The Immunological Basis of Asthma & Its Treatments

Introduction

Asthma is a chronic inflammatory lung disease characterised by variable, reversible airway obstruction and recurrent episodes of breathlessness or wheezing. Both the causes of the disease and the cellular machinations at play are complex, numerous and incompletely understood.

In defining the underlying cause of asthma it is necessary to understand that it is a multifactorial disease in which a complex interplay between a multitude of cells (immune and otherwise) and soluble mediators with influence from environmental and genetic factors all coalesce to bring about a variety of symptoms which can then vary between individuals.

Approximately 300 million people suffer from asthma worldwide1, and it is an increasingly common malady in the Western world. Asthma significantly burdens individuals, populations and healthcare systems despite effective and often readily available treatments. Effective prevention and treatment of asthma will require a fuller, more robust understanding of the epidemiology and immunology of the condition to be efficacious enough to truly address the burden of such a prevalent disorder.

This dissertation aims to outline the causal factors involved in the development of asthma, to detail the most important immunological mediators involved in the condition and to discuss the immunological impact of current treatments for asthma, with a view to how developing the current understanding may inform new, more specific treatments in the future.

 

Causes of Asthma

The causes of asthma (Fig.1) can be divided into: the fundamental determinants of atopy, the causal factors which facilitate the development of asthma in those predisposed by atopy and finally the trigger factors (many of which are also causal) that instigate an exacerbation of asthma symptoms or an asthmatic attack.

Myriad factors including: obesity2 (as quantified by BMI), air pollution3, exposure to common allergens (such as pets4or house dust mites5), housing6 respiratory infection7 and smoking8 are known to increase the incidence of asthma or to worsen the severity of the existing condition.

 

Figure.1 – Causes and influences on the development of asthma

Figure 1 shows how predetermined factors such as sex and genetics can serve as predisposing factors and then, with a contribution from environmental variables (causal factors) can bring about the asthmatic state.

Trigger factors are those influences which induce an asthma attack. These factors are numerous and their effects can vary greatly both between and within individuals. A single person’s response to certain stimuli may change over time or in the absence of other trigger factors which modify/exacerbate the response.

Causal Factors: qualifying importance

Obesity has a definite correlation with asthma incidence; however the causative role it plays is uncertain9 and the mechanisms it acts through are speculative10. It has been observed that weight gain is detrimental for asthma control11 and vice versa for weight loss12, but understanding the true contribution of obesity requires further study13.

Asthma attacks themselves have been observed to beget subsequent attacks14, making them a useful clinical predictor for asthma exacerbations along with excessive or incorrect use of short acting beta 2 agonists15.

The effect of smoking on the course of asthma progression and the effectiveness of treatments is pronounced. Clinical measures of severe asthma and related healthcare outcomes are markedly worse in smokers as compared to non-smokers and past smokers16. Similarly, smokers have more rapidly degenerating lung function and poorer asthma control as compared to non-smokers17.

An additional worrying consequence of smoking for asthmatics is that they exhibit increased insensitivity to the action of short term corticosteroids18.  Considering that these drugs are currently the most prevalent and most effective treatment for asthma, addressing this issue will be an important step in asthma treatment, especially considering the known benefits of smoking cessation as it applies to asthma sufferers19.

Viral infections early in life have been shown to influence the later development of asthma in children predisposed by atopy20. Furthermore, viral infections (particularly rhinovirus21) are known to be one of the most prominent causes of exacerbations in younger children22. While preventing early life infection may be a worthwhile avenue to explore23, certain children may be predisposed to respiratory infection by a damaged epithelium24, having for example tight junctions which are permeable and this phenomenon requires further research and understanding.

Suffice to say, the causal factors at play in asthma constitute a complex epidemiological issue which is not yet fully understood and requires further research in order to achieve better preventive interventions.

The Immune Cells Involved in Asthma

TH2 cells

TH2 cells can be seen as the conductor of the immune response in asthma. Rather than being effectors, they participate by directing the action of other cells via the release of cytokines.

