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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 -