INTRODUCTION
Allergic asthma is a diverse disorder of the conducting airways associated with chronic airway inflammation, declined airway function, and tissue remodeling.[1] Asthma is derived from the Greek term “asthma,” which means “breathing difficulty,” implying that any patient experiencing breathing difficulty is asthmatic. The term was refined in the late 19th century with the publication of Henry Hyde Salter’s treatise “On Asthma and its Treatment.” In this scientific article, Salter defines asthma as “paroxysmal dyspnea of a peculiar character with intervals of healthy respiration between attacks.”[2] During an asthma attack, the lining of the airways swells and the muscles surrounding the airways constrict. As a result, the inside of the airways shrinks, making breathing difficult. Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements, particularly mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells, play a role. Inflammation of the bronchial wall involving eosinophils, mast cells, and lymphocytes, as well as their cytokines and inflammatory products, provokes hyperresponsiveness of the bronchi, exacerbating them to narrow more readily in response to a variety of stimuli.[3]
EPIDEMIOLOGY
Epidemiologic data have shown that over the last few decades, the prevalence of asthma has increased both domestically and globally.[4,5] Asthma is one of the world’s most common chronic diseases, with a prevalence that is still escalating in some developing countries.[6] Bronchial asthma affects approximately 310 million people worldwide. As air quality and environmental conditions continue to deteriorate, bronchial asthma incidence escalates yearly.[7,8] While asthma incidence and prevalence are increasing, adults have a higher morbidity and mortality rate than children. Asthma in children is more common. Adult asthma is more common in women than in boys, and the reversal of this trend is possible. The sex difference in prevalence occurs around puberty, implying that sex hormones may play a role in the etiology of asthma.[9] Both the severity and incidence of this disorder are rising exponentially in developed nations, especially in children. The asthma prevalence rate has been rising across the nations, especially in children.[10] The latest Centers for Disease Control and Prevention (CDC) epidemiology data on asthma were released in 2012 and covered the years 2001 to 2010. A significant finding was that the number of people with asthma increased by 2.9% annually, from 20.3 million in 2001 to 25.7 million in 2010.[4] The two main causes of the rise in asthma in India are elevated air pollution and upper respiratory tract infections. A little more than half of the people get it before the age of 10 years, and only about a quarter get it before the age of 45 years. At the age of 30 years, it affects both men and women equally, but it affects young boys twice as often as young girls.[11]
PATHOPHYSIOLOGIC MECHANISMS
Role of T Cells in Asthma Pathogenesis
Asthma is a chronic inflammatory disease characterized by airway inflammation, hyperresponsiveness, and obstruction. The pathogenesis of asthma is complex and not fully understood. It involves several immune cells including the T-lymphocytes, B-lymphocytes, mast cells, eosinophils, neutrophils, macrophages, dendritic cells (DCs), etc. Recent research on this aspect has revealed the role of the T cells or macrophage dysfunction in the progression of asthma.[12,13,14] The identification and counting of distinct immune cell populations in the upper and lower airways have been key to characterizing airway inflammation. The four inflammatory phenotypes of asthma can be classified based on this quantification: eosinophilic (high eosinophils, normal neutrophils), neutrophilic (high neutrophils, normal eosinophils), mixed granulocytic (high eosinophils, high neutrophils), and paucigranulocytic (normal eosinophils, normal neutrophils).