Download Eman Mohamed Ali Hassan_Pathogenesis2

Review of literature
Immunopathogenesis
The pathogenesis and exact immune mechanisms of papular
urticaria are somewhat unclear (Demain, 2003). If many individuals
are exposed to the same antigen by the same route, only a few of
these people are at risk for allergic reactions upon reexposure. Why
only a minority of people makes antigen-specific IgE and become
allergic is unknown. If such events are to occur, however, a distinct
series of immunological events must happen. These include
internalization of the antigen by antigen-presenting cells, such as
dendritic cells, and its processing and presentation to T lymphocytes
(Sanico et al., 2002).
A very young child does not react when bitten by a blood–
sucking arthropod. Even though blood is abstracted by the insect
there is no oedema, erythema, pruritus or papule. All that may
sometimes be seen as minute haemorrhagic macule marking the site
of the bite. This is entirely traumatic in origin and quite
symptomless. This lack of reaction is typical of any person who
lacks a previous history of biting by any particular species of insect.
Lack of reaction persists throughout childhood, and indeed
throughout life, as long as the individual has had no significant
previous experience of being bitten by that particular species
(Maunder, 2000).
Once a child has received a sufficient number of bites by any
particular species of insects, sensitization will occur and all
- 32 -
Review of literature
subsequent bites by that species of insect will cause a bite reaction at
the site. How many bites are necessary before sensitization occurs is
primarily a factor of the constitutional make-up of the person
concerned. The type of insect concerned and the rate at which the
bites are sustained are factors which may have some effect but they
are entirely subordinate to the innate characteristics of the patient.
There is wide variation between patients in regard to how many bites
must be sustained for sensitization to occur (Maunder, 2000).
There is little cross-sensitization between insect species.
Sometimes sensitization to one species confers a partial sensitization
to the bites of an extremely closely related species. For example,
sensitization to the cat flea, Ctenocephalides felis, confers partial
sensitization to its very close relative the dog flea, C.canis. Again,
sensitization to the human head louse, Pediculus humanus capitis,
may confer partial sensitivity to the clothing louse, P. humanus
humanus. However, these are exceptions. Continued biting by
insects everyday leads to desensitization. For this reason by about
the age of 7 or 8 years papular urticaria becomes less common. It is
markedly less frequent in older children. Many adults no longer
experience the condition unless they exceptionally meet with biting
insects to which they have had insufficient prior exposure to become
desensitized (Maunder, 2000).
Reactivation can result in variable severity of pruritus and skin
lesions even when the number of new lesions seems to be waning.
Some individuals reactivated previous lesions after appearance of
- 33 -
Review of literature
new bites. This effect is thought to be secondary to circulating insect
antigen stimulating cutaneous T cells in previously sensitized sites.
Clinical evidence of this is seen in children with generalized
eruptions and pruritus after only limited exposure to biting insects at
a focal site. So, it is difficult to distinguish between new-onset
lesions and a reactivation event (Hernandez and Cohen, 2006).
The understanding of PU has been greatly enhanced as a
consequence of realizing the stages through which the evolving
sensitivity passes (Table:2). Following the initial bite, there is the usual
incubation period during which the sensitization develops. This is a
variable period of 1 or more weeks, depending on the frequency of
exposure (stage I, induction). The delayed papular reaction is the first
expression of the onset of an allergic state (stage II, delayed reaction
alone). The next stage of the immunologic cycle is marked by the
appearance of the immediate wheal response within few minutes of the
bite, followed by the delayed papular reaction (stage III, immediate
reaction with delayed reaction). As biting continues and sensitization
deepens, this stage gives way to the final stage in which the bite produces
only an immediate wheal (stage IV, immediate reaction alone).
Individuals who remain arrested in the transitional stage of this
progression are the very ones in whom insect bites produce papular
urticaria. One
further stage is possible, the ultimate one of
desensitization, which can be brought about in some individuals who
continue to be bitted massively over a period of years by fleas,
mosquitoes, flies, chiggers and so on (stage V, lack of immediate or
delayed reaction) (Moschella and Hurley, 1992).
- 34 -
Review of literature
Table(2): Stages of human mosquito-bite reaction (McCormak et al.,
1995):
Stage
Immediate reaction
Delayed reaction
I
No
No
II
No
Yes
III
Yes
Yes
IV
Yes
No
V
No
No
Heng et al., in 1984 reported granular deposits of C1q, C3 and
IgM in the superficial dermal vessels in three subjects with papular
urticaria, suggesting that immune complexes with complement
activation through the classic pathway might be involved in the
pathogenesis.
