Adaptive Immunity of Airway
Inflammation in Asthma
Cameron H. Flayer, Sarah S. Killingbeck,
Erik Larson, Zoulfia Allakhverdi,
and Angela Haczku
Abstract
Respiratory immunity is responsible for
pathogen elimination and prevention of
chronic inflammation through both innate and
adaptive mechanisms. Inappropriate activation
of these immune systems in the respiratory
mucosa results in chronic inflammatory
airways disease such as asthma. Adaptive
immunity is stimulated for example by
allergen exposure that activates T and B
lymphocytes leading to IgE production and
influx of eosinophilic granulocytes into the
airways. Presence of IgE and eosinophilia are
diagnostic hallmarks as well as key pathogenic
components that have been utilized in the
search for improved therapies of allergic
asthma for the past several decades. The recent
breakthroughs in successful clinical
application of biologicals in asthma were
driven by improved genetic, biochemical, and
immunological screening methods, novel
imaging and bioinformatics technology,
biomarker discovery and a better understanding
of immune regulation of allergic airway
C. H. Flayer · S. S. Killingbeck · E. Larson
A. Haczku (*)
School of Medicine, University of California at
Davis, Davis, CA, USA
e-mail: haczku@ucdavis.edu
Z. Allakhverdi
The Research Institute of the McGill University
Health Centre, Montreal, Québec, CA
© Springer International Publishing AG, part of Springer Nature 2018
C. Riccardi et al. (eds.), Immunopharmacology and Inflammation,
https://doi.org/10.1007/978-3-319-77658-3_3
inflammation. In this chapter we discuss our
current understanding of immune regulation
of airway inflammation in asthma, with a spe-
cial focus on the interactions between the
adaptive and innate immune systems and the
epithelial mucosal tissue.
Keywords
Asthma · Epithelial cells · Immune homeosta-
sis · Pattern recognition · Host defense
1 Introduction
The history of discovering the importance of the
adaptive immune regulation of asthma started
with John Bostock’s description of hay fever as
being an allergic disease affecting the upper air-
ways, in 1819 [1]. It took almost a century how-
ever to realize that cellular/humoral immune
pathways are involved in development of the
allergic condition. In 1906, Clemens von Pirquet
first described the ‘hypersensitivity’ symptoms
that some of his diphtheria patients developed
when treated with a horse serum antitoxin, and he
coined the term ‘allergy‘(From the Greek allos = 
“other” + ergon = “work”) [2, 3]. Unfortunately,
because anaphylaxis was already introduced as a
medical term by Besredka [4], Von Pirquet’s con-
cepts didn’t gain wide acceptance during his life-
time. Nonetheless, between 1911 and 1914
57
58
Leonard Noon and John Freeman were able to
establish the foundations for clinical allergy
treatment by immunotherapy or “allergy shots”
on an empirical basis [4]. It took another fifty
years until a new immunoglobulin isotype, (IgX)
was discovered by Johansson and Bennich [5]
(1967) and identified by Kimishige and Teruko
Ishizaka (at the National Jewish Center in
Denver) as the principal molecular mediator of
the allergic reaction, and was then named
IgE. How allergic responses are regulated at the
cellular level, however, was still unclear. In 1986
Tim Mosmann & Bob Coffman observed that the
“T-cell growth factor 2” (IL-4) producing T cell
clones were the same that helped IgE production
by B lymphocytes, but different from the IFN-γ
producing clones and they published the
“Th1-Th2 hypothesis” [6]. In the early 1990s, A
Barry Kay’s laboratory in London established
that atopic asthma is associated with activation of
Th2 cells, characterized by IL-4 and IL-5 but not
IFN-γ release [7]. IL-4 and IL-5 are cytokines
essential for IgE synthesis and tissue eosinophilia,
respectively. Discovering the central importance
of T cells in asthma pathogenesis explained the
phenomenal success achieved in its treatment by
the introduction of glucocorticosteroids (by
Philip Hench and Edward Kendall, in 1948).
Chronic glucocorticosteroid (steroid) treatment
of asthmatic patients, however, came with the
price of severe metabolic and immune side
effects, including global immunosuppression [8].
In addition, while steroids have been effective in
general and became the mainstay of treatment, a
significant proportion of asthmatics remained
unresponsive to treatment (steroid resistant) [9–
13]. Alternative approaches, therefore, had to be
found. Further advances in selective targeting of
the adaptive/allergic immune response were
made possible by the ability to synthesize
biologicals (monoclonal antibodies, 1975),
awarded by the 1984 Nobel prize to Kohler &
Milstein. In 2003 for adults and last year also for
children above 11  years of age, the Food and
Drug Administration (FDA) approved
Omalizumab (Xolair; Genentech/Roche and
Novartis), a non-anaphylactogenic monoclonal
antibody against IgE for the treatment of asthma.
C. H. Flayer et al.
This was followed by approval of an anti-IL-5
monoclonal antibody, Mepolizumab (Nucala,
GSK), in 2014, and the anti-IL-5R antibody
Benralizumab (Fasenra, MedImmune), the anti-­
IL-­4R antibody Dupilumab (Regeneron, Sanofi)
just last year, in 2017. The significance of a
monoclonal antibody-based treatment lies in the
capability to specifically target the major
pathogenic mechanisms (IgE production and
eosinophilic airway inflammation), while
preserving the rest of the functions of the immune
system. This long-awaited introduction of
selective biologicals to the clinic represents a
significant breakthrough in asthma treatment that
was (and continues to be) driven by better
understanding of how the antigen-driven T cell-­
dependent immune response (adaptive immunity)
is involved in regulation of asthma. T cells
normally function to eliminate infections by
certain pathogens and to activate B lymphocytes
and innate immune cells. Adaptive immunity is
based on the unique function of T cells to
recognize antigens (through their T-cell receptor)
presented by MHC bearing antigen presenting
cells (APCs) and respond in an antigen-specific
manner. Class II MHC molecules display
antigenic peptides derived from extracellular
proteins while class I MHC molecules present
peptides from cytosolic proteins to CD4 and CD8
expressing T cells, respectively. Allergy develops
because of altered T cell responses to otherwise
innocuous environmental-derived antigens.
2  ow Do Antigens Become
H
Allergens?
Allergens are diverse materials and can be defined
according to their chemical structures, by their
origins and by the route of exposure (Table  1)
[14, 15]. Generally, they have a low molecular
weight, are highly soluble, often carry
carbohydrate side chains and have various
enzymatic activities.
