Immunopathogenesis of Chronic Asthma

Asthma is a type of inflammatory disease that affects the respiratory airways present in the lungs (Holland & Goldman, 2021). This condition makes breathing very difficult and therefore some of the physical activities also become very difficult and challenging for the person having asthma. This disease develops when the lining of the respiratory airways is inflamed and the muscles surrounding these airways become tight and narrow. The airways are then filled with mucus and the amount of air that passes through the airways also decreases. These conditions can lead to an asthma attack which is characterized by coughing and a feeling of tightness in the chest. These are the basic features of asthma (Ratini, 2021).  The incidence of asthma has increased dramatically over the last 10 years and has reached the criteria of being an epidemic currently an estimate of 300 million people is suffering from asthma all over the world. It has been predicted that in the next 15-20 years the prevalence rate will increase (WHO, 2022). The clinical manifestation of asthma is shortness of breath, wheezing, and obstruction in the airflow (Ratini, 2021). This paper will discuss the role of airway inflammation in the pathogenesis of asthma.

Inflammation refers to the process through which the immune system shows the response to the injury which is very important for the host under the normal situation. There is an irregular type of immune response to the stimuli that are not pathogenic present in the airways that are affected. This leads to a chronic inflammatory response which is very relevant to the progression of the disease (Peebles & Aronica, 2019).  Even if there is no continuous exposure to the allergens there can be episodes of acute reactions of inflammation which are generally accompanied by a hidden chronic inflammation. There is a very complicated interplay between the inflammatory infiltrate which is made up of multiple cells and the cells of the lungs. This interplay is regulated by a very wide range of bioactive mediators which are amplified by self and these include cytokines, antibodies and growth factors (Saglani & Lloyd, 2019). The recruitment of the inflammatory leukocytes is directed by very small inflammatory soluble molecules which are called chemokines (Sokol & Luster, 2015).

The human system is divided into two main parts which are innate and adaptive immunity. The innate immunity system creates a network of immunosurveillance in the periphery so that it can start a beneficial response to the agents which are foreign to the body, immediately (Kaur & Secord, 2019). The lymphocytes of the adaptive immune system circulate again in the blood stream as well as the lymphatic system. These have the capability to start an immune response that is specific about the antigen and is followed by the development of a memory that is long lasting to the challenges offered by the same antigens (Schön, 2019). The effect of the adaptive immune system is in its ability that it can create billions of different types of receptors of antigens that are present on the multiple gene segments (Panda & Ding, 2015). Both these immunities, innate and adaptive are interlinked very closely as the response offered by the innate immunity describes the phenotype of the adaptive immunity which is very particular about the antigens (?erný, J., & St?íž, 2019). The proper type of immune response and function depends on the contributions from both the sections of the equilibrium with the components that can regulate the components of immunity (Riera Romo, Pérez?Martínez & Castillo Ferrer, 2016). The inflammation induced by the allergens is regulated by cells that are involved in both innate as well as adaptive immunity along with the tissues around (Lloyd & Saglani, 2015).