The absence of leukocytoclastic vasculitis and deposits of
immunoglobulins or complement provide evidence against a type III
hypersensitivity
reaction.
The
possible
role
of
type
IV
hypersensitivity is opposed by the absence of dendritic antigen
presenting cells, epitheloid macrophages, and granulomatous
inflammation. Papular urticaria is the result of a type I
hypersensitivity reaction
in
response to
a hematogenously
disseminated antigen deposited by an arthropod bite in a sensitized
patient. This hypothesis is supported by the frequent presence of
eosinophils and mast cells in the skin lesions of papular urticaria
(Jordaan and Schneider, 1997).
- 35 -
Review of literature
This comes in agreement with Stibich and Schwartz, (2003)
who stated that papular urticaria is generally regarded to be the result
of a hypersensitivity or id reaction to bites from insects, such as;
mosquitoes, gnates, fleas, mites, and bedbugs. Morphological and
immunohistochemical evidence suggests that a type I hypersensitivi-ty reaction plays a central role in the pathogenesis of papular
urticaria.
Humoral immune response:
Immediate hypersensitivity reaction (type I hypersensitivity) is
a type of pathologic reaction that is caused by the release of
mediators from mast cells (Fig.3). This reaction is most commonly
triggered by the production of IgE antibody against environmental
antigens in some individuals to which they have been exposed
previously and binding of IgE to mast cells in various tissues (Abbas
and Lichtman, 2006).
- 36 -
Review of literature
Fig.(3): Type I hypersensitivity reaction
(www-immuno.path.com.ac.uk/…/lec13_97.html).
- 37 -
Review of literature
Patients with papular urticaria must be previously sensitized to
parasitic antigens. This presumably explains why papular urticaria
rarely occurs in neonates. Most infants are not sufficiently exposed
to biting insects to develop hypersensitivity. Experiments have
shown that with repeated exposure to antigen, hyposensitization
takes place, and the child "out- grows" the condition. The adolescent
then responds to an insect bite in the way most adults do: a transient
wheal develop, but no persistent papule forms (Stibich and
Schwartz, 2001).
IgE is composed of two ε heavy chains and two light chains of
either қ or λ specificity. IgE is not capable of placental transfer or
complement fixation. It has a half- life of 2.5days in plasma but lasts
several weeks when bound to mast cells (Dahl, 1996).
If an IgE antibody response is to occur, these events must take
place in the presence of specific cytokines, the most important of
which is interleukin (IL)-4 released by T lymphocytes and other
cells. IL-4 is critical for the generation of the T lymphocytes (Th2
cells) themselves and for subsequent stimulation by these cells of B
lymphocytes. If this stimulation occurs in the presence of IL-4, the B
cells undergo immunoglobulin gene class switching, leading to their
terminal differentiation into plasma cells that produce antigenspecific IgE antibodies. Generation of IgE-producing plasma cells is
also facilitated by binding of CD40-ligand on the Th2 cell to CD40
on the B cell. Once plasma cells undergo these steps, they release the
exact same antigen-specific IgE for the rest of their lives. This IgE
- 38 -
Review of literature
secretion by plasma cells typically takes place at mucosal sites but it can
also occur in lymph nodes and other lymphoid organs (Fig.4) (Sanico et
al., 2002).
Mast cell granules contain several preformed mediators, enzymes,
and cytokines including histamine, chymase, heparin, tryptase and tumor
necrosis factor alpha (TNF-α), that are released within minutes of crosslinking of surface-bound IgE. Newly formed mediators, including lipid
mediators, made through the lipoxygenase pathway are synthesized de
novo at the time of mast cell activation (Mckay, 2003).
Histamine acts by binding to specific receptor subtypes; H 1, H2 and
H3 (the latter is located mainly in the central nervous system), the tissue
distribution of which determine the character of the response. Give the
wide range of biologic responses to allergen; the use of specific histamine
receptor antagonists has aided the definition of tissue responses.
Histamine binding to H1-receptors is linked to contraction of airway and
gastrointestinal smooth muscle, increased vascular permeability, mucous
production in the nose, pruritus and cutaneous vasodilatation. H 2 receptor
activation leads to increased gastric acid secretion, esophageal muscle
contraction, vascular permeability and dilatation, airway mucous
secretion, and pruritus. Furthermore, H2 receptors are on lymphocytes and
are mainly inhibitory while promoting CD8 + lymphocyte activity. Also,
H2 receptor activation of basophils, eosinophils and neutrophils
suppresses degranulation (Sanico et al., 2002).