How do antigens become allergens is not well
understood [15, 17] but the presence of “danger”
signals, a compromised physical barrier [18, 19]
and cooperation between structural components
Table 1  Classification of the most common allergens according to origin and biological functions
Internal Enzymes (especially proteases), ligand-binding proteins or lipocalins, albumins, tropomyosins and calcium-binding proteins
tissue-derived:
Foods: Lipid transfer proteins, profilins, seed storage proteins and tropomyosins
 The FDA identified the following list as allergenic food products by law (>10 ppm) (https://www.fda.gov/Food/IngredientsPackagingLabeling/
FoodAllergens/ucm530854.htm):
  1. Milk
  2. Eggs
  3. Peanuts
   4. Tree nuts (almonds, cashews, walnuts)
   5. Fish (bass, cod, flounder)
   6. Shellfish (crab, lobster, shrimp)
  7. Soy
Adaptive Immunity of Airway Inflammation in Asthma

  8. Wheat
 Other common allergenic foods: celery and celeriac, corn or maize; fruit, pumpkin, eggplant, legumes, beans, peas, soybean milk; seafood; sesame,
pecan nuts
Animal products Fur and dander; cockroach calyx; wool
Insect stings Bee sting venom; wasp sting venom; mosquito stings
Mold spores Alternaria alternata; Aspergillus fumigatus
Plant pollens The most widespread groups of plant proteins that contain allergens are the cupin and prolamin superfamilies and the protein families of the plant
defense system [16]
Pathogenesis-related proteins, calcium-binding proteins, pectate lyases, β-expansins and trypsin inhibitors;
   Grass: ryegrass, timothy-grass
   Weeds: ragweed, plantago, nettle, Artemisia vulgaris, Chenopodium album; sorrel
   Trees: birch, alder, hazel, hornbeam, Aesculus, willow, poplar, Platanus tilia, Olea, Ashe juniper, Alstonia scholaris
Drugs Salicylates (also found naturally in numerous fruits) penicillin, sulfonamides
Other Latex, metal, wood
Modified from http://www.allergen.org/; https://en.wikipedia.org/wiki/Allergen
59
60
of mucosal organs (or skin) and immune cells
through released mediators and physical
interactions are thought to be important in driving
this process [20–33]. Involvement of innate
(lymphoid cells/macrophages/dendritic) cells
and epithelial cells in allergic (Th2 type)
responses are also essential [34–37].
2.1 How Allergens Are Sensed?
Differential recognition of allergen molecular
patterns by the adaptive immune system is
dependent on a prior sensitization process and a
complex antigen presentation between antigen
presenting cells and antigen-specific T lympho­
cytes. Antigen-specific (cognate) activation of
T and B cells is a prerequisite of the adaptive
immune response.
Allergens can function as adjuvants shaping
their own immune response. Innate recognition
of allergens is mediated by constitutively active
pattern-recognition through a range of receptors
(PRRs) in epithelial and immune cells of the
barrier surfaces. PRRs can be surface bound,
such as the toll-like receptors (TLRs) or C-type
lectin receptors (CLRs); cytoplasmic, such as the
nucleotide-binding oligomerization domain
protein (NOD)-like receptors (NLRs) or the RNA
helicases (RIG-like receptors [RLRs]) [38–42].
PRRs can also be soluble such as the pentraxins,
mucins, and the initiator molecules of the
complement system, C1q, collectins and ficolins
[43, 44]. A recently described secreted pathogen
sensor is PLUNC (Palate, Lung, Nasal Epithelium
Clone), an abundant secretory product of epithelia
present throughout the conducting airways of
humans and other mammals. PLUNC is
evolutionarily related to the lipid transfer/
lipopolysaccharide binding protein (LT/LBP)
family [45].
PRRs  specifically recognize conserved motifs
called pathogen-associated molecular patterns
(PAMPs) and newly discovered self-derived
molecules after cell damage or death, through
damage-associated molecular pattern (DAMP)
C. H. Flayer et al.
recognition. DAMPs have recently emerged as
important proinflammatory mediators in chronic
allergic airway inflammation and include S100
proteins, the high mobility group box 1 (HMGB1)
protein, actin filaments, extracellular ATP,
glucose, monosodium urate (MSU) crystals and
calcium pyrophosphate dihydrate (CPPD).
Intratracheal administration of house dust mite
(HDM) to mice induced the production of uric
acid by epithelial cells and promoted Th2
sensitization by amplifying production of IL-25,
IL-33, and TSLP.  Uricase treatment reduced
allergic inflammation and airway hyperres­
ponsiveness [46]. Epithelial injury after fungal
airway exposure resulted in the release of
ATP,  acute extracellular accumulation of which
induced IL-33 and subsequent Th2 response [47].
Thus, DAMPs produced by epithelial cells can
promote initiation and persistence of allergic
inflammation. DAMPs are recognized by NOD-­
like receptors (NLRs) [48]. NLRs can also
recognize alum, cholesterol, environmental
irritants, silica and asbestos [49]. A subset of
NLRs (NLRP1, NLRP3 and NLRC4) can
assemble and oligomerize into a common
structure (inflammasome) that activates the
caspase-1 cascade leading to production of IL-1β
and IL-18, thereby initiating the inflammatory
response.
C-type Lectins (CLRs)  form a large family of
receptors that bind to carbohydrates in a calcium-­
dependent manner through conserved carbohy-
drate-recognition domains. CLRs include type I
(DEC 205, MMR) and type II (dectin-1, 2,
Mincle, DC-SIGN, DNGR-I) membrane mole-
cules [50–53]. Soluble CLRs are the collectins
(SP-A, SP-D and MBL) that participate in aller-
gen opsonization and suppression of inflamma-
tory cell activation.
Allergens can also have protease activities.
Extracellular serine, aspartic, and metallopro­
teases (components of many airborne pathogens
and allergens [54–56]) and novel membrane-
associated proteases, such as yapsins and ADAMs
[57, 58], can induce Th2 inflammatory responses
Adaptive Immunity of Airway Inflammation in Asthma 61

by altering the permeability of epithelial barrier TLR Activation  is critical not only to detect
(disrupting the epithelial tight junctions [21]) and pathogens in the epithelia but also to regulate Th2
allowing allergens to cross and interact with cell responses induced by inhaled allergens as well
mucosal dendritic cells [59]. Proteolytic enzymes [29, 73–80]. Activation of TLRs by allergens has
contribute to inflammation through interactions been implicated in allergic sensitization and experi-
with the kinin system [60] as well as the mental evidence demonstrates an increase in aller-
coagulation and fibrinolytic systems [61] and the gen-induced asthma severity after exposure to LPS
complement cascade [62–64]. Proteases can also [81]. Interestingly, Derp2 allergen of the HDM
induce proinflammatory cytokines through showed structural homology with the LPS-binding
protease-activated receptors (PARs) [57]. PARs protein MD-2 (TLR4 associated adaptor protein).
are identified on immune, inflammatory and Derp2 acted on structural cells to increase produc-
structural cells. Specifically, epithelial cells tion of Th2-­inducing cytokines, such as thymic
express PAR-1 and PAR-2 receptors, the more stromal lymphopoietin (TSLP), IL-33, IL-25 and
prominent of the four identified protease-­ GM-CSF, all closely associated with the develop-
activated receptor molecules. The mechanisms ment and pathogenesis of allergic inflammation
by which the seven transmembrane G-protein [77, 82]. Under conditions of low LPS exposure,
coupled protease receptors interact with proteases Derp2 interaction facilitated LPS signaling through
involve cleavage of the N-terminal region TLR4  in the absence of MD-2 and shifted the
exposing a cryptic “receptor activating sequence”. immune response towards a Th2 type [75].
