The interplay between airway epithelium and the immune system – a primer for the respiratory clinician

Abstract

The respiratory epithelium is one of the primary interfaces between the body’s immune system and the external environment. This review discusses the innate and adaptive immunomodulatory effects of the respiratory epithelium, highlighting the physiologic immune responses associated with health and the disease-causing sequelae when these physiologic responses go awry. Airway macrophages, dendritic cells, and innate lymphoid cells are discussed as orchestrators of physiological and pathological innate immune responses and T cells, B cells, mast cells, and granulocytes (eosinophils and neutrophils) as orchestrators of physiologic and pathologic adaptive immune responses. The interplay between the airway epithelium and the varied immune cells as well as the interplay between these immune cells is discussed, highlighting the importance of the dose of noxious stimuli and pathogens in immune programming and the timing of their interaction with the immune cells that determine the pattern of immune responses. Although each cell type has been researched individually, this review highlights the need for simultaneous temporal investigation of immune responses from these varied cells to noxious stimuli and pathogens.

Introduction

The respiratory epithelium is one of the primary interfaces between the body’s immune system and the external environment. In addition to serving as a physical barrier to noxious stimuli and pathogens, the respiratory epithelium is a key orchestrator of innate and adaptive airway immune responses to the external environment. In this review, we discuss the immunomodulatory effects of the respiratory epithelium, highlighting the physiologic immune responses that protect and maintain health as well as the pathologic ones that cause disease.

Types of Immune responses

The immune responses are classified as “innate”, that are elicited first, after exposure to the various environmental antigens), and “adaptive”, that are programmed by the innate responses. These responses are elicited by various cells that when stimulated release pro- and/or anti-inflammatory mediators [Figure 1]. The airway macrophages, dendritic cells, and innate lymphoid cells act as orchestrators of physiological and pathological innate immune responses whereas the T cells, B cells, mast cells, and granulocytes (eosinophils and neutrophils) are orchestrators of physiologic and pathologic adaptive immune responses

Figure 1.

The figure summarizes the innate and adaptive immune cells that interact with the airway epithelium to establish airway homeostasis. Their over or under-activation and altered interaction with the airway epithelium or with each other underlies airway disease states.

A. The Innate Immune Response

A1. Pulmonary Macrophages

A.1.a. Role of Airway Macrophages in Healthy Airway Epithelial Immune Response

Pulmonary macrophages, comprised of airway and interstitial macrophages, are the cornerstone of innate immune response of the airways.¹ They are the most abundant respiratory tract immune cells during homeostasis, and serve many important functions such as:

1. clearing cellular debris from the respiratory tract,

2. maintaining pulmonary homeostasis by controlling/ balancing defense responses to outside stimuli and pathogens,

3. distinguishing the external stimuli from self through pattern recognition receptors like the Toll Like Receptors (TLRs) that are located on their cell surface,

4. clearing noxious stimuli by producing cytokines, and

5. phagocytosing apoptotic cells and processing certain pathogens for antigen presentation to cells that are part of the adaptive immune response.

Airway macrophages, the better studied of the two forms of pulmonary macrophages, are derived from fetal monocytes in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) as early as the first breath and are replenished from circulating blood monocytes.² Their high expression of integrin CD11c and low/absent expression of CD11b distinguish them from interstitial macrophages.³ Airway macrophages are traditionally categorized as M1 or M2 macrophages [Table 1]. M1 macrophages, or classically activated airway macrophages, are pro-inflammatory and produce nitric oxide and release cytokines with a T helper 1 (Th1) pattern in response to bacterial endotoxin (lipopolysaccharide (LPS)) and play an important role in defensive capabilities against intracellular pathogens.¹ M2 macrophages, or alternatively activated macrophages, produce anti-inflammatory cytokines [Table 1] or Th2 cytokines (IL-4 and IL-13), that are crucial in removing apoptotic cells and extracellular pathogens,⁴ and are associated with pro-allergic responses. Given their myriad functions, M2 macrophages are further categorized into subsets known as M2a, M2b, and M2c. M2a macrophages are vital in capturing and destroying parasites while M2b and M2c macrophages regulate the immune system and tissue remodeling, respectively.

