neutrophils and eosinophils [72]
Cytokines and chemokines
Newly synthesised as well as preformed
Tumour necrosis factor-alpha
Upregulates expression of adhesion molecules on endothelial cells
Promotes leukocyte rolling and adhesion
Chemotactic for neutrophils [73]
Proinflammatory cytokine
Interleukin-1 Lymphocyte activator [74]
Activates mast cells after release from leukocyte [75]
Chemotactic for neutrophils
Interleukin-4
Recruits eosinophils [76]
Interleukin-5 Recruits eosinophils [77]
Proinflammatory cytokine
Interleukin-6
Activates lymphocytes [78]
Member of C X C chemokines
Interleukin-8/CXCL2 Potent neutrophil chemoattractant
Involved in neutrophil degranulation, respiratory burst, and adhesion to endothelial cells [79]
MCP-1/CCL2 Chemoattractant for eosinophils
MIP-1 alpha/CCL3 Chemoattractant for eosinophils
Interleukin-16 Chemoattractant for T-lymphocytes
RANTES/CCL5 Chemoattractant for eosinophils [79]
LTC4: leukotriene C4, LTB4: leukotriene B4, PGD2: prostaglandin D2, MCP-1: monocyte chemotactic protein-1, MIP-1 alpha: monocyte inflammatory peptide-
1, RANTES: regulated upon activation normal T-cell expressed and secreted.
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6 Dermatology Research and Practice