- 39 -
Review of literature
Fig.(4): Cell interactions in specific immune response, FDC;
follicular dendritic cell, Ag; antigen, TCR; T cell
receptor, mhc; major histocompatibility complex, Ig;
immunoglobulin
(www-immuno.path.com.ac.uk/.../cell_inter.gif).
- 40 -
Review of literature
Cytokines produced by mast cells stimulate the recruitment of
leukocytes, which cause the late phase reaction. The principal
leukocytes involved in this reaction are eosinophils, neutrophils, and
Th2 cells. Mast cell-derived tumor necrosis factor (TNF) and IL-4
promote neutrophil- and eosinophil-rich inflammation. Chemokines
produced by mast cells and by epithelial cells in the tissues also
contribute to leukocyte recruitment. Eosinophils and neutrophils
liberate proteases, which cause tissue damage, and Th2 cells may
exacerbate the reaction by producing more cytokines (Abbas and
Lichtman, 2006).
Eosinophils can function as phagocytes, but do so poorly. It
ingests immune complexes and mast cell granules. Its surface has
receptors for IgG, IgE, IgA, C1q, C3b (CR1), iC3b (CR3) and C5a.
The cell also has receptors for the cytokines IL-3, IL-5 and GM-CSF
and for lipid mediators; platelet-activating factor and leukotrieneB4.
T cells may control function and encourage accumulation of
eosinophils in tissues by releasing eosinophil specific lymphokines
(Weller, 1991).
In immediate hypersensitivity reaction, eosinophil products
oppose the action of mast cell products. Basophil and mast cell
degranulation is inhibited by prostaglandins and zinc in eosinophil
granules. Eosinophil histaminase destroys histamine, phospholipase
destroys the platelet-activating factor and major basic protein
destroys heparin (Dahl, 1996).
- 41 -
Review of literature
Neutrophil is the professional phagocyte. This polymorphonuclear
leukocyte migrates from blood vessels into tissues. The neutrophil
normally leaves the blood stream in a random fashion. At sites of
inflammation emigration; the attachment of neutrophils to
endothelial cells is an active process. Attachment involves special
structures on the neutrophil cell surface called adhesion molecules.
Selectins loosely bind neutrophils to endothelium, slowing the
phagocyte but still allowing it to roll along the vessel surface.
Integrins stop the cell. The CD11/CD18 complex of three separate
integrins (LFA-1, Mac-1 and P150, 95) seems most important.
Chemotaxis refers to the directed migration of phagocytic cells by
substances in their environment. This organized movement is
influenced by various chemicals called chemotactic factors as C5a.
Activated lymphocytes, activated endothelial cells, and even
activated keratinocytes synthesize interleukin-8. Other important
chemotactic factors in humans are kallikren, plasminogen activator,
fibrin degradation products, bacterial endotoxins and leukotriene B4
(Weiss, 1989).
From a quantitative point, IgG is the major immunoglobulin.
IgG antibodies provide a major defense against bacteria, toxins, and
other foreign immunogens. It constitutes approximately 75% of all
immunoglobulins in adult plasma. It is composed of two heavy
gamma chains and two light chains of either λ or κ type. There are
four subclasses (called isotypes) of IgG based on slight structural
differences in the constant portion of the heavy chain. IgG4 is
special. It does not fix complement, but it binds to mast cells and
- 42 -
Review of literature
basophils and can induce histamine release. It participates in allergic
reaction much as IgE does, but there are some differences.
Specifically, IgG4 sensitizes skin for a shorter period of time (2 to 4
hours compared with 50-80 hours for IgE); binds to mast cells more
weakly. Also, IgG4 resists heat and reduction better and crosses the
placenta. Serum levels of IgG4 are increased in patients with atopic
diseases, perhaps because IgG4 blocks IgE-mediated reactions.
Levels of specific IgG4 rise during immunotherapy (hyposensitization)
(Dahl, 1996).
Several attempts to characterize human IgE and IgG antibody
response to mosquitoes have been made using either ELISA or
immunoblotting (Wu and Lan, 1989; Konishi, 1990 and Das et al.,
1991). Using immunoblotting, Shen et al., (1989) found IgG and
IgE-binding antigens in Aedes albopictus mosquito whole-body
extract in several subjects studied.