If the cleaved region includes the receptor Allergens may also trigger synergistic effects
activating sequence, the receptor becomes between PAR-2 and TLR signaling in the epithelial
inactivated. Thus, proteases may activate or cells [70], mounting Th2 responses and allergic air-
inactivate PARs depending on the proteolytic way inflammation through the release of Th2-
cleavage site [65]. Because its major activator is inducing cytokines. Lastly, a recent paper indicated
thrombin, PAR-1 links the coagulation and that innate immunity of the upper and lower air-
inflammatory cascades. PAR-1 mediates ways was distinctive, because HDM-­derived beta-
production of protein C, an anti-inflammatory/ glucans, rather than LPS, activated innate immunity
cytoprotective molecule. The PAR-1/protein C in the nasal mucosa dependent on TLR2, but not on
pathway is impaired in asthmatic patients and in TLR4. In contrast, the LPS/TLR4 signaling axis,
mouse models of allergic airway sensitization rather than beta-glucans/TLR2, was critical to
[61]. PAR-2 is activated by trypsin, mast cell HDM-induced allergic asthma in mice. Thus, dif-
tryptase, leukocyte proteinase-3, bacterial ferential TLR activation on airway epithelial cells
enzymes and a wide variety of cockroach [66], may be responsible in determining the nature of
mold and mite [67] allergens that exhibit serine innate immune response of the nose and lungs,
protease activity. A number of studies in animals leading to allergic inflammation of the upper or
suggested that PAR-2 activation plays a lower respiratory tract, respectively [83].
proinflammatory role in asthma [67–71]. A
protective role of PAR-2 activation was also
suggested using a PAR-2 activated peptide in Role of Viruses  in allergic airway inflamma-
allergen-challenged rabbits [72]. Of note, pollen tion: Epithelial cells are the primary target and
grains with distinct allergenic abilities can also residence for respiratory viruses such as the
release proteases. These, however, work by human rhinoviruses (HRV), respiratory syncytial
attacking the epithelial tight junctions and virus (RSV) and influenza A virus. In fact, there
facilitating allergen delivery across the epithelium is considerable evidence that viral respiratory
(Fig. 1) [54]. infections and respiratory allergies are the two
most significant risk factors for the onset of
62
Fig. 1  Cell associated innate immune receptors: PAMPs
(pathogen-associated molecular patterns) and DAMPs
(damage-associated molecular patterns) are recognized
by PRRs (pattern recognition receptors). The receptor
families listed here are relevant to allergen-induced
inflammation because they bind pathogens that have a
asthma in children and exacerbations of asthma
in adults [84, 85]. Respiratory virus infection
occurs mainly through receptor-mediated
endocytosis. In case of influenza A virus
infection, epithelial mediated asthma exacer­
bations could be due to a damage to epithelial
cells and production of inflammatory mediators
[86, 87] or activation of innate immune effector
and inflammatory cells [88]. Influenza A virus
attacks epithelial cells via hemagglutinin that
recognizes sialic acid (N-acetyl neuraminic acid)
bound to underlying sugars on the tips of the cell
glycoproteins [87]. RSV and HRV receptors on
the other hand include a number of shared
­putative molecules such as intercellular adhe-
sion molecule (ICAM)-1 and TLRs. Heparin,
annexin II, and fractalkine (CX3CL1) receptor,
CX3CR1 additionally were shown to mediate
some of the biological functions of RSV, that
now also has a newly discovered selective recep-
tor, nucleolin [reviewed by [89]]. HRV infection
is the most common cause of asthma exacerba-
tion. The majority of HRV-A and -B strains bind
to ICAM-1 (CD54) and only the minority
(approximately 10%) of the HRV-A binds to
members of the LDL receptor family. HRV
upregulates its own receptor, ICAM-1 on epi-
thelial cells in an NF-kB-dependent manner [90,
91] and causes production of inflammatory
mediators and loss of glucocorticoid respon-
siveness [92].
C. H. Flayer et al.
modulating role in the inflammatory changes. The
Protease associated receptors (PARs), Toll-like receptors
(TLRs), C-type lectin receptors (CLRs), can also directly
bind allergens. Antibody binding receptors (not listed
here) are part of the adaptive immune response
In chronic airway inflammation, there is also
evidence for a role of membrane-bound and
cytoplasmic RNA sensing molecules, such as
TLR3 and TLR7/8 [93], that are localized to
endosomal and plasma membranes and bind
double-stranded and single-stranded RNA,
respectively. Activation of TLR3 leads to
induction of the RNA helicases (RIG-like
­
­receptors [RLRs] and melanoma-differentiation-­
associated gene 5 [MDA-5]). All three of these
(TLR3, RIG-1 and MDA-5) cooperate in the
upregulation of innate interferon (IFN) responses
to HRV infection [94]. In asthma the early TLR3
signaling is defective, leading to inadequate
IFN-β and IFN-λ responses that account for the
impaired viral clearance and consequent epithe-
lial damage in this disease [95]. Viral infections
with single- or double-stranded RNA can induce
NLRP3 activation and IL-25, IL-33, and TSLP
release by epithelial cells in vitro and in vivo,
mediating Th2-type airway inflammation.
Indeed, infection of mice with influenza virus
induces IL-33 release from alveolar macro-
phages, resulting in the production of IL-13 by
group 2 innate lymphoid cells [88, 96].
Expression of IL-25, IL-33, and TSLP  through
innate immune signaling is critical to drive the
Th2 response. These cytokines are initially
produced by epithelium at the mucosal surfaces
in response to challenges but they are subsequently
Adaptive Immunity of Airway Inflammation in Asthma 63

amplified by other tissue-resident and immune with mucus metaplasia [105]. Mice deficient for
cells during inflammatory responses. In recent the IL-17 receptor are protected from allergen-
years, the roles for IL-25, IL-33, and TSLP in induced airway inflammation, and in humans,
Th2 type airway inflammation have been asthmatic subjects have higher levels of BAL and
extensively studied in a variety of experimental sputum IL-17 [106–108]. Importantly, after ces-
models and in human systems. These studies sation of allergen exposure, the timely resolution
consistently find potent activities of these of allergic airway responses is also governed by
cytokines to induce and amplify Th2 type regulation of the Th17 pathway.