[15] T cells are derived from the lymphoid stem cells present inside the bone marrow. CD4+CD25+ natural regulatory T cells (nTregs) are produced in the thymus and exist in the blood and other peripheral lymphoid tissues at a frequency of 5 to 10% of all CD4+ cells and 20% in bone marrow in both mice and humans. Epidemiological data dating back to the 1960s show a linear rise in the prevalence of type 2 T helper (Th2)-mediated allergic diseases such as asthma and type 1 T helper (Th1)-mediated (auto)immune diseases including type 1 diabetes mellitus, multiple sclerosis, and Crohn disease.[16] When the naïve T cells come across the antigen, they differentiate into the effector T cells and memory T (Tm) cells. The effector cells consist of several cells including the Th1, Th2, Th17, Th22, Th9, Th25, T regulatory (Treg), T follicular helper, natural killer T cells, and cytotoxic CD8+ T lymphocytes. These effector cells regulate the innate immune cells (macrophages, eosinophils, mast cells, basophils) and stimulate the B cells. The T cells are also responsible for the generation of cytokines and chemokines to intensify the immune response leading to the escalation of smooth muscle contraction, mucus secretion, airway hyperresponsiveness, and airway obstruction (Figures 1 and 2).[17]
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Figure 1: Imbalance of T cells in the development of asthma. BCL6 = B-cell lymphoma 6; Blimp-1 = B lymphocyte-induced maturation protein-1; CTL = cytotoxic T lymphocyte; IFN = interferon; IgE = immunoglobulin E; IL = interleukin; MAIT = mucosal-associated invariant T; NKT = natural killer T cell; RORγt = RAR-related orphan receptor (ROR) γt; STAT = signal transducer and activator of transcription; Tfh = T follicular helper cells; Th1 = type 1 T helper; TGF = transforming growth factor; TNF = tumor necrosis factor; TSLP = thymic stromal lymphopoietin.
Figure 2: The pathogenesis of asthma and macrophage dysfunction. CCL = C–C motif chemokine ligand, CXCL = C–X–C motif chemokine ligand, IFN = interferon, IL = interleukin, iNOS = inducible nitric oxide synthase, LPS = lipopolysaccharide, MCP-1 = monocyte chemotactic protein 1, ROS = reactive oxygen species, TGF = transforming growth factor, Th1 = type 1 T helper, TNF = tumor necrosis factor.
Imbalance in Eosinophilic Asthma
The imbalance between the Th1/Th2 cells plays a significant role in asthma pathogenesis. Interleukin 12 (IL-12) and interferon (IFN)-γ stimulate the T-bet to activate the Th1 cells via the signal transducer and activator of transcription (STAT) 4 signal, whereas IL-4 stimulates (GATA3) to activate Th2 cells via the STAT6 signal. Th1 cells produce IL-2, IFN-γ, and lymphotoxin (LT-)α, that further promote type 1 immunity. They play two regulatory roles in asthma: they suppress Th2 cell activation to limit eosinophilic inflammation while promoting neutrophilic inflammation. Airway epithelial-derived cytokines (IL-33, IL-25, and thymic stromal lymphopoietin [TSLP]) stimulate Th2 cells. Subsequently secreting Th2-associated cytokines (IL-4, IL-5, and IL-13). IL-4 and IL-13 urge B cells to produce immunoglobulin E (IgE), mucus secretion, and Airway hyperresponsiveness (AHR). It was proved that IL-2-resident CD4+ Th2 memory cells produced IL-5 through IL-33-ST2-p38 kinase signaling and encouraged eosinophilic asthma.
Th17/Treg Imbalance in Neutrophilic Asthma
The Th1/Th2 imbalance is key in the pathogenesis of asthma. Th17 cells, a subset of CD4+ T cells that were first identified in 2005, are characterized by the secretion of IL-17. IL-17 mediates airway neutrophilic inflammation in asthma, mediates eosinophilic airway inflammation in asthma, and is associated with the severity of asthma.[18] Recent research has shown that the Th17/Treg imbalance continues to play an important role in the pathogenesis of asthma. Through the STAT3 signal, IL-6 and IL-23 activate Th17 cells, while transforming growth factor (TGF) induces Foxp3 expression to support Treg cell differentiation. Another study found that the toll-like receptor (TLR) 4/IFN-(toll/IL-1R domain-containing adaptor-inducing IFN-β [TRIF]) pathway was used by Th17 cells to produce the inflammatory mediators IL-17A, IL-17F, and IL-22, which had a proinflammatory effect on neutrophil activation and recruitment. Interestingly, IL-17 has two functions; while protecting the lungs by attracting neutrophils to the inflammatory site, it also makes neutrophilic asthma worse.