Penneys et al., (1989) used immunoblotting and salivary
glands from five mosquito species (Culex nigripalpus, C
quinquefasciatus, Aedes taeniorhynchus, Aedes aegypti, and
Anopheles quadrimacuiatus) and found IgG class antibodies, which
reacted against several proteins with molecular weights ranging from
14 KDa to 126 KDa. However, the antigen pattern identified from
the five human sera studied was unique for each subject, because
each individual serum sample recognized both species-specific and
species-shared antigens.
- 43 -
Review of literature
IgE and IgG subclass antibodies against Aedes communis
mosquito saliva were studied by immunoblotting in adults with
immediate and/or delayed skin reactions to mosquito bites. Almost
all subjects had anti-mosquito saliva specific IgE antibodies directed
against the 36 KDa protein. The IgG antibody response appeared to
be restricted mostly to IgG4 and IgG1 subclasses against the same
36 KDa antigen. Ten of the 12 subjects had both IgE and IgG4
antibodies to the 36 KDa protein. No anti- mosquito antibodies were
found in pooled sera of five infants never exposed to mosquito bites.
These results show that most persons with immediate skin reactivity
to Aedes communis mosquito bites have both IgE and IgG4
antibodies that recognize the 36 KDa antigen present in the mosquito
saliva, suggesting that anti-saliva antibodies may play a role in the
pathogenesis of mosquito bite reactions (Brummer-Korvenkontio et
al., 1994).
In a study by Peng et al., (1996) forty-one subjects were
experimentally exposed to mosquito (Aedes vexans) bites.
Immediate and delayed skin reactions were traced at 20 minutes and
14 hours, respectively, after the bites. Sera were analyzed for
mosquito salivary specific IgE and IgG by ELISA. Lymphocyte
proliferation assays with mosquito extract were also performed.
They found that the mean mosquito-IgE and -IgG concentrations
were higher in the subjects with immediate reactions than in those
without immediate reactions. The mean lymphocyte proliferation
stimulation index was higher in the subjects with delayed reactions
- 44 -
Review of literature
than in those without delayed reactions. Further, both mosquito-IgE and IgG levels correlated with skin immediate and delayed reactions.
Cell mediated immune response:
Antigen presenting cells such as macrophages and Langerhans cells
present antigens to T helper (CD4+ ) and T cytotoxic (CD8+) cells on
major histocompatibility class I and II respectively (MHC-I& II). The T
cells secrete interleukin 2 (IL-2) and at the same time express receptors
for IL-2 on its cell surface. Interleukin-2 is a T cell growth factor
necessary to sustain antigen-driven lymphocyte replication. There are 2
major types of CD4+ cells; Th1and Th2 cells. These subtypes of helper T
cells are identified by the profile of cytokines they produce. Th 1 cells
release Tumor necrosis factor-β, gamma interferon (IFNγ) and IL-2. They
operate cell-mediated immunity. Th1 cells act as a suppressor for humoral
immune response. Th2 cells secrete IL-4, IL-5, IL-6 and IL-10. These
cells and their cytokines promote the growth of mast cells and eosinophils
and enhance production of antibodies such as IgE. Th 2 cells are
suppressor cells for cell-mediated immunity (Table: 3)(Fig.5) (Dahl,
1996).
Table (3): Biologic actions of T cell cytokines (Abbas and
Lichtman, 2006):
cytokine Principal action
Cellular source(s)
IL-2
T cell growth stimulation
CD4+andCD8+ cells
IL-4
B cell switching to IgE
CD4+ and mast cells
IL-5
Activation of eosinophils
CD4+ and mast cells
IFN-γ
Activation of macrophages
CD4+ and CD8+ Tcells and natural
killer cells
TGF-β
Inhibition of T cell activation
- 45 -
CD4+ T cells and many other cell types
Review of literature
Fig.(5): Type IV hypersensitivity reaction: APC; antigen
presenting cell, MHC-II; major histocomptability
class II, Ag; antigen, TCR; T cell receptor, IL-1&2;
interleukin I and 2, DTH; delayed type hypersensitivity
(www-micro.msb.le.ac .Uk /MBChB /6c. html).