Table 1:

Cells associated with innate immune responses: surface markers and cytokines

Cell Type	Surface Markers	Cytokines
M1 macrophage	CD11c, CD14, CD80, CD206	IL-1β, IL-6, IL-12, TNF-β, TNF-α
M2 macrophage	CD11c, CD301, CD163, CD204, CD206	IL-4, IL-10, IL-13, TGF-β
Type 1 cDC (cDC1)	CADM1, CXCR1, IRF8, CD141	Type 1 IFN, IL-12
Type 2 cDC (cDC2)	CD172a, CD1c, IRF4	TNF-α, IL-1β
Plasmacytoid DC (pDC)	MHCII, CD123, IRF8, IRF4	IFNα
ILC-1	CD45, CD49a, CD69, CXCR3	IFN-γ, TNF-α
ILC-2	CD45, CD90, CD117, CD161, CD127, CRTH2	IL-4, IL-5, IL-9 IL-13, IL-17, IL-22
ILC-3	CCR6, CD25, CD45, CD90, CD117, CD127	IL-17, IL-22

It is believed that the differentiation of macrophages into M1 or M2 phenotype depends on the burden of exposure to noxious stimuli and/or pathogens early in life (“the so-called “hygiene hypothesis”). For instance, low-dose LPS exposure promotes the M2 phenotype while high dose exposure stimulates the M1 phenotype.³ The contribution of the M1 and M2 macrophages in maintaining is specific to each subset, and it is achieved through pattern recognition receptors (e.g. C-lectin receptor, mannose receptor, and TLRs) that recognize pathogen-associated molecular patterns (PAMPs).¹ However, it is increasingly recognized that macrophages are highly responsive to airway epithelial exposures and have transcriptional regulators that can cause class switching between M1 and M2 phenotypes.³

Interstitial macrophages have been studied to a lesser degree, due to their location in the lung. They release cytokines and regulate immune functions involving allergic airway inflammation and asthma by suppressing Th2 responses. A third type of macrophages lining the luminal surface of capillaries (intravascular macrophages) have been recently described, and they are thought to mount a response against pathogens entering the lung via the blood.⁵

A.1.b. Role of Airway Macrophages in Airway Epithelial Immune Response Associated with Disease

Despite their role in protecting the lung, airway macrophages play an important role in the pathogenesis of both viral (rhinovirus, influenza, and respiratory syncytial virus (RSV)) and bacterial (Mycobacterium tuberculosis, Streptococcus pneumoniae) illnesses⁵ as well as chronic airway disease like asthma and COPD.

Acute viral infections like rhinovirus and RSV can cause severe respiratory tract disease among the very young and the elderly, as well as in those with chronic diseases like asthma, COPD, and cystic fibrosis, by disrupting the airway epithelial cell barrier⁶ and mounting an immune response. Airway macrophages are vital in the early response to rhinovirus and RSV infection by releasing type-1 interferons (IFNs) and other pro-inflammatory cytokines [Table 1]. The intensity of response depends on the temporal relationship of infection and immune response at the airway epithelial interface. The early response of the macrophages to the viral infections attenuates their response to secondary bacterial infections that follow the viral illness. The decrease in cytokine production⁷ is likely due to attenuated TLR signaling and may persist for six months post-infection.⁸ To control the inflammatory response and facilitate resolution of RSV infection, macrophages mature into the M2 phenotype.⁹ However, this “protective” response also establishes a pro-allergic airway response, particularly among those with pre-existing atopic diseases like eczema.¹⁰ Those with higher severity of viral bronchiolitis infection are the ones more predisposed to allergic airway diseases like asthma.^11,12 In other words, it appears that “health” depends on the exposure to a viral load that is sufficient to elicit the protective M1 pattern of responses but without contributing to excess activation of M2 responses. Whether such “optimum” viral load exists is still an area of intense investigation.