Th22 Cells
The differentiation of Th22 cells, which are closely related to Th17 cells, is induced by IL-6 and TGF via STAT3 signaling. Another study demonstrated that ovalbumin (OVA)-induced IL-22-deficient mice had lower levels of IL-4, IL-5, IL-13, and IL-33 as well as lower eosinophil and neutrophil counts and AHR downregulated, suggesting that IL-22 had proinflammatory properties.[19]
Memory T Cells
Tm cells train the body to respond quickly during the secondary immune response and develop immune memory. Histone H3 lysine 4 (H3K4me2), B-cell lymphoma 6 (BCL6), and Blimp-1 all contribute to Tm cell differentiation.[17] ([Figures 1 and 2])
B-Lymphocytes
B-lymphocytes are the prominent cells of the immune system. These are the cells derived from the stem cells in the bone marrow.[20] Many studies have concluded the role of the T-lymphocytes in the development of allergic asthma. But there is less knowledge regarding the role of B-lymphocytes in asthma development except for the B-lymphocytes’ highly known ability to produce the antigen-specific IgE antibodies.[21] According to research, based on the cytokines they produce, B-lymphocytes can be divided into two subsets of effector B-lymphocytes (Be1 and Be2). Be2-lymphocytes (producing IL-4) regulate the differentiation to Th2-lymphocytes, while Be1-lymphocytes (producing IFN-γ) regulate the differentiation of naive Th-lymphocytes to Th1-lymphocytes.[22] B-lymphocytes can independently induce AHR and airway inflammation, even without the presence of T-lymphocytes. One research has concluded that B-lymphocytes are involved in regulating granulocytic inflammation in a murine model of fungal allergic asthma by limiting the IL-6 and IL-17A production.[21]
Mast Cells
Mast cells, which are derived from hematopoietic cells, are significant immune system cells. Mast cells originate from pluripotent progenitor cells of the bone marrow and mature under the control of the c-kit ligand and stem cell factor in the presence of other distinct growth factors provided by the microenvironment of the tissue where they reside. Mast cells are found throughout the body in mucosal and epithelial tissues. Mast cells can also be found in the peritoneal and thoracic cavities of rodents. Activated mast cells are responsible for the secretion of the various mediators including histamines, proteases, proteoglycans, leukotriene B4 (LTB4), leukotriene C4 (LTC4), prostaglandin D2 (PGD2), platelet-activating factor (PAF), cytokines (including IL-4, IL-5, and IL-13), and superoxide dismutase which is capable of inducing bronchoconstriction, mucus secretion, and mucosal edema, regulating both IgE synthesis and the development of eosinophilic inflammation.[23] When it comes to bronchial asthma, mast cells play a significant role in both early-phase reaction and late-phase reaction of asthma[24][25] It has been evident from the research that the mast cells mostly localize at three key sites: the airway smooth muscle (ASM), the airway mucous glands, and the bronchial epithelium. Various in vivo studies on rodents and humans have revealed the mechanism by which the mast cells act via IgE-mediated allergic reactions through the FcεRI receptor.[23]
Eosinophils