immune responses [reviewed in [97]]. Transgenic
overexpression of these cytokines induces Th2 Genetic and Epigenetic Influences  Genome-­
cytokine expression in tissues, airway wide association studies (GWAS) and meta-­
eosinophilia, increased release of IgE antibodies analyses of GWAS discovered new asthma
and Th2 cytokines into the serum, mucus susceptibility genes including IL1RL1/IL18R1
overproduction, with goblet cell hyperplasia, [109], IL-33, ORMDL3/GSDMB, SMAD3
airway thickening, and airway [110], and TSLP [111]. Associations with varia-
hyperresponsiveness, all consistent with human tion in the genes encoding IL1RL1/IL18R1 (the
asthma [98–100]. Such cytokine-induced IL-33 receptor ST2), IL-33, SMAD3, and TSLP
pathological airway changes are also apparent in indicated the importance of both innate immune
mice deficient in the Rag gene, emphasizing the response promoting Th2 pathways (atopy) and
significance of innate immune cells in initiating asthma. On the other hand, variation at the 17q21
the allergic immune responses [101]. asthma locus, encoding the ORMDL3 and
GSDML genes were specifically associated with
Chemokine and Cytokine Release  also plays risk for epithelial remodeling and childhood-
an important role in driving Th2-type immune onset asthma but not IgE [112]. Recent technical
responses. Following allergen challenge, CCL17 advances facilitated assessment of the effect of
and CCL22 mediate migration of Th2 and den- epigenetic modifications on development of
dritic cells to the airways by interacting with their allergic airways changes. Epigenetic changes
common receptor, CCR4 [78, 102]. CCL20 (the include post-translational modifications of his-
only chemokine that ligates CCR6) is also impor- tones and chromatin remodeling, DNA methy­
tant in attracting T cells and dendritic cells to the lation or mRNA regulation through small
epithelial area of the respiratory tract [77]. noncoding RNAs, including microRNAs (miR-
Autocrine cytokine stimulation of residential NAs) that interfere with translation [reviewed in
cells in the airways amplifies the initial PRR-­ [113]]. Epigenetic regulation can affect the pro-
induced proinflammatory gene activation. For moter region or the gene itself. It can result in
example, in the early stages during allergen-­ gene silencing or aberrant expression. Epigenetic
induced airway inflammation, IL-17 can upregu- alterations can be carried over in the genes
late release of the CXCR2 ligands, CXCL1, through meiosis, therefore specific periods in life
CXCL6 and CXCL8 as well as GM-CSF and such as in utero, during childhood or adolescence
G-CSF. It can also induce release of CCL20 and are highly susceptible to these influences.
β-defensins, both of which act on CCR6 to attract Environmental factors such as air pollution [114],
dendritic cells and memory T cells [103]. IL-17 psychosocial stress [115], cigarette smoke expo-
can also act synergistically with viral infection or sure, nutrition/obesity [116], can all alter the
other proinflammatory cytokines such as TNF-α epigenome that can in turn influence T cell phe-
and IL-1β to enhance inflammatory responses notype and affect the development of asthma
[104]. Transgenic expression of IL-17 in airway [113]. For example, methylation array data in
epithelial cells induced airway eosinophil and clinic visits of 141 subjects from the Normative
lymphocyte infiltration and structural changes Aging Study found that exposures to black
64
c­ arbon and sulfate were significantly associated
with the gene methylation pattern in the asthma
pathway [114]. In a study of the gene
ADCYAP1R1  in Puerto Rican children 9  years
and older, exposure to violence was associated
with promoter methylation and increased odds of
asthma [115]. DNA methylation in the
Neuropeptide S Receptor 1 (NPSR1) promoter
was also found to be significantly linked with
cigarette smoking and obesity in relation to
asthma [116].
3 Cellular Interactions
with T-cells Driving Th2-type
Inflammatory Response
in Asthma
Dendritic Cells  were named after their mem-
brane projections resembling the dendrites of
neurons. There are two major classes of these
cells, Classical (or conventional) and
Plasmacytoid. Conventional dendritic cells are
originated from myeloid (bone marrow-derived)
precursors. Similarly to tissue macrophages,
dendritic cells constantly sample the environment
in which they reside and capture tissue antigens,
migrate to the draining lymph nodes while
becoming activated, upregulate costimulatory
molecules, produce inflammatory cytokines, and
initiate adaptive T cell responses. Classical
dendritic cells may be divided into two major
subsets: (1) BDCA-1/CD1c (in humans) or
CD11b (in mice), is most potent at driving CD4+T
cell responses and (2) BDCA-3 (in humans or in
mice), CD8  in lymphoid tissues or CD103  in
peripheral tissues, is an efficient cross-presenter
(described later in this chapter). Some dendritic
cells may be derived from monocytes, especially
in situations of inflammation (Fig. 2).
Plasmacytoid dendritic cells (looking like plasma
cells) are poorly phagocytic and do not sample
environmental antigens. They secrete large
amounts of type I interferons and in viral
infections, present antigens to virus-specific T
cells [117]. Activation of selective TLRs on
epithelial cells enhances dendritic cell motility
C. H. Flayer et al.
and antigen sampling through the production of
Th2-promoting chemokines CCL17 and CCL22
[78]. Recruitment and local survival of dendritic
cells is mediated by CCL20 (a ligand for CCR6
present on immature dendritic cells) and
GM-CSF, respectively [32, 80, 118, 119].
Recruitment of dendritic cells to the airways is
essential in the adaptive B, T and NK cell-­
mediated immune responses important in defense
against infection by viruses and bacteria and in
allergen-driven inflammation of the airways
[120, 121]. The nature of the immune response
that occurs after dendritic cell exposure to
antigens is determined by the state of dendritic
cell activation and the context in which they
present antigen to T cells, i.e. the level and type
of co-stimulatory molecules and cytokine pattern
expressed by the dendritic cells. TSLP can
directly activate dendritic cells to prime naïve
CD4+ T cells to differentiate into proinflammatory
Th2 cells that secrete IL-4, IL-5, IL-13 and TNF,
but not IL-10; it can also stimulate the expression
of the prostaglandin D2 receptor CRTH2 [122–
124]. The process by which this polarization
occurs involves the induction of the Th2-cell
associated co-stimulatory molecule OX40L
(Tumor necrosis factor receptor superfamily,
member 4) by dendritic cells [125]. The
polarization of Th2 cells induced by TSLP-­
matured dendritic cells is further enhanced by
IL-25 [126].
Macrophages  have a central role in the mainte-
nance of immunological homeostasis and host
defense in the lung. They can be classified
depending on their localization as “alveolar” vs.
