Interleukin-5 and Interleukin-5 Receptor Polymorphism in Asthma

Abstract

Asthma is a common chronic inflammatory disease of the airways of the lungs, in the world. It’s associated with type 2 cytokines interleukin-4, IL-5, and IL-13, which promote airway eosinophilia, bronchial hyperresponsiveness, mucus overproduction, and immunogloubulin E synthesis. IL-5 is a cytokine known to play major role in the regulation of eosinophil formation, maturation, survival, and recruitment. Hence, an increased production of IL-5 may be contributed to the pathogenesis of asthma. The expression of human IL-5 receptor presented on eosinophils, basophils, and mast cells. Hence, a polymorphism in IL-5 receptor may be implicated in the development of asthma. Many candidate genes that could potentially contribute to the susceptibility to the disease have not been investigated to date, and not all of the polymorphisms of the candidate genes have been tested for a possible association with the disease. Taking this into consideration, IL-5 (together with the IL-5 receptor) polymorphism deserves attention as the subject of further investigations into asthma. In this review, we will address the role of IL-5 and IL-5 receptor polymorphism in asthma, describe the impact of these polymorphisms on the Blood parameters and clinical parameters. Further, give an overview of preclinical and clinical studies targeting the IL-5 and IL-5 receptor pathway.

1. Introduction

Asthma is the most common chronic lower respiratory tract and non-communicable diseases in children and adults throughout the world, characterized by inflammation which affects both proximal and distal airways [1, 2, 3, 4, 5]. Asthma is involving an abnormality of airway function, specifically to wide variations in airflow limitation over short periods of time and associated with airway obstruction, variable airflow limitation, bronchial hyper responsiveness and tissue remodeling of the airway structure [6, 7, 8].

Asthma is a separate disease entity, fails to identify a primary defining characteristic which separates it from other diseases and is long-winded [6]. The disease characterized by episodic or persistent symptoms of wheezing, dyspnea, and cough [9]. It is highly prevalent chronic inflammatory diseases of the airways, with differences in etiology, immunologic mechanisms, clinical presentation, pathogenesis, comorbidities, prognosis, and response to treatment, arising from not fully understood heterogenic gene-environment interactions, while environmental factors are important in the development of asthma, genetic factors could have a critical role in the expression of the disease, but the genetic background of bronchial asthma is complex, and it is likely that multiple genes contribute to its development both directly and through gene-gene interactions [8, 10, 11, 12].

2. Pathophysiology of asthma

2.1 Immune response

Asthma is primarily an inflammatory disorder of the airways associated with T helper type 2 (Th2), cell-dependent promotion of IgE production and recruitment of mast cells and eosinophils [13]. Allergic asthma may involve adaptive and innate, antigen-independent immune responses [14]. Th2 cell-driven inflammation is likely to represent an abnormal response to harmless airborne particles by polarized immune responses to its [15, 16].

However, some respiratory viral infections cause bronchiolitis of infancy and childhood wheeze and can exacerbate established asthma. Fundamental to innate immune responses to microbes are the interactions between pathogen-associated molecular patterns and pattern recognition receptors, which are associated with the production of type I interferon, pro-inflammatory cytokines, and the Th2 cell pathway in predisposed people [17].

Allergen exposure results in the activation of numerous cells of the immune system, include dendritic cells (DCs) and Th2 lymphocytes [18]. DCs in the airway epithelium and sub mucosa detect inhaled allergens [13]. DCs then migrate to the secondary lymphatic systems where they process and present antigens via major histocompatibility complex class II (MHC II) to T- and B-lymphocytes, leading to the proliferation of Th1 or Th2 cell types and B-lymphocytes produce IgE, which binds to high affinity FcεRI on basophils and mast cells [19]. In response to allergen presentation by airway DCs, T-helper lymphocytes of the adaptive immune system control many aspects of the disease through secretion of IL-4, IL-5, IL-13, IL-17, and IL-22, and these are counterbalanced by cytokines produced by T-regulatory cells (Figure 1) [20].

Figure 1.

Dendritic cells as antigen-presenting cells [21].