Eosinophils are granular cells that originate from the bone marrow. Eosinophils play a significant role in the pathophysiology of asthma by the secretion of lipid mediators, proteins, and other factors. Eosinophils are the storehouse of the four proteins in their granules, eosinophils store four basic proteins: major basic protein (MBP), eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), and eosinophil peroxidase (EPO). MBP is toxic to the respiratory epithelial cells and pneumocytes. It has been observed that mild asthma is characterized by elevated numbers of eosinophils, both in the bronchial mucosa and in bronchoalveolar lavage fluid (BALF). An analysis of BALF taken from a group of “intrinsic” asthmatics revealed more activated T cells, eosinophils, and neutrophils than in normal control. Blood eosinophil counts and the level of bronchial hyperresponsiveness appear to be correlated in longitudinal and cross-sectional studies of asthmatic patients. Patients with severe asthma who died showed signs of having elevated amounts of activated eosinophils in their bronchial mucosa after being immunostained.[26]
Dendritic Cells
Dendritic cells (DCs) are the immune cells, and they are known for their role to induce the primary immune responses. Immature DCs are present throughout the lungs and are vital in the immune response to inhaled antigens. DCs are involved in the differentiation of the Th cells into Th2 cells and are the key mediators of airway inflammation. Another study on the mice using an OVA sensitization model resulted in eosinophilic infiltration and elevated mucus secretion by airway epithelial cells.[27] It has been observed that there was a significant rise in the myeloid DCs in airway mucosa and bronchoalveolar lavage fluid of mice and rats. Administration of OVA-pulsed myeloid DCs to the airways of naïve mice and rats induces sensitization to OVA leading to Th2 cell response and eosinophilic airway inflammation, goblet cell hyperplasia, and bronchial hyperreactivity. Removal of airway DCs from sensitized mice eliminates asthmatic features induced by antigen aerosol. It has also been revealed that allergic airway inflammation is accompanied by an increase in the airway DCs.[14]
Macrophages
These are the immune cells present in the tissues of all vertebrates. These cells are responsible for the pathogenesis of foreign antigens. A study has demonstrated that mouse macrophages obtained after intraperitoneal stimulation with thioglycolate medium accumulated and secreted high levels of plasminogen activator in culture, whereas unstimulated mouse macrophages did not.[28] Macrophages are primarily derived from bone marrow-derived monocytes and are found in almost all tissues and are mainly classified into alveolar macrophages (AMs).[29] Research has shown that the absence of AMs caused type 2 inflammation and airway remodeling to be inhibited. It was countered, though, that asthmatic mice’s airway hyperreactivity was reduced by AMs’ adaptive immunity to them. Other mice with AMs removed had worsening lung function and an exacerbation of the Th2 type of inflammatory response. IFN-γ, lipopolysaccharide (LPS), and tumor necrosis factor alpha (TNF-α) stimulate M1 macrophages, whereas IL-4, IL-13, and IL-10 activate M2 macrophages.[17]
M1 Polarization and Proinflammation in Asthma Pathogenesis
Major histocompatibility complex (MHC) class II molecules, CD80, CD86, TLR4, and inducible nitric oxide synthase (iNOS), are all highly expressed by M1 macrophages. Proinflammatory molecules including the LPS, TNF-α, and IFN-γ further produce Th1-associated cytokines (TNF-α, IL-1β, IL-2, IL-6, and IL-12), Th17-associated cytokines (IL-23 and IL-27), monocyte chemotactic protein 1 (MCP-1), reactive oxygen species (ROS), and chemokines (C–X–C motif chemokine ligand [CXCL] 9, CXCL10, CXCL11, CXCL16, C–C motif chemokine ligand [CCL] 2, CCL5, and CCL8). These proinflammatory mediators are linked with neutrophilic infiltration, corticosteroid resistance, ROS production, AHR, and phagocytosis.