“interstitial”; depending on their origin as
“migratory vs. residential” and depending on
their function as “M1 vs. M2” (or “classically
activated” vs. “alternatively activated”) [127,
128]. Dependending on the activating stimulus
received, M2 macrophages can be further
subdivided into M2a (after exposure to IL-4 or
IL-13), M2b (in response to immune complexes
in combination with IL-1β or LPS), M2c (IL-10,
TGFβ or glucocorticoids), and M2d (induced by
TLR agonists through the adenosine receptor)
[129, 130]. Depending on their differential
Adaptive Immunity of Airway Inflammation in Asthma
Fig. 2  Dendritic cells and initiation of adaptive immunity
of airway inflammation. Classical dendritic cells have the
ability to either enter the air spaces or to extend their
dendrites out and sample the environment and capture
tissue antigens. Upon antigen uptake, dendritic cells
mature and express CCR7. This chemokine receptor is
ligated by CCL19 or CCL21 that are produced by
expression of mediators, M2 cell subclasses can
support allergic airway inflammation; help
resolution of airway changes through a heightened
phagocytic capability; facilitate remodeling; and
provide immunosuppressive activities. During
the allergic airway response, bone marrow-­
derived monocytes migrate through the
circulation and differentiate under the effects of
locally released cytokines, chemokines, and other
inflammatory mediators. These local factors are
important in the priming and skewing of these
cells into “alternatively activated” macrophages,
a proinflammatory Th2-type subclass of M2
macrophages [131]. The “classically activated”
M1 macrophage phenotype promotes Th1-type
inflammation [132]. In Th2-type allergic asthma,
the M2 macrophage phenotype is stimulated by
the absence of IFNγ signaling to the M1/Th1
pathway [132]. Indeed, in three different mouse
models of allergic inflammation, the M2
macrophage phenotype was predominant in
severe asthma [133]. The M2 phenotype can be
induced by IL-33  in alveolar and polarized
macrophages [134, 135]. M2 macrophages
65
endothelial cells of the lymphatic vessels in increasing
concentrations towards the lymph nodes. While becoming
activated, dendritic cells upregulate costimulatory
molecules, produce inflammatory cytokines, and initiate
adaptive T cell responses in the paracortex. T helper cells
then become follicular helper cells (Tfh), migrate to the B
cell follicle and help allergen specific B cells in class
switch recombination and IgE production
express CD206 (mannose-binding receptor, MR)
and promote the adaptive allergic immune
response through a unique mediator profile,
including IL-4, IL-5, IL-10, IL-13 and IL-33,
CCL17, CCL18, CCL22, CCL24, HO-1,
Arginase 1, chitinase-like Ym1, and Fizz1 (found
in inflammatory zone-1) [133, 136–138].
Innate Lymphoid Cells  In 2010, three indepen-
dent groups identified a novel innate immune cell
type that following alarmin cytokine (IL-33,
IL-25, TSLP)  activation, was an early producer
of IL-5 and IL-13 during allergic inflammation
[139]. These cells have since been named group 2
innate lymphoid cells (ILC2s). In mouse models,
ILC2s were demonstrated to play an essential
role in parasitic diseases and in allergic asthma,
producing levels of IL-5 and IL-13 that resem-
bled those derived from Th2 cells [140–145].
Subsequent investigations provided the first
direct evidence that in response to IL-25 and
IL-33, these cells mediated airway inflammation
by secreting Th2 cytokines [146, 147]. A patho-
genic role of ILC2s was shown in nasal polyps of
66
patients with chronic rhinosinusitis and in severe
asthmatics with high levels of eosinophils present
in the airways [147, 148]. Studies from our labo-
ratory and many others used mouse models to
demonstrate that ILC2s are required for Th2-type
inflammation [147, 149–151] and allergen-
induced airway hyperresponsiveness [152].
These findings indicate that as an innate counter-
part to Th2 cells, ILC2s can significantly shape
Th2-type immunity.
Eosinophils  are the major effector cells in aller-
gic asthma, contributing to airway hyperrespon-
siveness. As such, targeting and preventing these
cells from migrating to the airways has been the
focus for asthma therapeutics for some time
[153]. Epithelial cells infected with RSV produce
eotaxin and RANTES, major chemoattractants
for eosinophils [154]. TSLP and IL-33 directly
activate eosinophils, increasing their survival and
inducing superoxide anion and CXCL8 produc-
tion [155]. IL-25 induces production of IL-6,
CCL2, CCL3, and CXCL8 in human eosinophils
[156]. As a positive feedback, eosinophil-derived
cationic proteins can activate epithelial cells to
produce growth factors, matrix metalloprotein-
ases (MMPs), and other factors involved in air-
way remodeling processes [157].
Neutrophils  are the earliest cells to migrate into
damaged or infected tissues, usually recruited by
CXCL8 and CXCL1–3, chemokines released
from residential cells at the site of inflammation
[158, 159]. Growth factors, including G-CSF and
GM-CSF, are induced by allergens and IL-17
[160, 161]. GM-CSF expression activates and
promotes the survival of many inflammatory cell
types and is enhanced in patients with allergic
rhinitis and asthma [162]. Granulocytes in turn
can also alter host defense functions. Neutrophil
elastase can induce expression of CXCL8,
mucins, and epithelial anti-microbial substances,
such as secretory leukocyte peptidase inhibitor,
and human β-defensin 2, providing a self-­
amplifying defense mechanism [163, 164].
Neutrophil elastase also increased the biological
C. H. Flayer et al.
activity of IL-33 [165]. In turn, IL-33 enhanced
neutrophil migration in sepsis and psoriasis by
upregulating CCR2 expression [166, 167]. While
eosinophils are thought to be the main culprit in
allergic asthma, more severe forms of disease are
associated with chronic neutrophil accumulation
in the airways [168]. During acute exacerbations,
neutrophils are also found in significant numbers
in the airways, suggesting their importance in air-
flow obstruction [169]. Because of their apparent
importance in acute exacerbations and severe,
chronic disease, understanding the early and late
mechanisms that drive their recruitment to the
airways is an important future research
direction.
Mast Cell  infiltration of the airways mucosal
tissue is considered a hallmark of asthma [170].
Mast cells express TSLP receptor and respond to
TSLP by producing high levels of cytokines
including IL-5, IL-6, IL-13, GM-CSF, CCL-1
and CXCL8 without degranulation [171]. IL-33
also stimulates mast cells to produce Th2 proin-
flammatory cytokines and chemokines and
enhances their maturation and survival [172,
173]. These new findings suggest that mast cells
are a non-T-cell-dependent mechanism for initi-
ating and maintaining Th2 inflammation in aller-
gic asthma. Histamine released within minutes
from activated mast cells in turn can promote
proinflammatory responses and promote airway
smooth muscle constriction, impairing breathing
[174]. Current research trends seek to understand
how T-cell-mast cell crosstalk is skewed towards
proinflammatory Th2 responses in allergic
asthma, while preventing mast cell activation is
an appealing therapeutic target.
Basophils  are activated by epithelial-derived
TSLP and IL-33, while IL-3 is critical for their
development and activation [175]. Upon stimula-
tion with IL-33, basophils produce proinflamma-
tory cytokines including IL-1, IL-4, IL-5, IL-6,
IL-8, IL-13, and GM-CSF and chemokines
RANTES, CCL2, CCL3, and CCL4 [176]. IL-33
and TSLP can also induce basophil expansion
Adaptive Immunity of Airway Inflammation in Asthma
and their differentiation from the bone marrow
[177–179]. Functionally, several reports pointed
toward an important role for basophils in provid-
ing an early source of polarizing IL-4 to enhance
Th2 development [73]. In human patients that
died from asthma, basophils were highly enriched
in lung tissue [180]. Overall, the significance of
basophil-derived inflammatory mediators is
poorly understood.