The soluble mediators released by TH2 cells in the context of asthma include IL-4, IL-5, IL-9 and  IL-1325 (Table.1). IL- 4 & IL-13 bind IL-4R and while both are capable of inducing structural changes and airway hyper responsiveness, IL-13 plays a more significant role in this regard26 than IL-4 which is primarily responsible for propagating TH2 polarisation by acting on STAT6, maintaining TH2 prevalence, increased eosinophil presence in tissues, triggering B cell class switching to IgE and the differentiation of M2 macrophages.

While TH2 cells are important sources of IL-4 & IL-13, it would appear that they are not the exclusive producers of these cytokines in asthma. Experimental data27 suggest that airway epithelial cells detecting cysteine residues by PARs (protease activated receptors) and endotoxins by PRRs (pattern recognition receptors) respectively can secrete IL-25 and IL-33.  These cytokines bind the IL-25 and IL-33 receptors on so called “innate helper cells” (also known as ILC2s), activating them and instigating the production of IL-4 and IL-1328; providing an alternate route of TH2 inflammation in the absence of TH2 cells.

It is also suggested that these innate lymphocytes can produce IL-4, IL-5 and IL-13 in response to leukotriene D₄ binding CysLT1R29. This same study found that IL-4 release could be induced by leukotriene D₄ without the need for IL-33.

Considering the role of TH2 cells in the pathogenesis of asthma, therapies which target them are of particular interest. Montelukast appears to inhibit the proliferation of TH2 cells and to limit their viability to some degree30. Steroids such as fluticasone31and dexamethasone32 have pro-apoptotic effects on activated and allergen specific T cells.

However, it is also suggested that even where high dose steroids effectively reduce the TH2 mediators of inflammation, this is insufficient in mitigating the condition in the cases wherein other, non TH2 derived or otherwise steroid resistant factors are at play – such as in paediatric severe therapy resistant asthma33 (STRA).

These examples demonstrate the need to view TH2 cells as one part of a greater aberrant immune response.  While classically seen as the primary immune cell involved in asthma, current understanding of the condition has moved towards a broader view which encompasses a number of cells and their interactions as being important factors.

Table 1

Cytokine Contributions to asthma
IL-4 B-cell switch to IgE synthesis, Mast cell development, Eosinophil and Basophil activation, mucus, secretion, favours TH2 production, increased Endothelial VCAM expression, AHR.
IL-5 Eosinophil/ Basophil differentiation, maturation, and activation.
IL-9 Mast cell and Eosinophil development, AHR, mucus secretion, Mastocytosis.
IL-13 Mast cell development, B-cell switch to IgE production, eosinophilia, AHR, mucus hypersecretion.

 

Summary of TH2 derived cytokine contribution to asthma

Airway hyperresponsiveness (AHR).

Adapted from Larche et al 200234 & Finkelman et al 201035

Eosinophils

Eosinophils are secretory granulocytes which normally reside in the gastrointestinal tract. Their presence in the lung is abnormal and indicative feature of asthma. Eosinophil recruitment to the lung is largely achieved by the combinatorial action36 of TH2 derived IL-5 and the eotaxin protein family, which act by binding to CCR-3 on eosinophils. IL-4 and IL-13 are the initial trigger for the release of a myriad of chemokines by respiratory epithelial cells37, such as CCL13 (otherwise known as eotaxin-1) which draw eosinophils to the lung by chemotaxis.

IL-5 supplied by TH2 and mast cells acts to release mature eosinphils and eosinophil precursors from the bone marrow. This is important not just in recruitment but also for activation, proliferation, maturation and maintenance of eosinophils.

Thus, IL-5 is a pivotal mediator of eosinophil function, its role in recruitment is as a synergistic factor, colluding with other cytokines and chemokines (e.g. IL-4 & IL-13 or eotaxin 2) to aid in drawing eosinophils to the lung and then to perpetuate their activity38.

The absence of IL-5 has been demonstrated with knockout mouse models39 to abolish the AHR and eosinophilia which would normally result from aeroallergen exposure, thus demonstrating its central role in eosinophil function and by extension the role of eosinophils in asthma pathogenesis. Furthermore, IL-5 contributes to the ongoing action of eosinophils by delaying their apoptosis and enhancing their phagocytic ability via stimulating the release of superoxide.

Adhesion to the endothelium is initiated by the binding of PSGL-1 with P-selectin, beginning the process of rolling adhesion and allowing eosinophil contact with the integrin VCAM-1, which interacts with VLA-4 causing firm adhesion and enabling the cell to extravasate into tissue40.