2.2 Role of T helper (Th2) cytokines in asthma

Th2-type cytokines, such as interleukin-4 (IL-4), IL-5 and IL-13, are thought to drive the disease pathology in patients with asthma and play a role in driving many of the hallmarks of allergic inflammation [22, 23]. Whereas IL-4 is important for allergic sensitization and IgE production, and IL-5 is crucial for eosinophil survival, IL-13 has pleiotropic effects in the lungs, including a central role in the development of airway hyper responsiveness (AHR) and tissue remodeling (Figure 2) [24].

Figure 2.

Immunopathogenesis of asthma [25].

IL-5 is the critical molecular switch for development, migration, recruiting eosinophils to the lung during allergic inflammation [26, 27]. IL-5 exerts its biological actions via stimulation of the IL-5 receptor expressed by eosinophils and, to a lesser extent, also by basophils [28].

2.3 Interleukin-5

Interleukin-5 (IL-5) is an interdigitation homodimeric glycoprotein [29]. IL-5 produced by both hematopoietic and non-hematopoietic cells including T cells, granulocytes and natural helper cells [30]. It is a T cell-derived cytokine involved in the pathogenesis of atopic diseases and play important roles in the pathogenesis of asthma, hypereosinophilic syndromes and eosinophil-dependent inflammatory diseases, through recognized as a critical regulator of eosinophilia and has effects on eosinophil progenitors, eosinophil precursors and mature eosinophils [29, 31, 32], which is believed to regulate the growth, differentiation and activation of eosinophils [33]. Further, to preferentially acts on mature eosinophils to prolong maturation and survival and increased circulating eosinophil progenitors, suggesting a key role for systemic IL-5 in eosinophil mobilization. Moreover, IL-5 causes terminal maturation of the eosinophil by increasing CCR3 expression, potentially affecting CCR3-dependent chemotaxis by eosinophils and lymphocytes [34, 35]. In addition, over expression of IL-5 significantly increases antibody levels in vivo and reported to act as a B-cell differentiation factor by stimulating activated B cells to secrete antibody [32, 36].

Interleukin-5 is a very selective cytokine as a result of the restricted expression of the interleukin-5 receptor on eosinophils and basophils [28]. Hence, humanized monoclonal antibody to interleukin 5 significantly limited eosinophil migration to the lung [37]. Therefore; IL-5 inhibition may be an effective approach for the treatment of asthma, especially severe asthma. Interfering with eosinophil function or reducing their numbers has been one of the most important goals of therapeutic monoclonal antibodies, which target cytokine receptor interactions in asthma, particularly IL-5 [38].

IL-5 gene is located on chromosome 5 [39]. It is a potential candidate gene in the pathogenesis of asthma, may play a role in blood eosinophilia associated with atopic dermatitis [40, 41]. Locus over-expression of IL-5 significantly increases eosinophil numbers and antibody levels in vivo. Conversely, mice lacking a functional gene for IL-5 or the IL-5 receptor alpha chain (IL-5Rα) display a number of developmental and functional impairments in B-cell and eosinophil lineages [30, 32]. In addition, polymorphisms in the IL-5 genes may contribute to the susceptibility to atopic bronchial asthma and could determine the clinical course of the disease [42].

2.4 Interleukin-5 C-703T polymorphism

Interleukin-5 gene is located on chromosome 5 within a cytokine gene cluster IL-4 and IL-13 [43, 44]. Further, IL-5 gene, IL4, and IL13 may be regulated co-ordinately by long-range regulatory elements spread over 120 kilobases on chromosome 5q31.1. This gene encodes a cytokine that acts as a growth and differentiation factor for both B cells and eosinophils [44].

The IL-5 C-703 T polymorphism may play a role in blood eosinophilia associated with atopic dermatitis and it is a potential candidate gene in the pathogenesis of asthma [40, 41]. Asthma in children is associated with IL-5 C-703 T polymorphism. IL-5 C-703 T polymorphism has impact on IL-5 levels and eosinophil count. TT genotype of IL-5 C703T consider a risk factor for mild asthma in Iraqi asthmatic children [45]. In addition, IL-5 promoter polymorphism at −746A > G enhances serum total and specific IgE level responses to staphylococcal enterotoxins A, which may augment airway hyper responsiveness in adult asthmatics [46]. On the other hand, the previous results of meta-analysis suggest that IL-5 C-746 T polymorphisms are not associated with increased asthma risk, whereas IL-5 C-703 T polymorphisms are associated with asthma in children [47].