Natural Killer T Cells  that express the IL-17RB
(receptor for IL-25) and predominantly produce
IL-13 and chemokines upon stimulation with
IL-25 were implicated in AHR and airway
inflammation induced by airway administration
of lipid antigens or bacterial glycolipids [181,
182]. Invariant NKT cell responses to ambient
antigens promote sensitization to conventional
respiratory allergens [183]. NKT cells acted as an
adjuvant to enhance Th2-type inflammation and
allergic airway inflammation in asthmatic mice
[184]. In nonhuman primates, α-galacto­syl­
ceramide exposure (that directly activated NKT
cells) induced AHR in monkeys not sensitized to
an allergen, suggesting that NKT cells impact
lung function even in naïve animals [185]. Both
increased and decreased numbers of NKT cells
have been observed in human patients with
asthma, so their pathogenic role in allergic
asthma is still highly debated [186, 187].
B cells  B cells have been demonstrated to play a
critical role in allergic asthma, particularly when
the amount of allergen is low, by their ability to
uptake and present antigen on MHC II, similarly
to dendritic cells. In the germinal center of the
lymph nodes, B cells undergo rapid clonal expan-
sion (proliferation) and express the genome
mutator enzyme activation-induced cytidine
deaminase (AID). AID is indispensable for two
key GC processes, somatic hypermutation (SHM)
and class-switch recombination (CSR) [188].
SHM introduces non-templated mutations in the
immunoglobulin (Ig) variable region, changing
the antibody’s affinity for antigen [reviewed in
[189]]. CSR alters the antibody effector functions
67
by recombination of the variable region (linked
initially to the μ and δ heavy chain exons, encod-
ing IgM and IgD, respectively) with one of the
downstream constant region genes of the α, γ or ɛ
isotypes, encoding IgA, IgG and IgE. Each anti-
body isotype initiates different downstream
immune reactions and thus adapts the response to
the nature of the challenge faced. Together these
processes shape the antibody response, produc-
ing germinal center B cells with high-affinity,
class-­switched antibodies that can differentiate
into either antibody-secreting plasma cells or
long-­lived memory B cells [188, 189]. In addi-
tion to their key function in the production of
immunoglobulins, B cells can regulate immune
responses through their surface molecules and
secretion of cytokines (reviewed in [190]).
Regulatory B (Breg) cells produce IL-10, IL-35
and TGF-β. Breg cells in mice can be CD5(+)
CD1d(hi) B10 cells, CD21(hi)CD23(hi)CD24(hi)
transitional stage 2-like B cells, and CD138(+)
plasma cells and plasmablasts. Human Breg cells
are CD27(+)CD24(high) B10 cells, CD24(hi)
CD38(hi) immature transitional B cells, and
CD73(−)CD25(+)CD71(+) BR1 cells and a sub-
set of plasma cells [190]. Breg cell numbers
increase during the course of allergen-specific
immunotherapy. Human BR1 cells selectively
upregulate IgG4 antibodies on differentiation to
plasma cells that promotes the protective effects
of immunotherapy. Thus, Breg cells mediate
allergen tolerance.
CD34+ Hematopoietic Stem/Progenitor
Cells  can also function as inflammatory effector
cells during the asthmatic response without hav-
ing to first undergo differentiation. The hemato-
poietic progenitors express receptors for TSLP
and IL-33 and when stimulated with these mole-
cules produce very high levels of Th2 cytokines
including IL-5, IL-6, IL-13, and GM-CSF [191].
Epithelial Cells, Fibroblasts and Smooth
Muscle Cells  can all significantly shape the tis-
sue response during the adaptive immune effec-
tor function. These structural cells respond to
68 C. H. Flayer et al.

environmental stimulants such as cigarette allergen, perpetuating the allergic response. Th2
smoke, lipopolysaccharide, and oxidant and virus cells express STAT6 and GATA3 [202].
infection, by rapid activation of proinflammatory IL-4, IL-6, and TGF-β in combination induce
signaling and induction of immune and inflam- Th9 cells, that produce IL-9 and are thought to
matory cell migration cascades [192, 193]. Th1 play a role in asthma and autoimmunity by induc-
cells are attracted to the respiratory mucosa by ing survival and proliferation of Th2-­ cytokine
the CXCR3 ligands CXCL9, CXCL10 and secreting ILC2s. The transcription factor Foxo1 is
CXCL11, produced upon exposure to interferons essential for IL-9 production [203].
or infection with respiratory viruses [194–196]. IL-21, IL-23, TGF-β and IL-6 induce Th17
On the other hand, structural cells of the airwayscells, that secrete IL-17A and IL-17F, attracting
induce epithelial migration of Th2 cells via pro- neutrophils that contribute to neutrophilic airway
duction of the CCR8 ligand CCL1 and the CCR4 inflammation and asthma [reviewed in [204]].
ligands CCL17 and CCL22 [197, 198]. Epithelial Many patients have been found to exhibit a dual
expression of CCL17 and levels of CCL17  in Th2/Th17 phenotype and are particularly
BAL indeed is increased upon allergen challenge refractory to current treatments. Th17 cells
of asthmatic subjects [199]. CCL1 production express STAT3 and RORs.
can be induced in airway epithelial cells by Th2 TNF-α and IL-6 induce Th22 cells, which
cytokines, IL-4 and IL-13, but also IFN-γ [200] secrete IL-22 and can be proinflammatory or
suggesting that epithelial cells may control and protective to the epithelium depending on the
amplify both Th1- and Th2-type inflammatory context [205]. Inflammation is mediated by
responses locally depending on the predominant induction of antimicrobial peptides from the
cytokine milieu. epithelium and TNF-α, IL-17, and IL-1 secretion.
Tissue protection is carried out by amphiregulin
production, strengthening the epithelial barrier.
4 Transcriptional Regulation IL-21 and IL-27 lead to differentiation of Tfh
of Th2 Cell Differentiation: cells, which play a critical role in the induction
and maintenance of B cell class-switching inside
After the cognate interaction between dendritic lymph node germinal centers. These cells are
cell MHC-II:CD4+ TCR (T cell receptor) responsible for the production of high-affinity,
signaling occurs, the prevailing cytokine milieu antigen-specific IgE by plasma B cells. They
determines the phenotypic fate of the naïve CD4+ express STAT3 and Bcl6 transcription factors.