by suppressing IFN-alpha production [46]. Alternatively, 7. Chronic Urticaria and Coagulation System
regulatory receptors including BDCA-2, ILT-7, and NKp44
downmodulate IFN production [47–49]. It is also likely It has been observed that autologous plasma, anticoagu-
that histamine released into circulation from degranulating lated with substances other than heparin, generates positive
mast cells/basophils may regulate several cell types through autoreactive responses in a higher percentage of patients
stimulation of histamine receptors and pDC activated by CpG than autologous serum skin test (ASST) [62, 63]. As serum
respond to histamine through H2 receptors with downregu- and plasma do not differ in their autoantibody content, this
lation of IFN-alpha production [50]. observation points to a possible role of clotting factors in
The dysfunctional innate immune response in CU conse- wheal-and-flare reaction. It has been reasoned that plasma
quent to functional impairment of pDC to TLR9 activation contains more coagulation factors and complement, while
disturbs the cytokine production by T-cells, mainly of IL-17A consumption of such factors in serum during formation of
and IL-10 [51]. Besides, elevated serum levels of IL-1, IL-4, IL- clot is responsible for the discrepant reactivity of autologous
13, IL-18, tumour necrosis factor-alpha (TNF-alpha) [52, 53], plasma and serum. It has thus been inferred that clotting
B-cell activating factor (BAFF) [54], and factors related to cascade may be involved in pathogenesis of urticaria [64] and
inflammatory process such as neopterin [55] and C-reactive this may provide an explanation for therapeutic effects noted
protein have been documented. These observations suggest in some patients with drugs active on coagulation system
that there is an ongoing inflammatory process, creating a [65, 66].
proinflammatory environment in chronic urticaria that in The extrinsic pathway of coagulation is activated and
turn is responsible for an altered pattern of secretion of thrombin is generated from prothrombin by activated factor
chemokines. X, in the presence of activated factor V and calcium ions
Significantly higher serum levels of chemokines (C-C [64]. In vitro studies have confirmed that plasma of urticaria
and C-X-C) including CXCL8, CXCL9, CXCL10, and CCL2 patients has significantly higher levels of prothrombin frag-
have been observed in CU and are not correlated with ment F1+2 , a polypeptide of 34 kDa that is released into
either the clinical parameters of the disorder or the outcome circulation during the activation of prothrombin to thrombin
of basophil histamine release (BHR) and/or ASST assays by factor X [67], and severe exacerbations of urticaria are
[56]. These proinflammatory chemotactic cytokines interact associated with a strong activation of coagulation cascade that
with chemokine receptors on the surface of inflammatory leads to fibrin formation and fibrinolysis as shown by elevated
cells to trigger chemotaxis and transendothelial migration of D-dimer plasma levels.
leukocytes to the site of inflammation. Thrombin is a serine protease that enhances vascular per-
CXCL8/IL-8 is chemotactic for neutrophils, T-lympho- meability, activates and degranulates mast cells, and induces
cytes, and monocytes [56]. generation of anaphylatoxin C5a. The activation of extrinsic
CXCL9/Mig, a monokine induced by interferon- (IFN-) pathway of coagulation is thus proposed as yet another
gamma induced protein 1 (IP-10), is a type 1 C-X-C explanation.
chemokine and displays strong chemoattraction for T-helper It is likely that different pathomechanistic pathways,
type 1 (Th 1) lymphocytes [57, 58]. namely, seroimmunologic autoimmune, inflammatory, cellu-
C-C ligand 2 (CCL2) (monocyte chemoattractant protein lar defects, coagulative, and complement system, are inter-
1), prototype of C-C chemokine, is secreted mainly by linked rather than separate independent cascades and there
monocytes, as evidenced by increased mRNA expression in is extensive cross talk amongst them with mutual regulation
CD14 + cells in CU. CCL2 activates a variety of cells includ- of activation. They act synergistically or sequentially as either
ing monocytes, macrophages, lymphocytes, eosinophils, and independent or interlinked pathomechanisms to activate
basophils and is a crucial factor for the development of Th 2 mast cells with release of preformed mediators and/or secre-
responses [59]. tion of newly synthesized vasoactive molecules to produce
The upregulation of chemokines in CU contributes to final clinical expression of urticaria [68, 69] (Figure 1).
the maintenance of activated status of inflammatory cell The various mast cell mediators, preformed and newly
subsets. Basophils in CU display an upregulation of activa- synthesized, relevant to chronic urticaria, are summarized in
tion/degranulation markers, CD203c and CD63, and high Table 4.
responsiveness to interleukin-3 (IL-3) stimulation. It is likely Histamine is the principal vasoactive mediator and com-
that activated profile of basophils is triggered by in vivo bined histamine-1 and -2 receptor responses are required for
priming with potent basophil activating factor such as CCL2 the full expression of histamine vasoactivity, including imme-
[60]. diate vasodilation, alteration in vasopermeability, plasma
CCL2 induces degranulation of mast cell and has a potent extravasation, and dermal sensory nerve stimulation [69–71].
basophil histamine releasing activity. Furthermore, it has Its role in the pathogenesis of wheal is less certain and it is
been documented that an assembly of circulating chemokines probable that nonhistamine mast cell mediators regulate cell
CCL2, CCL5, and CXCL8 play an important role in mast cell recruitment. The leukotrienes, cytokines, and chemokines
activation and generation of histamine and serotonin [61]. upregulate adhesion molecule expression on endothelial cells,
It may be inferred that immunologic dysregulation con- promoting rolling and adhesion of leukocytes, followed
sequent to disturbed innate immune response alters the by chemotaxis and transendothelial migration and cellular
cytokine-chemokine network that triggers the inflammatory influx into whealing skin. These infiltrating cells in turn
status contributing to the pathogenesis of CU. release proinflammatory cytokines and chemokines that
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Dermatology Research and Practice 7

IgG
anti-FceRI
alpha
FceRI alpha
Gamma
Interleukin-1 Beta Substance P
ITAM C5a receptor
Lyn Syk
+ PKC
GTP Ca2+ Lymphocyte
C1 C1
C2
Interleukin-5
Eosinophil Mast cell + C5 C6 C7 C8 C9
Interleukin-6 C4 C4b C2a C5a
Histamine, chemokines Interleukin-4 C5b C5b C5b6 C5b67 C5b679 MAC
and cytokines C3 C3b
Fibrin Fibrinogen

Thrombin Prothrombin

X
VII
Tissue factor
Extrinsic pathway of
coagulation
ITAM: immunotyrosine activation motif PKC: protein kinase C
GTP: guanosine triphosphate MAC: membrane attack complex
Lyn, Syk: cytoplasmic tyrosine kinase

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

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sustaining, amplifying, and extending the host response. infiltrate of chronic idiopathic urticaria: Prominence of T-
The signals for resolution of urticaria are also not well lymphocytes, monocytes, and mast cells,” Journal of Allergy and
characterized. It involves downregulation of the histamine Clinical Immunology, vol. 78, no. 5, pp. 914–918, 1986.
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