Airway macrophages also play an important role in the eradication of bacterial pathogens. Streptococcus pneumoniae, a frequent airway pathogen leading to community-acquired pneumonia, also leads to increase in pro-inflammatory cytokine response. Unlike the viral response with increase in M2 macrophages, infection with S. pneumoniae incites a mixed M1 and M2 macrophage phenotype. As discussed above, when S. pneumoniae infection follows a viral illness, the phagocytic response by airway macrophages is due to reduced TLR signaling. This reduction is specific to the macrophages, with no effect on TLR signaling by the airway epithelial cells.⁸

Among the chronic pulmonary infections, airway macrophages have been best investigated for their role in the immune response to mycobacterium, an intracellular bacillus. Macrophages are fundamental in helping to phagocytose M. tuberculosis. Early on, airway macrophages trigger antimicrobial defense and recruit cell types like polymorphonuclear and mononuclear leukocytes to the site of infection. Consequently, these monocytes further differentiate into macrophages and form granulomas around the infected sites.¹³ Within the granulomas, the macrophages recruit Th1 cells, which produce IFN-γ that continues to activate airway macrophages in a continued effort to eliminate this microbe and prevent the destructive effects of neutrophilic inflammation.

This discussion highlights the complex interplay between the macrophage response to infection and its role in the development of chronic non-infectious diseases like asthma. The allergic responses are not only due to the presence of the M2 macrophages. M1 macrophages have also been linked to the development of both allergic and non-allergic asthma. The former is caused by the activation of fibroblasts,³ while the latter is believed to be due to proliferation of the M1 subset and excess secretion of its associated cytokines both in the airway and in the systemic circulation, thus causing prolonged and progressive lung injury and airway remodeling.¹⁴ In summary, it appears that development of airway inflammation and its severity, following airway epithelial exposure to an infectious or non-infectious agent, is based on the balance between the macrophage subsets and the adaptive immune responses they elicit.¹⁵ It is worth noting that this inflammation can persist even after the macrophages are depleted.¹⁶

A2. Dendritic Cells

A.2.a. Role of Dendritic Cells in Healthy Airway Epithelial Immune Response

Dendritic cells (DCs) are the second cell type involved in innate lung defense and programming of downstream adaptive immune responses [Figure 1]. Projections from dendritic cells present between airway epithelial cells perform dynamic surveillance of the airway epithelium for foreign proteins and noxious stimuli.

DCs are classified into three main subtypes, two types of myeloid or conventional DCs (type 1 (cDC1) or type 2 (cDC2) and plasmacytoid DCs (pDCs)¹⁷ [Table 1]. The cDC1 subtype cells are located in the airway mucosa and vascular wall. They promote the generation of DC precursors in the bone marrow and play a vital role in antigen presentation to CD8+ T cells leading to CD8+ T cell-based cytotoxic response to a viruses.¹⁸ Lastly, in response to infectious and non-infectious exposures, they stimulate Th1 responses. The cDC1 cells also contribute to airway homeostasis by removing apoptotic cells and controlling IL-2 release and downstream Th17 immune responses.¹⁹

The cDC2 cells are found in the lamina propria, and they produce proinflammatory chemokines that recruit effector T helper cells and inflammatory cells including neutrophils.²⁰ Less is known about the transcriptional control of cDC2s, that preferentially process allergens and promote Th2 cells differentiation, and proliferation²¹ into anti-inflammatory IL-10-producing T regulatory (Tregs) cells.²² cDC2s also facilitate maintenance of the bronchial associated lymphoid tissue (BALT)(discussed under B cells below), an additional source of antigenic memory.²⁰

The pDC subtype consists of cells dispersed throughout the respiratory system, including the lung parenchyma and alveolar septa.²³ They differentiate from DC progenitors in the bone marrow. pDCs play an important role in antiviral response,²⁴ following activation of TLR-7 and contribute to resolution of inflammation by promoting Treg cell differentiation.²⁵ In contrast to the other DC subtypes, pDCs are limited in their ability to handle allergen presentation. pDCs control allergic airway responses by promoting apoptosis of Type 2 innate lymphoid cells,²⁶ and through complement subunit, C1q, which decreases eosinophilia and airway hyper-reactivity.²⁷ DCs typically migrate to the mediastinal lymph nodes (MLNs) within a day after exposure to a pathogen or allergen exposure. ²² Dectin-1 expression is essential for migration and chemokine receptor expression on DCs.²⁸ They participate in antigen presentation to T cells (probably more than the macrophages) and they also respond to cytokines/chemokines produced by the epithelium to promote Th cell function. For example, receptor expression for thymic stromal lymphopoietin (TSLP), a pro-allergic cytokine, is increased on cDC2 cells, while IL-25 receptor expression is increased in the cDC1 and pDC subsets.

