- Allergy is an abnormal immune response of the adaptive immune system against non-harmful environmental allergens and organisms.
- An allergen is a (non) protein or substance which can induce an allergic response.
- Human can get sensitized to an allergen, resulting in an allergy.
- Sensitized subjects produce, after (re)exposure to specific allergens, an inflammation.
- Allergic inflammation is subdivided into three categories: early phase reaction, late phase reaction and chronic allergic inflammation.
- House dust mite (HDM) allergens which are inhaled are unusually exceptionally virulent. HDM allergens activate both the adaptive and innate immune response.
- Children atopic to HDM, have a poor clinical outcome in respiratory health.
- In general HDM allergens can trigger many different pathways, influenced by the allergen their molecular structure.
1.1 What is an Allergy?
Allergy is an abnormal immune response of the adaptive immune system against non-harmful environmental allergens and organisms. Some well-known allergic disorders are allergic rhinitis, allergic asthma, food allergies and anaphylaxis. These disorders have an immune response including T helper 2 cells (Th2) and allergen-specific IgE. Allergen-derived antigens are recognized by these two factors. In 2011, the prevalence of allergic disorders like house dust mite (HDM) allergy were approximately 65-130 million people worldwide (Calderon et al., 2015). Those numbers have increased the last decades mainly thought through the hygiene hypothesis. This hypothesis includes the theory that when living standards are higher, human are less exposed to allergens. The molecular mechanism of this hypothesis remains to be elucidated (Calderon et al., 2015). An allergic disease is overall not life threatening. Still those diseases cause a lot of morbidity among million of people (Holgate, 1999). The pathology of sites which are repetitive or continue exposed to allergens are nowadays clear, these are effects of long-term consequences of chronic inflammation (Galli et al., 2008).
An allergen is a (non) protein or substance which can induce an allergic response. Allergens are divided into two subtypes. The first subtype includes all non-infectious environmental allergens which can induce IgE production so individuals get sensitized. When individuals get sensitized a later re-exposure triggers the immune response and results in an allergic reaction. Some of these allergens are: animal dander, insect venoms, some medicines, grass and tree pollen, certain foods and house dust mite faecal pellets. The other allergen subtype is the subtype including non-infectious environmental allergens which induce an adaptive immune response. The adaptive immune response results in a local inflammation and is IgE independent (Galli et al., 2008).
1.3 Sensitization to allergens
When an allergen is able to trigger a Th2 cell response it tells something about the sensitization. Many different factors have an influence on clinically significant sensitization. Some of these factors are type of allergen, host genotype, way of exposure and allergen concentrations within the environment. Way of exposure is influenced by agents needed to enhance the sensitization process. These agents can be, for example, environmental pollutants, chitin, and ligands of toll-like receptors (TLR) which can trigger under some circumstances the Th2 cell response and normally trigger the Th1 cell response. The pattern of contact of the allergens with the immune system is also an important factor. This may vary for example by: frequency, amount, route of allergen exposure, type and phenotypic characteristics of dendritic-cells which are included in the response (Galli et al., 2008). Allergens communicate with T cells through dendritic, or other antigen-processing, cells. Th2 cells produce pro-inflammatory cytokines, whereby Th1 cells produce cytokines which antagonize the allergic response (Holgate, 1999).
The epithelium can be influenced by environmental or genetic factors. The permeability of the epithelium can be influenced by allergens, which can be proteases. When the epithelium is more permeable the allergen can enter more easily and by entering the cell it can trigger the Th2 cell response. One of these proteases is the der p 1 allergen of the house dust mite. Some proteases are capable of hydrolyzing substrates or directly reducing epithelial barrier function (Galli et al., 2008).
Figure 3. The process of sensitization within the airway. IL = Interleukin, Ig = Immunoglobin, TNF = Tumor Necrosis Factor, Th= T Helper cell, MHC = Major Histocompatibility Complex (Galli et al., 2008).
Figure 3 shows how the immune system is sensitized to allergen. An allergen is taken up by through the epithelial layer and processed by dendritic cells. Proteases can get access by cleaving the epithelial-cell tight junctions. When allergen is processed by dendritic cells, the dendritic cells migrate to the regional lymph nodes or sometimes to the local mucosa. In this region the dendritic cell presents the allergen derived peptide, through major histocompatibility complex (MHC) class II molecules to the Naïve T cell. Due to the fact that Notch of the naïve T cell is in contact with Jagged of the dendritic cell the naïve T cell transforms into a Th2 cell. Th2 cells secrete IL-4 and IL-13 cytokines, in combination with contact through CD40 + CD40 ligand and CD28 + CD80 or CD86 the B cells are stimulated to switch immunoglobulin class. Immunoglobulin class is changed in such a way that B cells start producing IgE. When IgE has entered the blood it distributes systemically. When IgE is inside the interstitial fluid it binds to the high-affinity receptor for IgE on mast cells. Mast cells are therefore sensitized, so the next time the allergen enters the system a Th2 response will occur (Galli et al., 2008).