- 46 -
Review of literature
The activation of T cells in conjunction with mature APCs is a
multiple-step process that requires both stimulation of the TCR and
several accessory signals delivered through other cell surface
receptors. The sequence of activation events can be termed primary
stimulation, costimulation, and mitotic stimulation (diagramed as
steps 1, 2, and 3).The initial interaction that triggers T cell
activation is recognition of an antigenic peptide that is bound to
either MHC-I (typical for intracellular antigens) or MHC-II (typical
for extracellular antigens) on APCs. The process of APC maturation
would have led to uptake and processing of antigenic peptides such
that they associate with extracellular MHC molecules on activated
cells. Antigens are recognized, in turn, by the TCR complex which is
present on the surface of all T cells. Peptide antigens presented on
MHC-I are recognized by a TCR complex that contains α/β chains of
the TCR protein, 5 protein subunits of CD3 (γ, δ, ε, ξ, η chains), and
α/β chains of the CD8 molecule, whereas antigens presented on
MHC-II are recognized by a TCR/CD3/CD4 complex (Trowsdale
and Campbell, 1992).
Cytotoxic T cells (CD8+) kill infected cells mainly by inducing
DNA fragmentation and apoptosis. It also, secretes IFNγ which
activates macrophages to destroy phagocytosed microbes by
macrophages and enhance the recruitment of additional leukocytes.
Thus, CD4+ and CD8+ T cells often function cooperatively to
eradicate intracellular infections (Abbas and Lichtman, 2006).
- 47 -
Review of literature
Naïve T-cells emigrant from the thymus and they are
distinguished by expression of high levels of CD45RA. After
antigen exposure the phenotype changes with reduction in CD45RA
and expression of CD 45RO. CD45RA and CD45RO are isoforms of
the leukocyte common antigen CD45 and are generated by alternate
splicing of the RNA transcript (Spickett and Schwarz, 2004).
Like humoral immunity, active immunization induces clones
of long-lived lymphocytes that provide long-lived immunity. In the
case of cell mediated immunity, the cells are T cells (memory cells)
with CD45RO on their membrane. As these cells die, the level of
sensitivity declines (Dahl, 1996).
Macrophage originates from monocyte when differentiated in
tissues. It processes antigen for presentation to T cells. The
macrophage secretes IL-1 which act as a signal to stimulate T cell
proliferation, releasing neutrophils from bone marrow, directing
them into inflamed tissue, increasing collagen production and
increasing prostaglandin E2 production. Macrophage secretes also
IL-6 which helps B cell differentiation and stimulates them to
produce immunoglobulins. Macrophage secretes tumor necrosis
factor (TNF) which stimulates phagocytosis by neutorophils and
augments antibody-dependent cellular cytotoxicity (Dahl, 1996).
The surface counterreceptors LFA-1 (lymphocyte function
associated antigen) and ICAM-1 (intercellular adhesion molecule)
maintain adhesion between a T cell and an APC. If a match occurs
- 48 -
Review of literature
between a peptide and a particular TCR variant a complex set of
biochemical signals ensues (sequential protein phosphorylation,
calcium entry, calcineurin activation, and transcription factor
activation) that increase synthesis of messenger mRNAs for
activation-associated genes such as IL-2 and the α-subunit of the IL2R (CD25 molecule). Accessory or costimulatory signals are also
critical for optimal T-cell activation. CD28 binds to CD80 and
CD86, which are up-regulated on the surface of dendritic cells
during antigen-triggered maturation. The coordinated stimulation of
TCR and CD28 pathways regulates the transcription of several
cytokines involved in T-cell activation, including IL-2, TNF-α, IFNγ, and granulocyte-macrophage colony-stimulating factor (GMCSF). In contrast, the absence of CD28 costimulation produces only
a partial TCR generated intracellular signal and, consequently,
decreased T-cell responsiveness. Other accessory or costimulatory
counterreceptors
include
ICAM-1/LFA-1,
LFA-3/CD2,
and
CD40/CD40L. The third set of signals delivered to the Tcell is from
the cytokines IL-2 (made by activated T cells) and IL- 12 (made by
mature Langerhans cells). Binding of these cytokines to surface
receptors expressed on activated T cells regulates mitotic activation
and differentiation of T cells (Fig.6) (Kruger, 2002).
- 49 -
Review of literature
Fig.(6): T cell interacts with a mature Langerhans cell to become
activated: LFA; lymphocyte function associated antigen,
ICAM;
intercellular adhesion molecule,
histocompatability
complex,
CTLA;
lymphocyte associated antigen,
TCR;
(Kruger, 2002).
- 50 -
MHC;
major
cutaneous
T
T cell receptor
Review of literature
Toll-like receptors are a recently discovered family of cell surface
receptors that have received considerable attention because they are
helping to unravel the details of the immune response to infection. They
are key components of the innate immune response, the arm of the
immune system that provides a rapid frontline attack against organisms to
contain infection while the adaptive arm generates an antigen-specific
response. Toll-like receptors are transmembrane proteins with a series of
leucine-rich repeats in the N-terminal extracellular domain and a
cytoplasmic portion greatly similar in structure to that of IL-1 receptor. It
contains intracytoplasmic domain, but instead of an immunoglobulin (Ig)
extracellular domain like the IL-1 receptor, it showed a structure
composed of leucine-rich repeats (Kang et al., 2006).