A.2.b. Role of Dendritic Cells in Airway Epithelial Immune Response Associated with Disease

The role of DCs in acute and chronic pulmonary diseases has been primarily investigated in murine models, with few human studies, primarily in asthma.²⁹ For instance, in murine models of COPD, DCs initiate persistent airway inflammation in response to cigarette smoke, that progresses to airway fibrosis.³⁰ Although cDC2s are key to allergen processing, patients with allergic asthma have higher levels of cDC1s and cDC2s in the peripheral blood, induced sputum, and bronchoalveolar lavage after allergen inhalation.²⁹ Expression of CD141, a cDC1 marker, plays a role in asthma pathogenesis. cDC1s develop a Th2 phenotype in asthmatics during viral infections²². cDC2s activate both Th2 as well as Th17 immune responses.²² pDCs are more abundant in the airway lumen following allergen inhalation, with decreased IFN-α production, especially following a viral infection, like influenza²⁸. These findings emphasize the overlapping roles of these cell subsets in chronic airway disease pathogenesis and suggest that murine models may not be truly reflective of more complex airway immune responses in humans.

Moreover, with inflammation, monocytes can differentiate into monocyte-derived DCs, or moDCs. Increased moDCs were present in the lung within 48 hours of dustmite exposure³¹. Ex-vivo exposure of moDCs from patients with allergic asthma to house dustmite resulted in release of Th2-cytokines/chemokines.³² moDCs proportions in mediastinal lymph nodes directly correlated with inhaled allergen load and perpetuated Th2 immune response.³² While these studies shed light on the role of DCs in immune responses to inhaled allergens, more detailed investigation on the role of DCs in lung homeostasis as well as disease causation is needed to better define its role in an airway disease states, an area of research limited by the very low proportion of DCs in peripheral blood and lung.

A3. Innate Lymphoid Cells

A.3.a. Role of Innate Lymphoid cells in Healthy Airway Epithelial Immune Response

Innate lymphoid cells (ILCs) are the third and most recently identified cells linked with innate immune response, and include cytotoxic natural killer cells (NK cells) and non-cytotoxic ILCs [Figure 1].³³ The phenotype of non-cytotoxic ILCs overlaps extensively with T cells (detailed below) and it is only recently that they were distinguished from T cells based on their ability to process antigen without requiring processing by an antigen presenting cell. Their nomenclature still overlaps with T cells, and includes ILC1, ILC2 an ILC3 cells. There is limited understanding of their role in airway immune response. There is some evidence suggesting that the majority (up to 60%) of all ILCs in the airway are ILC-2 with ILC-1 and ILC-3 being recruited specifically in response to airway irritants.³³

A.3.b. Role of Innate Lymphoid Cells in Airway Epithelial Immune Response Associated with Disease

There is paucity of data on the role of ILCs in airway disease. ILC1s are recruited in airways both in response to viral illness, like influenza, and to airway irritants like cigarette smoke. ILC1 proportions in the airway and blood are increased in smokers and correlate with COPD development and severity.³³ Being associated with airway homeostasis, ILC2s also play a key role in allergic asthma, are enhanced by TSLP, a pro-allergic cytokine produced by epithelial cells, and facilitate Th2 cell differentiation. ILC2s also reveal plasticity with potential to convert to IFN-γ producing ILC1s in response to infections or exposure to cytokines like IL-12. Intriguingly, increased as well as decreased frequency of ILC2s have been reported in the context of severe persistent steroid resistant asthma. Similar to Th17 cells (detailed below), ILC3s have been found in the lungs following bacterial infections, leading monocyte-driven immune response to S. pneumoniae and K. pneumoniae. The production of IL-17 by ILC2s and ILC3s is associated with severe asthma, while the production of IL-22 production by ILC2s is protective against allergic airway hyper-responsiveness. These divergent results highlight the need for continued research of these cell types.

B. Cells associated with adaptive immune response

B1. T cells

B.1.a. Role of T Cells in Healthy Airway Epithelial Immune Response

CD4+ T cells or helper T (Th) cells are the primary cell associated with both cellular and humoral adaptive immune responses [Figure 1]. In addition to their central role in cellular immune response, Th cells present the processed antigen to B cells facilitating production of antigen-specific antibodies. Th cells also support the CD8+ T cell or cytotoxic T cell (CTL) response. Naive Th cells, typically found in the T cell zone of peribronchial lymph nodes, are the primary recipients of processed antigens from dendritic cells. Antigen presentation activates a cascade of intracellular events causing maturation of naive T cells into specific Th cell subsets (Th1, Th2, Th9, Th17, Th22, Tfh and Treg cells), based on their respective cytokine profile and the extent of T cell receptor (TCR) signaling [Table 2].