Both the cytokines eotaxin and RANTES (regulated upon activation normal T cell expressed and secreted) act on the VLA-4 integrin, improving eosinophil migration to tissue and facilitating degranulation41.  Additional chemotactic factors also come into play, including the C3a/C5a complement proteins42, mast cell derived eosinophil chemotactic factor of asthma (ECF-A) and histamine.

Eosinophils affect the body’s reaction to allergen informing the actions of structural cells (Fig.2) as well as immune cells (Fig.3). Figure 4 visualises some of the structural changes imposed on the asthmatic airways by chronic inflammation. Eosinophil effector function can be attributed to the release of mediators broadly divided into those which are preformed and those which are synthesised upon activation.

Eosinophils play a complex, multifaceted role in the development of asthma – modulating the function of both immune cells and structural cells as well as providing positive feedback for other eosinophils directly through the production of cytokines (e.g. IL-5) or indirectly by acting through other cells.

Figure.2 Action of eosinophils on structural tissue –

The preformed mediators released by eosinophils consist of 4 highly toxic arginine rich proteins: major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO) and eosinophil derived neurotoxin (EDN). MBP and ECP damage the airway epithelium resulting in AHR, and induce the expression of a number of remodelling factors43.

EPO assists in the generation of reactive oxygen by catalysing the oxidation of nitric oxide while EDN can both induce DC migration as well as enhance TH2 polarisation by MyD88 dependent activity44.

The cysteinyl leukotrienes LTC4, LTD4 and LTE4 are synthesised mediators, causing increased vascular permeability, mucus secretion and extended bronchial constrictions45.

Eosinophils contribute to fibrosis through their production of TGF-β46, IL-4 and IL-13 47, 48.

Figure.3 Action of eosinophils on immune cells –

Eosinophils, rather than being purely end stage effector cells have a number of roles in directing other cells of the innate and adaptive response49.

By using MHCII, CD80 and CD86, eosinophils act as APCs for CD4+T cells, abetting the production of TH2 cytokines crucial for eosinophil function. Eosinophils also promote TH2 polarisation by the production of indoleamine 2,3-dioxygenase (IDO) which by converting tryptophan to kynurenines (KYN) acts to induce TH1 apoptosis therefore biasing the T cell response towards TH2 cells50. TH2 cells then inhibit the production of TH1 cells by acting on T-bet through the STAT4 pathway51.

EDN acts on the (TLR) 2–MyD88 signalling pathway, causing the migration and maturation of myeloid DCs52.

Once recruited to the lung, DC’s can undertake a number of roles in disease progression, such as producing IL-8 & eotaxin to further eosinophilic damage, signalling other DC’s to mature and proliferate and aiding TH2 polarisation53.

MBP has been demonstrated to increase the production of superoxide anion (O2) by neutrophils54, possibly furthering another source of epithelial damage.

Finally, MBP, ECP and EPX trigger mast cell degranulation55,56 . As such the subsequent release of histamine, PGD2, IL-4, IL-5, IL-1357 and the cysteinyl leukotrienes LTC4, LTD4 and LTE4 is partly attributable to eosinophils.

Figure.4 Comparison of asthmatic and normal lung structure –

This image compares sections of airways from a normal (left) and severely asthmatic (right) patient, clearly demonstrating pronounced smooth muscle (Sm) hypertrophy and basement membrane (Bm) thickening. Epithelium (Ep), Blood vessel (Bv).

Figure originally published by Wadsworth et al58 2012.

Mast cells

Mast cells are tissue resident, densely granulated cells predominately found in areas of the body which interface with the exterior. They serve, upon activation by allergen binding to surface IgE antibody59 to innervate the immune system by utilising soluble mediators – histamine in particular – which are rapidly released from cytoplasmic granules.

Histamine can act on TH2 cells to either promote or inhibit the production of IL-4 and Il-1360, depending on the cells receptor expression. Histamine also has a role in T cell recruitment as the T cells of mice deficient in the histamine receptor H1 have been observed to be unable to migrate to the lung61.