Allergic Sensitisation

It has been ambiguous for long about how the sensitization process to the allergens that occurs naturally, opposed to the antigens that are linked to the pathogens, not all the allergens are immunogenic intrinsically. One of the first steps in establishing allergic sensitization is the process through which the response of the T cells which are specific to the antigens are generated (Oksel & Custovic, 2018). In allergic asthma, the Th2 response is very common. But these Th2 do not show the direct reaction to the antigens that are inhaled and also need critical instructions which are given by the innate immunity system. In the network of innate immunity present in the lung tissues, the Dendritic cells (DCs) are among the most potent antigen-presenting cells (APCs). These are responsible for presenting a wide range of old families of receptors that are germline-encoded which are known as pattern-recognition receptors (PRRs).  These PRRs enable the continuous monitoring of the airways. They identify a very wide variety of invariant structures including the components of the microbes which are known as pathogen-associated molecular patterns (PAMPs). The PAMPs enable the immune system to recognize the pathogens and thus promote the elimination of the pathogens (Lamiable, et al., 2020). The agonists of PRR are contaminated by many types of allergens which help in inducing the maturation of the Dendritic cells (DCs). This also involves the up-regulation of the molecules that can be co-stimulated and also involves the acquisition of the ability can migrate the draining lymph nodes and thus enables them to interact with a primer that is effective to the T cell response which is specific to the antigen. Th2 cells are activated by the APCs and it leads to producing the cytokines such as the IL-4. The cytokine which is rich in IL-4 is produced by APCs once the Th2 cells get activated. The milieu of cytokine which is rich in IL-4 promotes the co-stimulation and interaction between the T cells as well as the B cells.  It initiates the class switching and the secretory plasma B cell affinity maturation so that it can produce IgE basophils. These are basophils have the potential to initially produce the cytokine (Leffler, et al., 2018).

When the allergens present in the environment are inhaled, the pulmonary epithelium is its first point of contact. They play a very important part in the sensitization of the Th2 cells. The relationship that is between the innate immune system of the pulmonary cells and the tissues surrounding it is very important for the events that lead to the sensitivity of the allergens which are mediated by Th2. This leads to the contribution of the innate immune system of asthma. The functioning of the dendritic cells is influenced by the epithelial cells through the process of direct interaction among the cells and also through the release of the mediators (KleinJan, 2016). Any sort of allergens such as the house dust mites can form direct or indirect interactions with the functions of the innate immunity of the epithelial cells present in the airways and the dendritic cells. There are many allergens that have epithelial modulatory activity and also enhance the permeability of the barrier (Konradsen, et al., 2015). The allergens that are inhaled are responsible for having a direct stimulation on the epithelial cells so that they can produce a variety of mediators known as the thymic stromal lymphopoietin (TSLP), IL-33, and IL-25. These mediators are responsible for directing a polarised response of the Th2 cell effector and thus perpetuate the clinical manifestations of asthma (Seumois, et al., 2016).

Allergic Response and t-helper 2 Lymphocytes

IgE binds with the Fc?R1 receptors which are present on the mast cells surfaces and the basophils. When there is the next encounter with the allergens the antigen then bins to the IgE which are present on the membrane, this stimulates the secretion of mediators such as the histamines, leukotrienes, and cytokines (Froidure, et al., 2016).  As in this process, the antigens bind to the complex of the antibody and the receptor which leads to immediate response. This forms the basis of the immediate type of hypersensitivity reactions (Froidure, et al., 2016). The other type of cytokines that are produced by the Th2 cells have the ability to activate other leukocytes and plays a very important part in the process of inflammation caused by the allergens. For the survival of eosinophils, interleukin is very important. These eosinophils are the central effector cells in asthmatic people. When IL-5 is administered to patients suffering from asthma, it increases the number of eosinophils in the blood circulation and their precursors present in the bone marrow (Zhao & Wang, 2018). IL-9 is also released by the T helper cells which are in much higher concentration in the respiratory airways of patients suffering from asthma. It helps in promoting the growth of mast cells, eosinophilia of tissues as well as production of other cytokines of Th2 (Neurath & Finotto, 2016). There is a class of Th cells which are known as the Th17 cells that have been recognized as a component in the process of inflammation in asthma. The Th17 releases IL-17, which is present in increased levels in the airways as well as the blood of the patients suffering from asthma. Interleukin-17 also upregulates the wide range of cytokines, chemokines, adhesion molecules as well as growth factors (Liu, et al., 2020).