Table 2:

Cells associated with adaptive immune response: surface markers and cytokines

Cell Type	Surface Markers	Cytokines
Th1	CXCR3, CCR5	IFN-γ, IL-2, TNF-α
Th2	CRTH2, CCR3, CCR8	IL-4, IL-5, and IL-13
Th17	CCR4, CCR7, CD3, CD4, IL-6Rα	IL-17A, IL-17F
Th9	CD3, CD4, IL-4α	IL-9
Th22	CCR4, CCR6, CCR10, CD3, CD4, IL-6Rα	IL-21 and IL-22
Treg	CCR4, CCR7	TGF-β, IL-35 and IL-10
Tfh	CXCR5	IL-4, IL-10, IL-17A, IL-17F, IL-21, IFN-γ
Plasma cell/ memory B cell9	CXCL13, CXCR5	IL-4, IL-10, IL-21, TGF-β
Mast cell	IL-33R, TSLP-R, CD117, CD45, CD33	TNF-α, IL-4, IL-5, IL-6, IL-10, IL-13
Basophil	CCR3, CD11c, CD69	IL-4, IL-13
Eosinophil	CCR3, CD11b, CD15, CD45	IL-2, IL-3, IL-4, IL-5, IL-6, TNF-α
Neutrophil	CD15, CD44, CD45, CD49d, IL-17RA	IL-4, IL-10, IFN-γ, TNF-α, IL-1β

Th1 and Th2 cells are the two major Th cell subclasses that have been extensively investigated and are discussed to a limited extent [Table 2].³⁴ The Th1 cells produce IFN-γ that trigger CTLs to mature, recognize, and destroy infected cells. Some of these CTLs persist as resident memory CD8+ T cells capable of recognizing a subsequent interaction with the same pathogen^35,36. The Th2 cells have been best investigated in the context of allergic responses. Following allergen presentation by cDC2 cells, Th2 cells produce IL-4 that causes preferential naive Th cell differentiation to Th2 cells, maturation of precursor myeloid cells to eosinophils, and recruitment of eosinophils to the airway mucosa³⁷. In addition, a subset of Th2 cells remain in the airway submucosa as resident memory Th2 cells to mount a response to subsequent exposure to the specific allergen.

Additional Th cells (Th17 cells, Th22, Th9 and Tregs cells) are involved in airway epithelial immune response regulating or suppressing other immune system cells.³⁴ Th17 cells coregulate IL-21, and IL-22, produced by Th22 cells, Th9 cells, and Tregs play a role in regulating or suppressing other immune system cells.³⁴ Th17 cells contribute to airway immune homeostasis by controlling epithelial cell response to extracellular pathogens.³⁸ Less is known about Th9 and Th22 cells. While Th22 promote Th17 cell function, Th9 cells play a role in pro-allergic responses. Tregs are abundant in the lamina propria, and they function as Th cell “police”, keeping all forms of Th cells in check and thereby controlling all patterns of Th cell-mediated inflammation. Lastly, T follicular helper (Tfh) cells, found within germinal centers in lymph nodes and lymphoid organs, interact with B cells, specifically promoting anti-viral responses.

B.1.b. Role of T Cells in Airway Epithelial Immune Response Associated with Disease

Th cells are the facilitators of cellular and humoral immune response, especially against viral pathogens such as influenza and RSV. Following influenza infection, Th1 cells are recruited to the lung to release cytokines (IFN-γ) while they simultaneously provoke a CTL response to eradicate cells infected with the virus ,^39-41 while they simultaneously prevent Th2 cell migration into the respiratory tract.⁴² In contrast, RSV inhibits Th1 responses while promoting Th2 response, which are associated with attenuated type I and type III IFN responses and are major contributors to the development of allergic airway disease.³⁶ As with other infections, Tregs are crucial in reducing airway inflammation following RSV infection.⁴³