1.4 Allergic inflammation
Sensitized subjects produce, after (re)exposure to specific allergens, an inflammation. Allergic inflammation is subdivided into three categories. One allergen exposure can lead to an acute reaction. This acute reaction is also known as early-phase or type I immediate hypersensitivity reaction, and occurs within seconds to minutes after exposure to allergen. After the acute reaction, the late phase reaction mostly follows within various hours. Those early and late phase reactions can develop by repetitive or persistent exposure to allergens into a chronic allergic inflammation (Galli et al., 2008).
1.4.1 Early phase reactions
Within seconds to minutes an early phase reaction to allergen exposure occurs. The range of the reaction can differ between systemic or localized. Early-phase reactions reflect primarily the secretion by mast cells (figure 4). When individuals are sensitized, allergen-specific IgE binds to high-affinity IgE receptors (FcεRI). Allergen cross-linking IgE molecules binds to FcεRI on basophils and mast cells. The cross-linking results in release of various mediators existing of three different groups of biologically active products. The three biologically active products are these mediatiors: cytokines, chemokines, growth factors and other products, lipid-derived mediators. Resulting in acute functional changes like increased mucus production, bronchoconstriction, vasodilatation, increased vascular permeability resulting in oedema. Local recruitment and activation of leukocytes can also be promoted through released synthesized mediators, this can contribute to the development of late-phase reactions (Galli et al., 2008).
Figure 4. Early phase reactions within the airway. IL = Interleukin, Ig = Immunoglobin, TNF = Tumor Necrosis Factor (Galli et al., 2008).
1.4.2 Late phase reaction
The late-phase reaction is partly coordinated by the early-phase reaction. Due to antigen-stimulated T-cells and mediators released by activated mast cells in the early-phase, the late-phase reaction is a long-term consequence. The late-phase reaction peaks at 6-9 hours after allergen exposure, and the reaction develops after 2-6 hours after allergen exposure. After 1-2 days the late-phase reaction is completely resolved. The late-phase reaction in the skin includes the classical symptoms of an inflammation: rubor, calor, dolor and tumor. Within the airways the late-phase reaction results in increased mucus production and bronchoconstriction (figure 5). Due to Th2 cell activation, neutrophils, macrophages, easinophils and basophils and other leukocytes are recruited. Neutrophils secrete elastase therefore another consequence is the degradation of type III collagen through the activation of matrix metalloproteinases (MMPs). Another consequence is that easinophils secrete basic proteins which can cause epithelial damage (Galli et al., 2008).
Figure 5. Late-phase reaction within the airway. IL = Interleukin, Ig = Immunoglobin, TNF = Tumor Necrosis Factor (Galli et al., 2008).
1.4.3 Chronic allergic inflammation
A chronic allergic inflammation consist of a continues inflammation which is induced by repetitive or extended exposure to allergens. This inflammation is characterized by substantial alterations in the number, phenotype and function of structural cells and changes within the extracellular matrix in the affected tissue. Large numbers of derived adaptive (Th2 cells, T cells and B cells) and innate (basophils, monocyte-macrophage lineage cells, easinophils and neutrophils) immune cells are also present in the tissue at a chronic-allergic inflammation (figure 6). The chronic allergic inflammation can be worsened by environmental factors and pathogen exposure (Galli et al., 2008).
Chronic allergic inflammation in patients with chronic asthma causes important, structural changes in the affected tissue. Including; increased number of goblet cells followed indirectly by more mucus production, epithelial cells can produce more chemokines and cytokines, and epithelial suffers more from damage and repair. Also the submucosa suffers from a considerable inflammation. Within the submucosa, increased deposition of extracellular-matrix molecules in the lamina reticularis (Type I, III, V collagen and fibronectin). Resulting in the thickening of the lamina reticularis. A substantial thickening of the airway walls like submucosa, epithelium and smooth muscle is also going on. An increased development of vascularity, myofibroblast, and changes in fibroblasts result in the thickening of the muscular layer of the airways. Next to this, the smooth muscle cells are increased in function, size and number. Concluding that all layers of the airway wall are involved in the chronic inflammation (Galli et al., 2008). The thickening of the airway wall results in the following symptoms in patients: wheeze, shortness of breath, cough and chest pressure (Longfonds, 2015).