Like eosinophils, mast cells release preformed and synthesised mediators which marshal both immune cells and structural cells. They are central to the allergic inflammation seen in asthma, and the diverse range of mediators they release have the potential to act on all cells, structural (Fig.5) and immunological (Fig.6).

Figure.5 Mast cell interaction with structural tissue

Mast cells can be identified by the high affinity FCεRI bound to their surface, expression of the KIT (CD117) receptor for stem cell factor (SCF).

SCF provided by the epithelium binds KIT on mast cells62, which is essential not only in triggering degranulation63 but also: in the initial differentiation of mast cells from CD34+ progenitors in the bone marrow62; in preventing apoptosis by acting on the transcription factor FOXO3a, thus lowering the output of the pro apoptotic Bim protein64; and in recruiting further mast cells to the tissue65, 66.

Mast cells stimulate fibroblast proliferation via histamine67, TGF-β and follicular growth factors  (FGF) 68.The proinflammatory cytokine TNF-α has recently been shown to induce bronchial hyperresponsiveness69 and is more prevalent in cases of severe asthma, suggesting a prominent deleterious role.

The increased vascular permeability mediated by heparin could facilitate the entry of leukocytes into the airway giving mast cells a role in recruitment through their actions on structural tissue.

Figure.6 Mast cell interaction with immune cells

TNF-α appears to aid the migration of T cells indirectly by increasing expression of the adhesion molecules VCAM-1 and ICAM-1 on airway smooth muscle cells70.

B cells are induced to class switch to producing IgE Ab by TH2 derived cytokines and then supply mast cells with this immunoglobulin. IL-4 and exposure to IgE Ab causes the mast cell to upregulate its expression of FCεRI. IL-4 and IL-9 supplied by TH2 cells are also crucial for mast cell development71.

Mast cells contribute to eosinophilic inflammation by producing IL-3 and IL-5, essential eosinophil cytokines. IL-8 is chemotactic for neutrophils, and is produced by mast cells after interacting with TH2 cells72. Mast cells also contribute to neutrophil recruitment by producing IL-8 and TNF-α73.

Mast cells produce thymic stromal lymphopoietin (TSLP), which assists in the maturation of DCs and their presentation to naïve T cells. DCs activated in this manner generate a TH2 biased response, partly due to a decreased production of TH1 promoting IL-12 and partly due to OX40L signalling – both of which are caused by TSLP exposure74

 

Dendritic cells

DCs are important in the initial induction of the asthma phenotype due to their presentation of allergen to naïve T cells. DCs have a demonstrable role in asthma pathogenesis, increasing in number in the airways and worsening existing asthma75.

DCs have been implicated in presenting inhaled allergen encountered in the bronchial alveolar lavage compartment to naïve T cells in the mediastinal lymph nodes and driving their polarisation to the TH2 phenotype76 (Fig.7) – thus playing a role in TH2 dependent eosinophilia. DCs which mature in response to TSLP stimulate the development of TH2 cells which produce the inflammatory cytokines IL-4, IL-5, IL-13 and TNF-α but crucially do not generate immunomodulatory IL-10 – making them potent drivers of allergic inflammation77. DCs then stimulate mediator release from effector T cells which have entered the lung.

Additionally, PDE278 and PGD279 received from mast cells can assist the DC in driving TH2 responses by upregulating the release of TH2 chemokines (CCL17 & CCL22) and suppressing IL-12 respectively. Thus, DCs are crucial in the sensitisation to inhaled allergens, in the initial instigation of the allergic immune response in asthma and in perpetuating the ongoing action of effector T cells in the lung.

Figure.7 DC Ag presentation and interaction with T cells –

A mucosal DC network lays beneath the basement membrane of the lung epithelium80, providing a site for the sampling of airway derived antigen. When an immature DC in this network encounters an allergen (e.g. house dust mite allergen81) they mature into a presenting state, process and load the allergen onto MHC-II and migrate to the mediastinal lymph node where this allergen is presented to the repertoire of naïve T cells resident in the T cell area.

The probable cause of DC driven TH2 polarisation is the accompanying signals of programmed death ligand 1 (PDL-1), CD86 and IL-1082 which are presented to naïve T cells along with the processed allergen.

