Immunopathogenesis of Allergic Disorders: Current Concepts

Yashwant Kumar, Alka Bhatia

Disclosures

Expert Rev Clin Immunol. 2013;9(3):211-216. 

In This Article

Allergic Rhinitis

AR is one of the most common ADs, afflicting approximately 20% of the world's population. Patients develop a symptom complex that consists of sneezing, nasal congestion, itching and rhinorrhea with involvement of eyes (rhinoconjuctivitis), ears, sinuses (rhinosinusitis) and throat.[74] Approximately 10–40% of patients have asthma comorbidity, while most patients with asthma have rhinitis. Previously, AR was classified based on the time and type of exposure and symptoms as seasonal, perennial and occupational; however, the Allergic Rhinitis and its Impact on Asthma (ARIA) initiative has revised this classification by introducing the terms 'intermittent' and 'persistent'.[75,76] Some patients with AR display symptoms comparable with IgE-mediated AR, yet lack increased serum IgE levels and/or antigen-specific IgE. Such phenomena of localized nasal allergy and existence of Th2 disease pathway in the absence of systemic atopy was termed as 'entopy' by Powe et al..[77,78] Recently, it has been suggested that localized IgE switching is upregulated in AR mucosa as a result of selective B-cell proliferation. This could give rise to a localized IgE-mediated Th2 inflammatory response in such cases of allergic inflammation. A similar phenomenon has also been observed in food allergies, dermatitis and asthma.[79]

Atopic Dermatitis

Atopic dermatitis is a chronic inflammatory skin disease that commonly begins in early infancy, runs a course of exacerbations and remissions and is associated with a characteristic distribution and morphology of skin lesions. It results from a complex interplay between strong genetic and environmental factors. Genes involved may be divided into those involved in the epidermal barrier function and those involved in the regulation of the innate and adaptive immune systems including the regulation of IgE sensitization.[80] Moreover, there are chromosomal regions that overlap with other skin diseases, such as inflammatory and autoimmune diseases. This may be one of the reasons that atopic dermatitis is often associated with asthma, AR (hayfever) and food allergy.

Numerous trigger factors for atopic dermatitis have been identified over recent decades, including food allergens, inhalable respiratory allergens, irritant substances and infectious microorganisms such as Staphylococcus aureus and Malassezia furfur. Atopic dermatitis manifests itself by means of the heightened capacity of B lymphocytes to produce IgE antibodies against allergens, which trigger the immune response after contact. This may be due to defective regulation of the T lymphocytes, which is associated with inadequate function of the CD8+ lymphocytes in suppressing IgE.[81,82]

Normally, the food antigens that are ingested enter the gut and encounter the intestinal immune system (gut-associated lymphoid tissue). Here, they are captured by the APCs, which then cause apoptosis among the antigen-specific T cells or differentiation in the suppressor T cells, which produce suppressive TGF-b. A breach in the gut immunity and crossreactivity of the IgE antibodies with skin antigens or direct interaction with specific IgE, Fc receptors on Langerhans cells, mast cells, monocytes, basophilic granulocytes or skin-infiltrating T lymphocytes leads to skin allergy.[83]

Cow's milk, eggs, wheat, maize, crustacea, hazelnuts, almonds and peanuts are the most common allergens implicated in atopic dermatitis and may cause sensitization and an outbreak or worsening of skin changes. Some vegetable gums, carmine red, ethylvanillin, vanilla and tartrazine can also trigger an IgE-mediated response. In addition to the aforementioned food items, the way in which a food is cooked also influences its level of allergenicity. In general, allergens of animal origin continue their activity for longer, whereas vegetable allergens are more easily broken down by cooking or by other processes.[84]

Breastfeeding for at least the first 6 months of life is considered to be an important measure in prevention of atopic dermatitis. During breastfeeding, atopic mothers' diets should consist of frequently varied organic foods on the basis of their individual food intolerances. Moreover, as a therapeutic measure, patients with atopic dermatitis should strictly use foods of strictly organic origin, particularly for fruit, vegetables and whole grains. Frequent use of sunflower oil is also useful due to its high content of -3 and -6 polyunsaturated fatty acids. Topical corticosteroids are still a mainstay of treatment for atopic dermatitis.