The T cells and the epithelial cells are stimulated through which the other effector leukocytes to the respiratory airways, as well as the mediators that are produced by these cells, will result in inflammation, damage to the issues, remodelling. The mast cells are the effector cells that are central in allergic conditions and are present in the increased amount in the respiratory airways of the patients (Bradding & Arthur, 2016). When the allergen to IgE on the surface of the cell induces a series of signal transduction cascade that results in the secretion of inflammatory mediators. The secretion of histamine and prostaglandin D2 (PGD2) results in bronchoconstriction. The mast cells produce cysteinyl leukotrienes, lipid mediators derived from arachidonic acid (Virk, Arthur & Bradding, 2016). The leukotrienes bind to the receptors which are present in the G protein on the surface of the cells of the airways. They produce contraction of smooth muscles, enhance the vascular permeability of the tiny blood vessels, enhance the secretion of mucus and also recruit the leukocytes in the respiratory airways. The cysteinyl leukotrienes play a very major part in the pathogenesis of asthma (Liu & Yokomizo, 2015).

Mast cells also secrete the inflammatory cytokines, chemokines and proteases which contribute to the inflammation of the airways. These mediators help in stimulating the response of inflammation in the epithelium which causes direct damage to the airways and also brings more leukocytes in the airways. In patients suffering from asthma, the concentration of eosinophils is elevated. The factors that are released from the epithelial cells, Th2 cells, mast cells present on the airways help in the recruitment, growth as well as survival of the eosinophils. The chemokines especially the CCL5 and the CCL11, supply the eosinophils to the airways. These eosinophils express a wide range of proinflammatory cytokines, Th2 cytokines and chemokines that have the capability of activating the mast cells and stimulating the epithelium (Nakagome & Nagata, 2018). In addition to this, the eosinophils can also present the antigens of the T cells and secretes the growth factors such as TGF- β. This highlights the significance of eosinophils in multiple facets of inflammation in asthma (Caminati, et al., 2019).

Phagocytes are also found in the airways affected by asthma, even though their roles and functions are not described that well (Baharom, et al., 2017). Macrophages are found in much higher numbers in the airways and they create many types of inflammatory cytokines and chemokines. In severe asthma, neutrophils are present in much higher numbers, especially in people who smoke (Ciepiela, Ostafin & Demkow, 2015).

In patients suffering from asthma, T cells play a very crucial part in playing the role of the effector (Muehling, Lawrence & Woodfolk, 2017). Th2 produces the IL-13 which induces the hyperresponsiveness of the airways and multiple types of impacts on the structure such as subepithelial fibrosis, the proliferation of smooth muscles of the airways and goblet cell hyperplasia. The inflammation is induced by IL-13 as it acts on the epithelium of the airways and also increases the numbers of eosinophils by regulating the chemokines such as CCL11 (Bagnasco, et al., 2016).

Chronic inflammation is generally accompanied by the remodelling of the tissues in the airways and there are alterations in the structures of the architecture of the respiratory airways in people suffering from asthma, which as a whole is termed remodelling (Hough, et al., 2020). The calibre of airways is determined by the forces of ASM and the elasticity of the parenchymal cells.  The changes because of the remodelling lead to the thickness of the walls of the airways, a decrease in the diameter of the airways. This eventually results in fixed obstruction in the flow of air through it, persistent AHR and a very poor short term response to the treatment (Fehrenbach, Wagner & Wegmann, 2017). Changes in the remodelling include a reticular basement membrane which gets thick, dysregulation of the deposition of the proteins in the extracellular matrix (ECM) and an increase in the vasculature. The lungs that are remodelled also have a very influential increase in the mass of ASM with evidence for changes in hyperplastic and hypertrophic along with the recruitment of the progenitors of ASM (Boulet, 2018).

Conclusion

In conclusion, it can be said that asthma is a chronic disease that is associated with inflammation of the respiratory airways that comprises numerous phenotypes as well as the triggers of inflammation. All these phenotypes have a very common feature of inflammation even though their specific pathways for an immune response might have differences. As these mechanisms are discussed at molecular levels, the treatments of asthma can be developed with respect to the particular phenotypes. The mediators are targeted and the cells are described in this essay showcase the basic treatment of asthma.

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