Effector and memory cells arise from this presentation then move to the lungs and spleen respectively. Mature effector TH2 cells are attracted to the lung by DC secreted CCL-17, which selectively binds CCR4 on these cells83. The importance of the CCR4/CCL-17 mechanism is demonstrated by recent experiments which concluded that selectively eliminating CCR4 positive cells resulted in attenuated inflammation in the lungs and a decrease in TH2 derived cytokines84.

Basophils

The role of basophils in asthma is unclear. They are recruited to the lung during allergen sensitisation and can produce IL-485, IL-1386 and histamine, though their actual contribution to the asthmatic phenotype has not been qualified87.  Basophils are likely to provide an additional source of IL-4 and IL-13 to B cells, aiding their class switching to IgE.

B cells

B cells contribute to asthma by producing IgE antibody, which triggers the degranulation of mast cells and so B cells can be viewed as an essential step in all subsequent effects mediated by mast cells.

B cells switch affinity from IgM to IgE by interacting with CD40L on TH2 or mast cells in combination with IL-4 and IL-13 supplied by TH2 cells88.  This immunoglobulin is then able to innervate the degranulation of mast cells. B cells appear to be able to secrete IgE locally in the lung89 

Treatments for Asthma

Asthma treatments are broadly divided into “controllers” (Table 2) – anti-inflammatory treatments used continuously in the long term – and relievers (Table 3), which are used intermittently to provide rapid relief of bronchoconstriction. Inhaled corticosteroids (ICS) are the most prevalent, most effective controller treatment for persistent asthma; though they must often be paired with complementary types of controller medication to achieve optimal asthma control.

Reliever medications on the other hand are used infrequently to redress bronchoconstriction when it arises. Short acting β2 agonists (SABAs) bind the β2 adrenergic receptors on smooth muscle cells, causing smooth muscle relaxation in the lower airways by cyclic adenosine monophosphate (cAMP) mediated activation of protein kinase A and phosphorylation of muscle regulatory proteins90. Thus they have structural, rather than immunological effects

Table 2 – Summary of Controller Medication in Asthma

Treatment Examples Immunological action
Inhaled Corticosteroids Beclometasone dipropionate,

Fluticasone propionate/furoate91

Budesonide92

Mometasone

Eosinophil apoptosis, decreased numbers of mast cells & DCs93, decreased migration of inflammatory cells, increased expression of anti-inflammatory mediators.
Mast Cell Stabilisers Sodium cromoglicate,

Nedocromil sodium

May prevent mast cell degranulation. Weak anti-inflammatory effect.
Leukotriene Modifiers Montelukast94

Zileuton95

Alters the action of cysteinyl leukotrienes by antagonising their receptor or inhibiting 5-lipoxygenase conversion of arachidonic acid in mast cells and eosinophils.
Long-Acting Bronchodilators Formoterol96

Salmeterol97

 

NA – Structural action to reverse bronchoconstriction.
Monoclonal Ab Therapy Omalizumab98

Mepolizumab

Lowers circulating serum then airway IgE count, decreases number of eosinophils and reduces mast cell activation.

 

Blocks binding of IL-5 to receptor, reduces exacerbation in eosinophil driven, ICS resistant severe asthma99.

 

Summary of common classes of asthma controller treatments with example drugs and their effects on the immune system.

Table 3 – Summary of Preventer Medication in Asthma

Treatment Examples Immunological action
Short-Acting Bronchodilators Salbutamol,

Terbutaline

 

NA – Structural action to reverse bronchoconstriction.
Oral Corticosteroids Prednisolone100 Reduction in T cell & Ab numbers, diminished cytokine release, likely diminished resistance to respiratory infection101.
Theophylline Theophylline tablets102

Combination inhaler with Formoterol

Anti-inflammatory action by suppressing pro-inflammatory genes103.
Anticholinergics Ipratropium bromide104

Oxitropium bromide

NA – Structural action to reverse bronchoconstriction.

 

Summary of common classes of asthma preventer treatments with example drugs and their effects on the immune system.

Conventional corticosteroid treatments impact immune cells

While immunologically nonspecific, ICS have general effects on the immune system, tempering inflammation105 and interrupting the migration of lymphocytes to the lung. By binding glucocorticoid receptors on lung epithelial tissue, ICS can alter gene transcription of inflammatory mediators and inhibit the migration of inflammatory cells to the lung.