Figure 6. Chronic allergic inflammation within the airway. IL = Interleukin, Ig = Immunoglobin, TNF = Tumor Necrosis Factor (Galli et al., 2008).
1.5 House Dust Mite allergy
House dust mite (HDM) allergens which are inhaled are unusually exceptionally virulent. Instead of activating only the adaptive or innate immune response, it stimulates both. An enhanced study about house dust mite allergen showed that 1-2% of all people in the world might be sensitized for HDM allergens. This was in 2011 equal to 65-130 million people. The prevalence of HDM allergy is linked to the exposure of the mite itself. Increasing exposure to the major allergens of HDMs, which are group 1 and group 2 allergens of D. pteronyssinus, leads to an increase in development of allergy. HDM allergy can undergo all allergy stages described above (Calderon et al., 2015).
Although allergen exposure is linked to sensitization, there is no linear pattern detected. Children in the age of 0-5 years showed the highest and lowest quantity of exposure leaded to the lowest prevalence of mite atopy. Another study reported that children sensitized in their first years of life, lung function according wheeze is affected. In long-term, children have a poor clinical outcome in respiratory health. Therefore it is reasonable to include primary prevention of sensitization as early in life as possible (Calderon et al., 2015).
HDM allergy is arranged by two different immune reaction routes. Firstly Th2 cells are triggered, which induce the IgE dependent response. Secondly the innate immune system is triggered these include the easinophils, basophils, neutrophils and macrophages. Because HDM allergens can trigger both pathways, the allergens are very strong. Immunogenic epitopes, proteases, chitin and microbial compounds are all components which can trigger the immune system (Calderon et al., 2015).
Of the HDM allergens, group 1 and group 2 allergens are present the most, both having a very different effect on the immune system. Group 1 allergens are the most powerful, they have the largest capacity to activate different routes at the same time. Allergens of group 1 can also be recognized by toll-like receptors and protease-activated receptors, therefore they trigger the pathogen-associated molecular pattern. Proteases of group 1 can influence the epithelial tight junctions by breaking them down. Group 2 allergens might mimicry the TLR4 and co-receptor MD-2 effect. These allergens can also activate mast cells independently of IgE, therefore causing direct damage to epithelial cells. In general HDM allergens can trigger many different pathways. This is influenced by the molecular structure of the allergen (Calderon et al., 2015).
Figure 7 describes all the immune responses related to HDM allergens. It shows that proteases of the HDM has an effect on both IgE mediated immediate response and late-phase response in inflammation. Number 1 in figure 7 shows that inhaled HDM allergens are continuously exposed on the airway mucosa. This is the starting point of an immune system response. Number 2 shows the epithelium. Here allergens are taken up by dendritic cells. HDM allergens can also trigger Toll-like receptors immediately, thereby triggering the Th2 immune response. Number 3 demonstrates the antigen presentation either within the local mucosa or within the draining lymph nodes. The dendritic cells present the allergen to T naïve cells promoting Th2 cell differentiation. Number 4 displays the IgE production. Continues exposure of allergens leads to continuous allergic inflammation and IgE production. Number 5 shows the early phase response by releasing IgE which binds to receptors on mast cells and basophils. Triggering the degranulation process of those cells. The proteases of HDM can also react on smooth muscle cells, smooth muscle cells will increase contraction. Finally number 6 demonstrates the continual inflammatory responses which are maintained by continuous exposure to allergens, leading to a chronic allergic inflammation (Calderon et al., 2015).
Figure 7. The immune responses correlated with house dust mite allergen exposure. IL = interleukin, TNF = Tumor Necrosis Factor, DC = Dendritic Cell, TLR = Toll-like Receptor, PAR = Protease-activated Receptor, Ig = Immunoglobulin (Calderon et al., 2015).
- Calderon et al., M. (2015). Respiratory allergy caused by house dust mites: What do we really know? Journal of Allergy and Clinical Immunology , 38-48.
- Galli et al., S. (2008). The development of allergic inflammation. Nature , 445-454.
- Holgate, S. (1999). The epidemic of allergy and asthma. Nature , B2-B4.
- Longfonds. (2015). Symptomen van astma. Opgeroepen op 01 28, 2016, van Longfonds: