Immunopathogenesis of Allergic Disorders: Current Concepts

Yashwant Kumar, Alka Bhatia

Disclosures

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

In This Article

Etiologic Basis of Allergy

In a given time frame, besides ethnic variation, the genetic makeup of a stable population does not change. Therefore, frequency of genetically mediated disorders is unlikely to change in that population. However, this is not true for AD; a rapid increase in prevalence clearly indicates that other factors may be equally or more important in etiopathogenesis. In fact, ADs are believed to be caused by a combination of both environmental and genetic factors (Figure 1), each accounting for approximately 50% of risk of susceptibility.[4]

Figure 1.

Factors predisposing to allergy.

Environmental Factors

A high prevalence in the western population and increasing prevalence in developing countries suggests that factors like western lifestyle, which is spreading around the globe, could be important. Changes in the level of air pollution, indoor exposure to allergens and general living standards may be additional environmental factors associated with the risk of allergy.

The hygiene hypothesis, a concept related to lifestyle changes, proposes that early and repeated childhood infections reduce the tendency to develop AD.[9,10] This is supported by the fact that children in western countries who are protected from infections due to their cleaner and germ-free surroundings are at an increased risk of developing allergy. On the other hand, infants and children in developing countries are frequently exposed to infections. Problems related to sanitation, clean drinking water, malnutrition, and overcrowding all contribute to early exposure to infections. It has been observed that, in the developing world, besides exposure to parasitic, viral and bacterial infections, intestinal colonization with Gram-negative bacteria tends to occur early in life. Differences in intestinal flora have also been found between allergic and nonallergic children in Europe.[11] Antibiotic use during the first 2 years of life may also accentuate the risk of developing AD.[12]

A balanced exposure to microbes, parasites, allergens and other environmental substances usually promotes normal development of the immune response (Th1 and Th2). However, as exposure to allergens is increased, there is a propensity in genetically predisposed individuals for an exaggerated Th2-cell type response to a variety of environmental allergens. The counter-regulation hypothesis proposed by van den Biggelaar et al. showed that, in response to parasitic and bacterial infections, the regulatory T cells (Tregs), monocytes, macrophages and dendritic cells (DCs) secrete IL-10.[13] IL-10 has an immunoregulatory role and dampens both Th1 and Th2 responses resulting from activation of either the innate or adaptive immune system (Figure 2).

Figure 2.

Hygiene hypothesis and counter-regulation theory for allergy. Poor hygiene is associated with frequent infections, which result in strong Th1 and Th2 type of immune responses. However, this also favors the development of Tregs, which maintain a balance between Th1 and Th2 immune responses, thus preventing their harmful effects. On the other hand, reduction in pathogen burden due to excess hygiene shifts immune response against environmental allergens or self antigens, especially in atopic individuals. Moreover, the regulatory check by Tregs is minimal or absent, making individuals more prone to allergic or autoimmune disorders. DC: Dendritic cell. Data taken from [9–10].

Allergic sensitization is another environmental predisposing factor for the development of allergy. The properties of an allergen (e.g., type, size, dose and root of exposure) are believed to decide the development of the aforementioned phenomenon (Box 1). Concentration in environment and whether the exposure occurs together with the agents that can enhance the sensitization process (i.e., adjuvants) are other factors that may be important.[14] Allergens are almost always proteins (but not all proteins are allergens) and often have enzymatic functions such as proteolytic activity. Abundance of such proteins in the food, high number of linear IgE-binding epitopes and resistance of these proteins to digestion and processing make them powerful allergens.[15] Such properties, besides eliciting a strong IgE-mediated Th2-cell response, may also participate in augmenting mucosal permeability and other aerodynamic properties.[16]

Allergic sensitization, usually to food substances such as egg or milk, begins early in life and occurs primarily in high-risk infants who have a parent with underlying AD. This sensitization may lead to mild symptoms, but by 3–5 years of age tolerance to food has often developed. Sensitization to aeroallergens, such as house dust mites, generally beginning at 1–2 years of age may lead to future development of an AD.

Genetic and Epigenetic Factors

Genetic factors were believed to be one of the important etiological factors in allergy. With widespread use of genome-wide association studies, hundreds of genes associated with asthma or other ADs have been identified in recent years. Although a definitive etiological link remains to be drawn, these genes have helped us in understanding several pathways crucial in the etiology of allergy. Depending upon their association with the innate or adaptive immune response, the genes can be divided into those regulating the immune function or those affecting the structural tissues like epithelium or connective tissue (Table 2).

Epigenetic regulation could also be an important mechanism by which environmental factors may interact with genes involved in the development of AD.[17,18] Recently, it has been shown that DNA methylation and histone modification are involved in effector T-cell polarization and differential secretion of Th1 and Th2 cytokines.[19,20] As epigenetic modifications may be inherited, besides altering immune response in allergy in an individual, they may also influence development of allergy in the subsequent generations.[21]

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