ICS such as budesonide can inhibit cytokine induced upregulation of adhesion molecules106      (ICAM-1 & VCAM-1), which are critical components of T cell107 and eosinophil108 trafficking.          Oral corticosteroids reduce the number of T cells and eosinophils, as well as cells expressing IL-4 and IL-5 mRNA109.

Some evidence exists that ICS may be able to restore the function of Treg cells which are impaired in asthmatics – implying that some amount of their anti-inflammatory effect may be attributable to the reinstated suppressive action of these cells110.

Inhaled corticosteroids are mostly safe, but leave many patients with improperly controlled symptoms111. As broad treatments, ICS provide worthwhile symptomatic relief, however a safer, more specific alternative is required.

Monoclonal Antibodies

One such example of a more specific asthma treatment comes in the form of monoclonal antibodies. Omalizumab lowers free IgE levels by binding the Abs Fc region112 which would normally bind FCεRI on the surface of mast cells and facilitate their degranulation.

Omalizumab has been shown to be capable of reducing free IgE and sputum eosinophil numbers113 as well as down regulating FCεRI expression on mast cells114 and DCs115. In practice, Omalizumab has demonstrated clinical use, reduced asthma related hospitalisations116 and improves quality of life117.

Another monoclonal Ab, mepolizumab, blocks IL-5 receptor binding thereby lowering eosinophil numbers118.  Like Omalizumab, it appears to be a safe, viable treatment in particular types of asthma119. These drugs serve as examples of the benefits of targeting treatments based on asthma pathology and the necessity for improved understanding of new targets going forward120.

Novel treatments, allergen immunotherapy, addressing the root cause of allergy

A number of new treatments target components of asthma pathophysiology to better manage the disease. The eosinophil inhibitor TPI-ASM8 blocks CCR3 and uses a common β chain antagonist to target granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, and IL-5. Limiting several crucial eosinophil development and recruitment factors all at once121 aids the mitigation of eosinophilic inflammation.

Mast cell degranulation is clearly an essential component of asthma, and preventing this has therapeutic benefit. Cromones, so called mast cell stabilisers, have a poorly understood mechanism of action, the duration of which is too short to be suitable as a controller medication. Elucidating this mechanism may present a useful new innovation in drug design122.

The surgical approach, in the case of bronchial thermoplasty appears to benefit patients with severe asthma123. This procedure uses heat to remove some of the excess smooth muscle from the airways, resulting in fewer asthma attacks and hospitalisations.

Allergen immunotherapy can correct the aberrant immune response on a more fundamental level than current treatments. Exposure to allergens such as house dust mite124 and animal dander125 via injected or sublingual routes has proven efficacy in treating hypersensitivity and in preventing the progression of allergic rhinitis to asthma, with both routes of administration seeming viable126.

The immunological underpinnings of allergen immunotherapy have yet to be clearly defined. Two likely explanations are that a TH1 (rather than TH2) response is promoted, or that an induction of Treg cells results in a tolerogenic effect mediated by IL-10 and other cytokines leading to mitigated inflammation127. Allergen immunotherapy is a promising new avenue for a curative asthma intervention, however at this early stage, a great deal of research and development is still required before such an innovation can be realised.

 

Concluding thoughts

Asthma, while an important cause of death in the developed world has a pronounced morbidity impact for afflicted individuals and the healthcare systems which support them. Asthma treatments, while effective are not full proof and must be taken regularly throughout life. Many asthma patients must live with inadequately controlled symptoms and the burden of asthma remains high for the individual128. As asthma becomes increasingly prevalent, the need for better treatments becomes more pressing.

Treating asthma in the future will require developing our knowledge of the condition, targeting treatments to make them more efficient and addressing the underlying causes and exacerbating factors on a population level. While an outright cure for the disease is unlikely to be found in the near future, a multitude of novel treatments utilise the current understanding of asthma to provide a chance for new tailored interventions which may be able to enhance or supplant current useful yet imperfect therapies.

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Figures

AsthmaVSNormalAirwayThe Etiology of AsthmaCausal Factors in Asthma developmentDC interaction with T cellsEosinophil in immune directionEosinophil in structureMast cell interaction with immune cellsMast cells interactions in structural tissue

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