Food Allergy

Food allergy is a specific immune response that occurs reproducibly on exposure to a food. It can be broadly categorized on a pathophysiologic basis into IgE-mediated (immediate), non-IgE-mediated (cell-mediated, delayed) and mixed responses. Acute allergic responses such as urticaria, vomiting, wheezing and anaphylaxis to food are generally due to IgE antibody directed against various food allergens.[58] In the human gut, there is a complex immune system that can discriminate between pathogens and harmless food antigens to avoid an uncontrolled immune response to food antigens or the components of the commensal microbiota.[85] The gut epithelial barrier is generally protected by immune exclusion of foreign antigens via secretory antibodies and by anti-inflammatory tolerance mechanisms. Efficient removal of foreign antigens requires IgA and IgM. IgA is the most abundant immunoglobulin secreted across the mucosa. It is constantly exposed to pathogenic or harmless microbes and also food antigens, hence it provides an immunological defense by transporting antigens across the intestinal layer to the lumen. Besides IgA, DCs and Tregs also play an important role in the allergic response. DCs in the intestinal mucosa are considered to be crucial mediators as they drive T-cell polarization towards Th1 and regulatory phenotypes. DCs migrate from the intestinal mucosa to mesenteric lymph nodes where they produce retinoic acid and TGF-b, which in turn induce Tregs involved in tolerance induction.[86] A profound shift of DC population may be seen in intestinal tissue towards a more inflammatory and less regulatory phenotype in a person sensitized to food allergens.[87] Moreover, there appears to be a link between Tregs and commensal flora, which are likely to promote the development of Tregs, thereby causing food tolerance.[88]

Intraepithelial lymphocytes, particularly T cells, are the other cells supposed to play a role in food allergy. They facilitate crosstalk between epithelial cells and immune cells. Reduced number of T cells has been correlated with intestinal epithelial injury after sensitization.[89]

Drug Allergy

Drug allergy is another immunologically mediated hypersensitivity reaction. Like food allergy, it also may be either an IgE-mediated or a non-IgE-mediated hypersensitivity reaction. These reactions generally occur after prior development of an immune response to a hapten–carrier complex. On subsequent encounter with the drug, a hapten–carrier complex is formed again, which then crosslinks preformed drug-specific IgE on mast cells, activating a cascade for allergic reaction. However, in 50% of patients with immediate reactions and 80% with lethal anaphylaxis, there may be no prior contact with the drug. This may be due to silent sensitization to a crossreactive compound or due to presence of preformed IgE.[90]

Common drugs associated with IgE-mediated allergies include b-lactam antibiotics (e.g., penicillin and cephalosporin), immunoglobulin preparations (IgA, IgE), pyrazolones, quinolones, neuromuscular blocking agents and foreign proteins (chimeric antibodies). In non-IgE-mediated drug allergy, different mechanisms are involved. These include cytotoxic/cytolytic reactions involving the interaction of IgG or IgM antibodies and complement with a drug allergen (e.g., immune hemolytic anemia and thrombocytopenia), drug–immune complex reactions (e.g., serum sickness and drug-induced lupus) and T-cell-mediated reactions, which are generally the most prevalent type of reaction.[91]

Anaphylaxis

Anaphylaxis is a life-threatening, systemic, IgE-mediated allergic reaction caused by sudden release of mast cell- and basophil-derived mediators into the circulation.[6] Anaphylaxis occurs within seconds or minutes of allergen exposure. Besides IgE, other mechanisms including IgG–antigen interaction and complement activation may also play an important part in the pathophysiology of this fatal condition.[92]

In younger individuals, food is the most common trigger, while medications and insect sting are more common in middle-aged and older adults.[93] The symptoms of anaphylaxis range in severity from those that are mild and resolve spontaneously to those that are fatal within minutes, termed 'anaphylactic shock'. The anaphylactic shock involves multiple organs such as the respiratory and cardiovascular system, GI tract, skin and CNS and is characterized by rapid fall in blood pressure, swelling in throat and mouth, chest tightness, difficulty in breathing and unconsciousness.[94] Prompt injection of epinephrine is life saving in such cases.[95] Anaphylactic responses to insect stings, injected medications, foods and other agents are thought to be caused by IgE/antigen-dependent mast cell activation. In addition to this classic pathway of systemic anaphylaxis, IgG antibodies can also induce anaphylaxis in a basophil-dependent manner in the mouse. Histamine is primarily responsible for the development of shock in the classic pathway. By contrast, PAF is responsible in the alternative pathway.[96]

Immune Response in Allergic Disorders

Allergic sensitization Most ADs begin after sensitization to allergens derived from house dust mites, cockroaches, animal dander, fungi and pollens. Sensitization is a phase of immune reaction occurring after an atopic individual is exposed to an allergen for the first time. Microbes and irritants damage and activate the respiratory epithelium, which then secretes GM-CSF and a variety of chemoattractants such as CCL20, CCL19 and CCL27. As a result, the DCs migrate from the bone marrow to epithelium and underlying mucosa. GM-CSF and other structural and immune cells under the influence of IL-4 and TNF-α also induce DC maturation and their differentiation into fully mature and competent APCs.[79,97] The activated APCs then process the allergen, further mature and migrate to draining lymph nodes or to the site of local mucosal lymphoid tissue. The processed small peptides are then presented via the class I and II MHCs to the naive T-cell receptors. The presentation of processed allergic peptides to naive T cells stimulates their differentiation into Th2 cells. Excess of IL-4 (produced by accessory cells like mast cells or basophils or by naive T cells) and low levels of IL-12 are critical for this differentiation. Some epithelial cell-derived cytokines secreted as a result of activation of TLR3 and TLR5 or following epithelial injury also exert Th2-polarizing action, namely, IL-1, IL-25 and IL-33.[44,98] Activation of receptors for IL-33 and IL-1 on T cells leads to Th2 cell expansion. Th2 cells then produce IL-3, IL-4, IL-5, IL-9, IL-13 and GM-CSF. Nuocytes possibly also assist Th2 cells in secreting these cytokines.[40,98] IL-25 mediates a Th2 memory response initiated by TSLP-primed DCs.[99]

Th2 polarization is also to some extent under epigenetic check. Certain miRNAs are supposed to set a balance between Th1 and Th2 responses. Reduction in levels of miRNAs induce production of increasing amounts of IL-12 by DCs and IFN-γ by allergen-challenged T cells, but inhibit production of IL-4, thus enhancing the Th1 response.[100]

Once the Th2 polarization process is complete, IL-4 and IL-13 promote binding of costimulatory molecules (CD40 with CD40 ligands and CD80 or CD86 with CD28) on Th2 cells and B cells, thereby leading to differentiation of B cells into plasma cells and immunoglobulin class switch recombination. In class switch recombination, the gene segments that encode the immunoglobulin heavy chain are rearranged such that antibody of the IgE class is produced. IgE then diffuses locally and enters the lymphatic vessels. It subsequently enters the circulation and is distributed systemically. After gaining access to the interstitial fluid, allergen-specific IgE binds to FcRI on tissue-resident mast cells, priming them (Figure 3). Upon re-exposure to allergen, these mast cells respond immediately and release their preformed mediators, resulting in allergy-related symptoms.[101]

Figure 3.

Sequence of events in IgE-mediated immune response. Allergic sensitization is the first step in the development of IgE-mediated immune response. There is continuous screening of all the molecules coming in contact with surface epithelium or skin cells. After antigen capture, antigen-presenting cells process them and migrate to draining lymph nodes, where they present allergic peptides to naive T cells and promote their activation and differentiation into Th2 cells under the influence of cytokines such as IL-4. The Th2 cells then bind with B cells and induce class switch recombination and plasma cell differentiation, thereby leading to production of IgE immunoglobulins. These allergen-specific immunoglobulins via circulation reach the site of allergen exposure and bind to FcRI receptors on resident mast cells. Subsequent allergen exposure leads to crosslinking of the IgE–FcRI complex on mast cells, thereby causing degranulation of preformed mediators. After immediate effects of preformed mediators, cells are recruited at the site of the immune response to sustain inflammatory reaction. Persistence of stimulus or repeated exposure causes continuous recruitment of cells, leading to complex interaction between innate, adaptive, epithelial and other structural cells. In respiratory mucosa, an epithelial–mesenchymal trophic unit is established, which sustains Th2 response, leads to goblet cell hyperplasia, mucus hypersecretion, smooth muscle hyperplasia, myofibroblast migration in the subepithelium and deposition of fibronectin and collagen and thickening of lamina reticularis. The aforementioned events increase severity of allergic symptoms such as bronchoconstriction, mucus secretion, cough, rhinorrhea, itching and pain.