The influence and importance of IL-5 polymorphism that is single nucleotide polymorphism located within promoter regulatory sequences of cytokine gene; the promoter mutation known to cause functionally important consequences for gene expression. Although promoter mutation analysis is complex, difficult to perform, and often laborious, it is an essential part of the diagnosis of disease-causing promoter mutations and improves our understanding of the role of transcriptional regulation in human disease (Figure 3) [42, 45, 48].

Figure 3.

Molecular location of IL-5 gene. Cytogenetic location, Chr.5q31.1 [44].

2.5 Interleukin 5 receptor (IL-5 R)

The human IL-5 receptor is a heterodimer consisting of a unique alpha subunit and a signal transducing beta subunit shared by the receptors for interleukin 3 (IL3), colony stimulating factor 2 (CSF2/GM-CSF), and interleukin 5 (IL-5) [39, 49]. The expression of human IL-5R alpha (IL-5Rα) subunit presented on eosinophils, mast cells and basophils whereas the beta subunit is more widely expressed [50].

The IL-5Rα is required for ligand-specific binding while association with the beta-chain results in increased binding affinity [51]. Further, Interleukin-5 receptor α-subunit expression may be implicated in the development of allergic diseases [52]. In addition, IL-5Rα has regulatory pathway in human eosinophils and their gene has a role for controlling eosinophils in the peripheral blood [53, 54]. It has been suggested that neutralizing antibodies to IL-5Rα could serve as a therapeutic agent in eosinophil-associated diseases [55]. An anti-interleukin 5 receptor α monoclonal antibody that depletes blood and airway eosinophils [56].

2.6 Interleukin-5 receptor alpha G-80A polymorphism

The gene for the IL-5R alpha subunit is a protein coding gene located on chromosome 3 in the region 3p24-3p26. The alternative splicing of the IL-5 Rα gene which contains 14 exons can yield several alpha IL-5 receptor isoforms [57, 58].

Polymorphisms in IL-5 Rα might be among the genetic risk factors for asthma development, especially in atopic populations [59]. Functional polymorphism in IL-5Rα may contribute to eosinophil and mast cell activation [46]. Additionally, increased expression of IL-5Rα on CD34+ cells favor eosinophilopoiesis and may thus contribute to the subsequent development of blood and tissue eosinophilia, a hallmark of allergic inflammation [60].

The G-80A polymorphisms in IL-5Rα located in the promoter region (regulatory gene region) [42]. Analyses of the activity of the IL-5Rα promoter constructs in various other eosinophils, myeloid, and non-myeloid cell lines indicated that the promoter was relatively myeloid and eosinophil lineage-specific in its expression [61]. While, previous study detected that, asthma in children is not associated with IL-5 Rα G-80A polymorphism. IL-5 R α G-80A polymorphism did not have any risk factor to develop asthma or increased asthma severity. IL-5 Rα G-80A polymorphism has not any impact on IL-5 levels, eosinophil count, and total serum IgE [62]. Other international previous studies mentioned interchangeable results explain the correlation between asthma and IL-5 Rα G-80A because of the existence of racial and ethnic specificities in the frequency distributions of the IL 5 receptor encoding polymorphic alleles (Figure 4) [42].

Figure 4.

Molecular location of IL-5 Rα gene. Cytogenetic location, Chr. 3p24-3p26.1.

3. Conclusion

The IL-5 C703T polymorphism could be an important risk factor for asthma in children, while IL-5Rα G80-A genotypes aren’t associated with asthma in children. The IL-5 C703T gene polymorphism in the promoter sequences may result in the altered IL-5 production that leads to altered inflammatory responses by increased absolute eosinophil count and, hence, contributes to the pathogenesis of asthma. Serum IL-5 level had a positive linear correlation with eosinophil count. IL-5 levels, absolute eosinophil count and total serum IgE were not associated with IL-5 Rα G-80A polymorphism.