In chronic airway diseases like asthma, T cell-mediated inflammatory responses are major contributors to the pathogenesis of disease development and exacerbations. Asthma is due to an imbalance between Th1 and Th2 immune responses, with increased Th2 cytokines, with elevated IgE levels and eosinophils in systemic circulation.^37,44 In keeping with the mutually inhibitory relationship between Th1 and Th2 cytokines, the hygiene hypothesis, which supports the importance of exposure to pathogens early in life, postulates that allergic asthma development is due to reduced Th1 cytokine production in childhood due to fewer infections. However, recent studies have found a complex interaction between Th1 and Th2 responses in influenza infection, which augments acute Th1 response but plays a role in modulating Th2-mediated asthma by modifying dendritic cell function in the airway.⁴⁵ In a subset of asthmatics, these T cell responses interact with subsequent viral illnesses, such as rhinovirus, to augment existent Th2 and IgE responses, resulting in augmented IgE-mediated airway hyperreactivity.⁴⁶ Although Th17 cells are best studied for their role in promoting neutrophilic response to epithelial exposure to bacterial pathogens (e.g. Streptococcus, Klebsiella, and Pseudomonas sp.), there is increased recognition of the role of Th17 cells in both neutrophilic asthma and COPD,^47-50 while simultaneously highlighting the importance of the balance between T regulatory cells and Th17 cells. Th22 cells contribute to severity of multi-drug resistant TB infection,⁵¹ as well pro-fibrotic effects found in auto-immune diseases but have not been associated with allergic or non-allergic airway diseases. IL-9, on the other hand, is not only associated with pulmonary responses to intracellular pathogens such as chlamydia, but is also postulated to augment Th2 responses.⁵² The complex interactions between these Th cell subsets highlight the need for their simultaneous investigation to better define patterns associated with acute and chronic airway diseases.

B2. B cells

B.2.a. Role of B Cells in Healthy Airway Epithelial Immune Response

B cells in the airway are important effector cells for a healthy immune response by producing antibodies, including IgM, IgG, IgE and IgA [Figure 1]. B cell development is tightly regulated and involves common lymphoid progenitor cells that mature into pro- and pre-B cells, which then enter the spleen to become mature B cells. The majority of mature B cells in systemic circulation are follicular B cells and marginal zone B cells, which can differentiate into Ig-secreting plasma cells, in response to antigen presentation from dendritic cells or effector T cells [Table 2].⁵³

Within the lung, plasma cells are located in the airway submucosa and secrete IgA and IgM in the airway lumen for mucosal humoral response, while memory B cells in the peribronchial regions stimulate secondary immune responses with IgG production to re-infection with a previously identified pathogen.⁵⁴ Naïve B cells circulate through the lung and migrate to lymphoid follicles to mature into plasma cells, or to pulmonary lymph node germinal centers to mature into memory B cells, in response to antigen presentation by macrophages, dendritic cells or effector T cells.⁵⁵ Similar to macrophages and dendritic cells, the antigen load determines B cell maturation. High antigen load facilitates formation of plasma cells that produce high-affinity immunoglobulins as well as increase expression of high-affinity B cell receptors (BCRs) on memory B cells.⁵⁶ The antibodies mature as clonal B cell expansion occurs in the germinal centers, and Tfh cells assist in the selection and class switching of B cells within the germinal centers through the production of IL-21 and IL-4.⁵⁷ Subsequent antigen exposure to plasma cells or memory B cells is associated with release of high-affinity immunoglobulins within the lymph nodes and production of cytokines, which assist in production of other immunoglobulin subtypes.⁵⁸ In response to lower allergen load, B cells continue to recirculate through the germinal center.⁵³

B cells may also be activated via a T cell-independent process. Some microbial antigens bind to TLRs found on B cells or some microbes cause cross linking of the BCR that continues through a signaling process involving Bruton’s tyrosine kinase. This activation process stimulates extra-follicular PCs to produce immunoglobulins and cytokines.⁵⁹

B.2.b. Role of B Cells in Airway Epithelial Immune Response Associated with Disease

B cells are an integral part of the bronchus-associated lymphoid tissue (BALT), which is formed in response to viral infections, as well as a result of autoimmune disorders and in response to environmental irritants like tobacco smoke. The BALT areas are structurally comparable to lymph nodes with presence of antigen-presenting cells, germinal center B cells and follicular dendritic cells.⁶⁰ During an acute viral infection, the Tfh produce IFN-γ in the germinal center, the leads to the production of high-affinity IgG2 by B cells. These B cells subsequently enter BALT sites and reside as memory B cells to be recruited in response to reinfection.⁶¹