M2 Polarization and Its Modulation of Inflammation in Asthma Pathogenesis
M2 macrophages have the lower expression levels of MHC class II molecules and CD86 as well as the higher expression levels of macrophage mannose receptor C (MRC) type 1, arginase (Arg) 1, CD206, and CD163, alternating eosinophilic infiltration in type 2 inflammation. IL-4, IL-10, and IL-13 further produce M2a macrophages to express IL-10, TGF-β, and chemokines (CCL17, CCL18, CCL22, and CCL24). Immune complex (IC) promotes the activation of M2b macrophages, participates in the regulation of the Th2 type of immune system, and expresses TNF-α, IL-1, IL-6, IL-10, and CCL1. After being stimulated to differentiate into M2c macrophages by IL-10 or PGE2, monocytes then express IL-10, TGF-β, CCL16, CCL18, and CXCL13, which suppresses inflammation and improves tissue repair.[15,17,30]
Inflammatory Mediators
Chemokines
Chemokines (chemotactic cytokine mediators) are the tiny proteins that are secreted by the cell signaling molecules called cytokines. The role of chemokines is to promote chemotaxis. That is important for the recruitment of inflammatory cells into the airways. The human chemokine system consists of 50 chemokines and 20 G-protein-coupled serpentine receptors. Every chemokine receptor plays an important role in the pathogenesis of the diseases such as asthma, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, psoriasis, rheumatoid arthritis, atherosclerosis, cancer, and multiple sclerosis. Several chemokines such as CCL5, CCL7, and CCL13 have been recognized for their role in the bronchial airways of asthmatics. In human asthma CCL5, CCL11, and CCL13 are produced in the airway epithelium. A research study has concluded that the development of status asthmatics was associated with higher levels of CCL2, CCL13, and CCL5 in the bronchoalveolar lavage fluid.[31]
Cytokines
Cytokines are the glycosylated, cell signaling group of low molecular weight (<80 kDa) synthesized by different immune cells, mainly, by T cells, neutrophils, and macrophages, which are responsible to promote and regulate the immune response. There are different cytokines including chemokines, IFN, IL, lymphokines, and TNF. (Table 1)
Table 1: Role of Cytokines in Asthma Pathogenesis.[
3 , 14 , 31]
Lipid Mediators
Lipids are the important building blocks of the cell. The lipid-derived metabolites participate in the manifestation of cellular inflammatory conditions. However, the dysregulation of lipid derivatives can lead to inflammatory diseases such as diabetes mellitus, cancer, asthma, etc. Leukotrienes (LT), prostaglandins, epoxyeicosatrienoic, thromboxanes, and isoprostanes are the lipid mediators produced in the body. Interestingly, new research suggests that phospholipase A2 (PLA2) may regulate a variety of other biological functions including DC maturation and migration. T-cell proliferation and cytokine/chemokine production by monocytes, macrophages, neutrophils, and eosinophils are involved in the pathogenesis of asthma. Indeed, increased serum and leukocyte PLA2 activity have been observed in asthma patients. Most of these derivatives particularly Thromboxanes (TXs), PGD2, and cysteinyl LT are produced by mast cells and eosinophils.[32,33]
Histamine
Histamine is a key mediator released from the mast cells. It plays a significant role in airway obstruction via smooth muscle contraction, bronchial hypersecretion, and airway mucosal edema. Histamines have four types of histamine receptors H1, H2, H3, and H4. However, smooth muscle bronchoconstriction is mediated via H1 receptors, and it is related to the respiratory system. It has been found that the number of mast cells was higher in the BALF of asthmatic patients compared to that of the control subjects. Dale and Laidlaw were the first to report bronchoconstriction via histamine. Histamine concentration was reported to be higher in the BALF of patients with asthma compared to the normal subjects. Histamine is synthesized and stored in vesicles of mast cells and basophils themselves.[34]
CONCLUSION
The experimental studies and findings reveal that asthma is induced by the stimulation of different inflammatory cells. These inflammatory cells exhibit orchestration of the pathophysiology associated with the progression and worsening of asthma symptoms. T-cells, macrophages, and their interplay are of great importance in asthma. Cytokines are responsible for asthma pathogenesis through the release of the chemokines promoting chemotaxis. On the other hand, histamines produced by the mast cells have a significant role in airway obstruction via smooth muscle constriction, bronchial hypersecretion, and airway mucosal edema. Lipid metabolism controls several cellular processes that are crucial to the development of asthma. LT and prostaglandins are known to worsen asthma symptoms. Hence, further research should be focused on the inhibition of the cell receptors that are responsible for the progression of asthma pathogenesis.
Financial support and sponsorship
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Conflicts of interest
There are no conflicts of interest.
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