T cell [201]. IL-12 secreted by dendritic cells IL-10 and TGF-β induce Treg cells, whose
induces activation of Th1 cells, which then role is to dampen inflammation once the antigen
produce TNF-α and IFN-γ. These cells are has been cleared. They also play a role in
specialized to help during viral or bacterial preventing autoimmunity. The typical Treg
clearance, but autoimmunity and inflammation transcription factor is FOXP3.
can occur if they become sensitized to self-­ Allergic airway inflammation is driven by pro-
antigens. High doses of allergen have been also duction of IL-4, IL-5 and IL-13. A major pro-
shown to favor Th1 polarization. Th1 cells ducer of these cytokines is the differentiated
express the transcription factor Tbet. CD4+ T-helper 2 (Th2) cell. IL-4 is important in
IL-4 and IL-10 induce differentiation of Th2 allergic sensitization, IgE production and Th2
cells which then produce IL-4, IL-5, and IL-13, cell differentiation while IL-5 is critical in
induce eosinophilia and B cell class-switching to accumulation of eosinophilic granulocytes and
IgE.  These Th2 cells are classically associated their activation in the lung. IL-13 has pleiotropic
with eosinophilic allergic asthma, and the IgE effects in tissue remodeling and the development
bound to the high-affinity IgE receptor of mast and progression of airway hyperresponsiveness.
cells causes degranulation upon contact with Th2 cytokines were, therefore, identified as
Adaptive Immunity of Airway Inflammation in Asthma
therapeutic targets with high hopes for the
treatment of asthma [206]. Anti-Th2 cytokine
therapeutics, however, originally had poor results
[207], because these cytokines have numerous
overlapping functions. The fact, therefore, that
the IL-4, IL-13 and IL-5 genes fall under similar
transcriptional regulation [204, 205], especially
during allergic airway inflammation [208], is
therapeutically intriguing. The genes for IL-4,
IL-13 and IL-5 are clustered in a 120 kb region
on chromosome 11 in mice and a 160 kb region
on chromosome 5  in humans and are activated
in  a T cell lineage-specific fashion. Their tran-
scription is coordinately regulated by an intricate
network of transcription factors and other regula-
tors of the gene promoters that activate and/or
repress them [reviewed in [208]]. This process
results in characteristic chromatin structure
changes [209] in the Th2 cytokine locus that also
serves as a general model system of chromatin
conformation of immune genes [210]. Trans­
cription activators interact with the core tran-
scription machinery through binding to enhancers
while repressors work by recruiting co-repressor
complexes leading to chromatin condensation of
enhancer regions. Repressors and activators may
also function by competing with each other for
occupation of shared DNA-­ binding sequences
[211]. Whether a transcription factor is activated
or not is determined by its localization and ability
to bind DNA. The initiation, termination and reg-
ulation of transcription are influenced by epigen-
etic and metabolic processes [212, 213] and
requires “DNA looping”, an important mechanism
to bring the promoters, enhancers, transcription
factors and RNA polymerases together [214].
The transcription factors that can induce sig-
nature cytokines for distinct effector CD4 T cell
lineages and are both necessary and sufficient to
elicit this process, are called “master regulators”
[212]. These bind to a specific region of DNA,
critical for transcription factor binding and com-
plex formation that allows for efficient activation
of the Th2 cytokine genes [215]. These genes are
expressed preferentially from one chromosome
rather than at random, suggesting coordinated
expression. A locus control region (LCR) is a cis-
69
acting element that confers tissue-­specific high-
level expression to linked genes [reviewed in
[208]]. To identify the Th2 cytokine LCR, inves-
tigators deleted a conserved noncoding
sequence-1 (CNS-1) between the IL-4 and IL-13
genes and found that this reduced the ability to
produce IL-4 by Th2 cells but not mast cells
[216] in transgenic mice suggesting that CNS-1
is not an LCR but rather an important T-cell
specific enhancer. Another study demonstrated
that none of the previously described DNase I
hypersensitive sites or conserved sequences in
the Th2 cytokine locus had LCR activity, either
individually or in combination as a minilocus.
However, by evaluating copy number dependency
in mice containing transgenes encoding the
whole Th2 cytokine locus, other investigators
recently found the LCR, located within a 25 kb
region containing the 3′ portion of the RAD50
gene [217, 218]. The Rad50 gene separates the
IL-4 and IL-13 genes from the IL-5 gene [219–
221]. There are four sites within the Th2 LCR
that are “DNase I hypersensitive”, [i.e. exposed
chromatin, highly susceptible to binding by
proteins like DNase I or transcription factors
[219]], implying their importance in transcription.
The DNase I hypersensitive sites of the Rad50
gene are RHS4, RHS5, RHS6, and RHS7 [220,
222]. Indeed, it has been demonstrated that these
sites coordinate transcription of the Th2 cytokine
genes, although the importance of RHS4 has not
been fully established [213, 221, 223]. RHS6 is
thought to be the most important of the four sites
for Th2 cytokine transcription as it is essential for
the expression of each of the IL-4, IL-5 and IL-13
genes [221]. RHS6 contains a number of sites for
transcription factor binding, including two direct
sites for GATA3 [224, 225]. While several
transcription factors are implicated in the
regulation of the Th2 cytokine genes, GATA3 is
the master regulator of Th2 cell differentiation
and is essential for expression of IL-5 and IL-13,
but not IL-4 [226]. Large protein complexes
formed at the RHS6 DNA subregion suggest that
additional transcription factors may also
participate in Th2 cytokine gene activation [208,
224, 225].
70 C. H. Flayer et al.

Such transcription factors are SATB1 and of vaccines has been among the greatest medical
IRF4, also found in all the isolated subregions of breakthroughs [233] aimed at preventing
RHS6. SATB1 regulates GATA3, coordinating infections, treating allergic and autoimmune
Th2 development [227]. IRF4 is required for Th2 diseases, organ transplantation pathologies,
cell differentiation, it binds the IL-4 promoter chronic infection and cancer [234, 235]. In AIT
and acts both upstream and downstream of vaccines (increasing doses of allergens) are
GATA3 [226]. In the absence of RHS6, GATA3, administered to restore immune tolerance and
IRF4, and SATB1 binding was reduced at all reduce allergic symptoms, once the cause(s) of
sites in the Th2 cytokine locus control region allergy are identified. The allergen can be given
[225]. Thus, RHS6 is a critical regulatory element intramuscularly, subcutaneously, sublingually,
for effective Th2 cytokine transcription, as orally, or intra-lymphatically. The doses of
suggested by others [221]. The role of RHS6 in allergen are increased as the patient’s tolerance
mediating Th2 cytokine transcription is conserved grows over time [236]. AIT has been used for
among cell types. Because RHS6 is located IgE-mediated allergic diseases since the early
between the IL-4/IL-13 and IL-5 genes, it is 1900s [234, 237–242], though it remains fraught
intriguing, that RHS6 can mediate the with problems [234, 237–242]. It is not easy to
transcription of up- and downstream targets. This produce a closely regulated composition for the
fact brings up the importance of the three-­ allergenic compounds and adjuvants, or to
dimensional structure of chromatin and suggests establish consensus in regards to the doses,
that regulatory elements throughout the genome intervals, and length of application. The danger
can have profound effects on genes both up- and of anaphylaxis occurring during administration
downstream. of AIT also remains high. When successful
Thus, GATA3, IRF4, and SATB1 physically however, AIT treats and prevents development of
complex at RHS6 in the Rad50 gene of the Th2 allergic asthma, rhinitis and venom-induced
cytokine locus, during allergic airway anaphylaxis and was demonstrated to prevent
inflammation. A number of genome-wide sensitization with new allergens for up to 12 years
association studies have revealed that single [234, 243]. Therefore, the quest to develop safer
nucleotide polymorphisms in the Rad50 gene are and more effective AIT continues today [244].