Although B cells play a key role in IgE production, they have been studied to a limited extent in chronic airway diseases like asthma. With chronic lung inflammation, naive B cells migrate to the lung as a result of lung epithelial cells expressing specific chemokines.⁵³ B cells can also produce IL-10, and thereby attenuate airway hyper-reactivity.⁶² COPD, as a complication of smoke exposure, is associated with increased memory B cells and plasma cells,⁶³ and B cell infiltration correlated with disease severity. Although these studies have begun to identify key roles for B cells in airway pathology, more detailed investigations are needed to identify therapeutic targets for this cell population.

B3. Granulocytes

Role of Mast cells, Basophils, Eosinophils and Neutrophils in Airway Epithelial Immune Response Associated with Disease

Granulocytes are cell populations that are effector cells for a protective immune response but can also cause airway epithelial damage [Figure 1][Table 2]. The mast cells play an important role in the pathophysiology of conditions like asthma. They produce IgE, as well as type 2 cytokines in response to cytokines like TSLP and IL-33 secreted by the activated airway epithelial cell.⁶⁴ Cytokines, such as IL-3, IL-4, and IL-6, contribute to survival and proliferation of mast cells, while transforming growth factor-β has an inhibitory effect. Basophils are similar to mast cells in both function and phenotype and promote a Th2 immune response in the airway [Table 2]. IL-3 plays an important role in the survival and development of basophils.⁶⁵. Eosinophils have been better investigated in the context of allergic airway diseases. They are recruited to the airway, in response to Th2 cytokines, and perpetuate allergic inflammation by releasing substances, such as major basic protein. IL-33, produced by the airway epithelial cell, causes eosinophil activation, but further studies are needed to determine the mechanism that underlies eosinophilic airway inflammation following viral illness.⁶⁴

Neutrophils also contribute to the pathogenesis of chronic airway disease states such as asthma and COPD [Table 1]. Neutrophils respond very early in the course of an infection (bacterial and viral) and lead to a post-viral airway disease state.⁶⁴ In asthma, increased number of neutrophils are associated with elevated levels of IL-17, whereas IL-17 receptor blockade is associated with a decrease in neutrophils.⁶⁶ Although it has been difficult to distinguish patients with IL-17-mediated asthma, there is a subset of severe asthmatics and patients with COPD that consistently have sputum neutrophilia during exacerbations. These studies suggest that these granulocytes are excellent drug targets for attenuation of airway inflammation. While medications have been developed against the eosinophil, there is limited research on modulation of neutrophilic responses, for which more precise therapeutics is needed to target those with non-allergic IL-17 mediated chronic airway disease.⁶⁷

Conclusion

In summary, there is a continuous and complex interaction between the airway epithelium and the airway innate and adaptive immune responses. It is important to note that most or all of these cell populations have properties that can be protective or damaging to the airway epithelium. What the outcome of every exposure will be depends on the interplay and balance between all these cell subtypes.

Educational Aims.

The reader will be able to appreciate:

1. The airway epithelium interacts closely and dynamically with cells involved in innate and adaptive immune responses to maintain airway homeostasis

2. Macrophages are the most abundant of innate immune cells in the airway epithelium that contribute to airway homeostasis by distinguishing self from foreign antigens, phagocytosing apoptotic cells and pathogens, and releasing cytokines in response to a noxious stimulus.

3. Dendritic and innate lymphoid cells are the other two innate immune cells associated with normal airway defense, that play a key role in programing T cells to antigens and noxious stimuli.

4. T and B cells are key players in airway adaptive immune responses. T cells mediate cellular immune responses, that include cytokine release, such as interferons in the context of pathogen exposure, and program B cells, that reside in bronchus-associated lymphoid tissue, as memory B cells to ensure timely response to repeat exposure to the antigen.

5. Airway homeostasis is dependent on the antigen load that is sufficient to elicit the protective pattern of responses without contributing to excess activation of anti-inflammatory responses, which overlap with pro-allergic responses. Whether such an “optimum” antigen load exists is still an area of intense investigation.