Cys-LT: Cysteinyl leukotriene; DC: Dendritic cell; EBP: Eosinophil basic protein; GF: Growth factor; GM-CSF: Granulocyte–monocyte-colony stimulating factor; Hist: Histamine; LR: Lamina reticularis; LT: Leukotriene; MFB: Myofibroblast; PAF: Platelet-activating factor; PGD2: Prostaglandins D2; SCF: Stem cell factor; SM: Smooth muscle; TSLP: Thymic stromal lymphopoeitin.

Propagation of allergic response After sensitization, re-exposure to allergens leads to an ongoing allergic response driven by memory T cells after they interact with activated DCs. This immediate immune response may be further enhanced by defective barrier function of epithelium, proteolytic and other biological activities of allergens. Moreover, the multivalent and bivalent nature of the allergens results in binding of more than one IgE molecule resulting in their crosslinking. This results in aggregation of FcRI, which in turn triggers a complex intracellular signaling process causing release of preformed mediators from mast cells. These secreted mediators then result in bronchoconstriction, increased mucus production, vasodilatation, increased vascular permeability (leading to tissue swelling and epiphora) and erythema (reddening of skin in case of atopic dermatitis). The mast cells also contribute to transition to late-phase reaction by promoting influx of inflammatory leukocytes, both by upregulating adhesion molecules on vascular endothelial cells and by secretion of chemotactic factors (Figure 3).[102,103]

Mast cells responding to IgE and allergen also release a broad range of newly synthesized cytokines, CCs and growth factors, albeit much more slowly than the preformed mediators. Some mast cell products have the potential to recruit other immune cells either directly or indirectly (TNF-α, LTB4, IL-8, CCL2 and many other CCs) to activate innate immune cells and to affect many aspects of DC, T- and B-cell biology. Some products of mast cells can influence the biology of structural cells including vascular endothelial cells, epithelial cells, fibroblasts, smooth muscle cells and nerve cells. Other products that contribute to late-phase reactions are derived from resident or recruited T cells that recognize allergen-derived peptides. Therefore, late-phase reactions are coordinated by activated mast cells and antigen-stimulated T cells (Figure 3); the clinical features reflect the activities of both resident cells and circulating leukocytes that are recruited to the site.[103]

Chronic or persistent allergic inflammation In the case of continuous or repetitive allergen exposure, inflammation persists, and many innate and adaptive immune cells derived from blood are found in the tissues at the site of allergen challenge.[104] This persistent inflammation is associated with changes in stimulated cells at the affected site and in many cases with markedly altered functions of the affected organs. There is an increase in the number of goblet cells in the respiratory epithelium leading to copious mucus production, increased production of cytokines and CCs by epithelial cells, excessive epithelial injury and repair and inflammation of the submucosa. The latter includes increased deposition of extracellular matrix molecules in the lamina reticularis, changes in fibroblasts, increased numbers of myofibroblasts, increased vascularity and hypertrophy and hyperplasia of the muscular layer of the airway (Figure 3).[31] Repetitive epithelial injury due to chronic allergic inflammation can be exacerbated by exposure to pathogens or environmental factors, and the consequent repair response ultimately results in establishment of an epithelial–mesenchymal trophic unit. This unit is thought to sustain Th2 cell-associated inflammation to promote sensitization to additional allergens or their epitopes (e.g., epithelial cell-derived TSLP can upregulate the expression of costimulatory molecules such as CD40 and CD80 by DC) and to regulate the airway remodeling process.[105]

A number of in vitro tests can be used to confirm the involvement of allergens in allergic inflammation. Some of the commonly used tests include skin-prick test, patch test or direct challenge with an allergen. Allergen-specific antibody test, basophil activation assay, measurement of inflammatory mediators released, (i.e., mast cell tryptase) and lymphocyte stimulation studies are other tests used as common laboratory methods for detection of allergy.

Future Research

Despite extensive research, allergy still remains an unsolved mystery for clinicians and researchers. New discoveries in allergy have greatly enhanced our knowledge; however, they have also given rise to many new questions. The role of genetic factors described years previously has been verified, yet many of the potential genes involved in its etiology remain to be explored. The identification of miRNA and their regulatory effects on immune responses has opened a new vista in molecular pathogenesis of allergy. Although therapeutic means have also progressed, we remain far from our goal to cure and prevent AD. Recent efforts directed on understanding the epigenetic regulation of allergic response, mechanisms of immunologic tolerance breakdown, role of extracellular vesicles in the development of allergy, impact of environment and lifestyle factors, discovery of new therapeutic targets and immune modulation, and personalized medicine, among others, may further help to answer many queries related to the enigma of AD.

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