There are 10 TLRs that have been identified in human beings.
When a specific TLR is engaged by a microbial ligand, an ‘‘outside-in’’
signaling cascade is initiated, with the transcription factor nuclear factorkB being mobilized to the nucleus to generate a protective inflammatory
response. In addition to initiating an inflammatory response, the cytokine
pattern secreted by the activated APCs can shape adaptive immune
responses (Th1-vsTh2-dominant responses)during APC-T-cell interactions
(Gasperi, 2006).
Engagement of Toll-like receptors by microbial products initiates
the expression of the second signals of T cell activation. If this critical
communication between the T cell and the APC does not occur, the T cell
will invariably meet a fate of apoptosis or permanent anergy to the
antigen stimulus. This phenomenon constitutes a valuable safety
mechanism to prevent an inadvertent expansion of a T-cell clone; it
requires that a pathogen must be recognized by the Toll-like receptors of
- 51 -
Review of literature
the innate immune system before a fully developed adaptive
immunologic reaction can occur. The APCs produce cytokines that
instruct the expanding clone of T-cells to differentiate toward either a Th1
or a Th2 profile. It is becoming increasingly clear that the nature of the
antigen and the Toll-like receptor to which it binds can determine the
specific cytokine milieu that the APC will produce to influence the
polarity of the Th response (Kang et al., 2006).
In one histopathologic study of patients with papular urticaria,
T lymphocytes (CD45RO, CD3+) and macrophages (CD68+) were
present in all cases, while B lymphocytes (CD20+) and dendritic
antigen-presenting cells (S100+) were entirely absent. Lesions
revealed perivascular aggregation of mononuclear cells and slight
edema of the papillary dermis. In most cases, variable numbers of
eosinophils and neutrophils were present (Jordaan and Schneider,
1997).
Immunohistochemical studies performed on skin biopsy
specimens taken from the different lesions (papules, wheals and
vesicles) showed the predominance of a T cell response in all
lesions, with a greater (almost 2- fold) presence of T cells in vesicles
compared with wheals or papules. These findings suggest that the
disease’s initial clinical manifestations are produced by an alteration
in the cutaneous T cell mediated response. Such alteration appears to
be due to an enrichment of CD8+ T cells in these patients, indicating
that the early stages have larger amounts of T cytotoxic/suppressor
cells and, with the evolution of the disease; helper cells are recruited
- 52 -
Review of literature
simultaneously with an increase in the eosinophilic reaction. Patients
in this study presented with vesicles earlier than those patients with
papules and wheals. No significant differences were observed
regarding cell populations found in wheals and papules. The
predominance of eosinophils within the granulocytic infiltrate may
suggest an important role for these cells in the pathogenesis of PU.
Dendritic cells did not increase in the epidermis respecting normal
tissue and were absent in the dermis. An interesting finding was the
low number of mast cells in the lesions, suggesting a marginal role
for these cells in the immunopathogenesis of PU (Garcia et al.,
2004).
It is likely that the clinical manifestations of papular urticaria
are mediated by a complex immune response involving more than
one mechanism, with evidence for both an IgE response and a cellmediated type IV response. This was suggested by Garcia et al.,
(2004) in a study aimed to characterize the immune response to the
flea bite in patients with papular urticaria. Immunoblotting did not
show significant differences in IgG response between patients and
controls while IgE recognition of flea proteins appeared to decrease
as the disease progresses.
Delayed type hypersensitivity is the basis for both the clinical
chronicity and variable severity of papular urticaria. The elapsed
time between an insect bite and the formation of a firm, intensely
itching papule begins to lengthen as children gain exposure to these
allergens. Consequently, it can be difficult for a patient and/or
- 53 -
Review of literature
parents to accurately report "bite events". Continued and repeated
exposure to the inciting antigen results in not only immediate skin
reactions but also a cycle of delayed type hypersensitivity-mediated
lesions. Parents subsequently go on to find more new skin findings
as the child persists at itching and scratching from previous sites.
This sequence is perpetuated until the offending agent is identified
or the individual becomes desensitized, which can take weeks,
months, and sometimes years (Hernandez and Cohen, 2006).
- 54 -