associated with asthma and allergy [228–230] but
the involvement of the RHS6 region remain Induction of allergen tolerance requires a
unclear in these. Interfering with the physicaldecrease in IgE and increase in allergen-specific
association of the GATA3, SATB1, and IRF4 IgG levels [245]. Successful allergen-specific
complex by targeting RHS6 maybe an attractive, immunotherapy can result in a 10- to 100-fold
novel therapeutic possibility to reduce Th2 reduction in the allergen-specific IgE/IgG4 ratio
cytokine production during chronic airway [190]. IgG4 is a non-proinflammatory
inflammation. immunoglobulin that is uniquely capable to form
bispecific and functionally monovalent antibodies
through Fab arm exchange [246]. IgG4 has low
5 Targeting T-cell Dependent affinity for activating Fcγ receptors and cannot
Inflammation in Asthma activate complement. Allergen-specific IgG4
protects against allergic responses by
Allergen-specific Immunotherapy (AIT)  T competitively sequestering the allergen from IgE
cells can be manipulated to induce or suppress binding [245, 247, 248]. By changing the ratio of
immune responses for example, with the use of allergen-specific IgE and IgG, effective AIT
vaccines (biological preparations of disease-­ should desensitize the high affinity IgE-receptor-
causing agents). When successful, such (FcεRI) bearing mast cells and basophils,
manipulation can elicit broad and specific decrease the numbers and activity of eosinophils
immune responses [231, 232]. The development and basophils in the circulation and mast cells in
Adaptive Immunity of Airway Inflammation in Asthma
mucosal allergic tissues, and induce regulatory T
and B cell activation [reviewed in [235]].
The heat-labile enterotoxigenic E. coli entero-
toxin (LT) contains an “A” and a pentameric “B”
subunit (AB5) and it has been successfully used
for vaccination purposes. Skin-patch vaccines
containing LT have been recently tested in a large
clinical trial for travelers’ diarrhea. Although it
did not prevent diarrhea, the skin patch vaccine
induced a strong IgG response in volunteers
[249] indicating high immunogenicity. In addi-
tion to its proinflammatory and immunogenic
properties, when co-administered with different
antigens, LT also markedly enhances the antigen-
specific immune response (against the co-admin-
istered antigens) indicating adjuvant effects
[reviewed in [250–252]]. However, neither the
proinflammatory properties nor the high immu-
nogenicity of this molecule can explain its
remarkable “adjuvanticity”. It is speculated that
this effect is due to induction of MHC-class II
expression on antigen presenting cells, cell clus-
tering and delay/arrest of T cell proliferation
[253]. Based on the literature showing that
LT-treated dendritic cells had a slower rate of
antigen endocytosis, suggesting that prolonged
retention of intact antigen on the cell surface may
allow B cells to recognize the bound antigen by
their immunoglobulin receptors [254] emphasiz-
ing the importance of dendritic cells in mediating
“adjuvanticity”.
Acting as the crucial link, dendritic cell target-
ing is a major vaccination strategy against many
diverse pathogens. In the skin, these cells are the
prime initial mediators of protection. As they
become activated upon exposure to allergen, they
migrate to the draining lymph nodes (Fig.  1).
This in turn activates the adaptive immune
system, inducing a T cell cytokine profile that
favors the production of large amounts of IgG
antibodies by plasma cells that are able to block
allergy-causing IgE molecules specific for the
same allergen [255]. In addition to the use of
novel adjuvants, current immunotherapy research
is focused on enhancing antigen-presenting cell
function in several different ways. For example,
71
in a design targeting dendritic cell subsets,
recombinant proteins with the vaccine epitope in
question were fused to GM-CSF [256]. To
investigate alternate routes of administration,
allergen tolerance was recently induced after
intra-lymph node injections of a molecular
allergen translocation-Fel d 1 vaccine, mediated
by increased cellular internalization of the
allergen, activation of inflammasome, and
generation of allergen-specific peripheral T-cell
tolerance [257]. Adoptive transfer of antigen-­
specific T cells to allogeneic hematopoietic
transplant recipients is also being explored in
human studies and holds the promise of
vaccinating against aspergillosis [233]. Other
potential future strategies employ microspheres
made of biodegradable polymers containing the
epitope of the allergen in question, given to
maximize delivery to antigen presenting cells.
This method has a specific advantage in that it is
designed to induce both B and T cell responses
and lasting memory to certain immunodominant
epitopes [258]. Epicutaneous patch AIT may be
suitable for various allergens in patients. Patch
vaccination is an attractive needle-free alternative
to allergy shots (offering the possibility of self-­
administration for patients) and it targets profes­
sional antigen-presenting cells (i.e., dendritic
cells, Langerhans cells) residing in the skin [259].
The fields of vaccine design and allergen
desensitization are constantly evolving. Recent
advancements in AIT mechanisms and use in
clinical practice were described in the practical
allergy (PRACTALL) initiative report that was
endorsed by both the European Academy of
Allergy and Clinical Immunology and the
American Academy of Allergy, Asthma &
Immunology [234, 243]. AIT, especially in light
of the recent evidence of Sublingual Immu­
notherapy (SLIT) tablet efficacy and safety in
mite allergic asthma patients, is considered to be
a prototype of Precision Medicine [244]. In spite
of all the advances made, however, safer and
more effective AIT strategies are still needed,
especially for patients with asthma, atopic
dermatitis, or food allergy [234, 243].
72
Glucocorticoids  Despite continued advances in
the development of small molecule and biological
anti-inflammatory therapeutics, monotherapy
with corticosteroids remains the most effective
first-line treatment for asthma. Glucocorticoid
receptors in the cytoplasm bind to corticosteroids
and translocate to the nucleus, where they act as
transcription factors to induce the synthesis of
anti-inflammatory proteins as well as to repress
proinflammatory transcription factors such as
NF-kB and AP-1. Because of the complex,
heterogenic inflammatory pathophysiology that
underlies the syndrome of asthma, the broadly
distributed mechanism of action of glucocorti-
coids in downregulating inflammatory signaling
underlies their utility in clinical practice.
However, the pleiotropic effects of corticosteroid
therapy extend beyond general
immunosuppression into regulation of central
metabolism and development, and these often
adverse effects limit their therapeutic potential.
Many strategies have been employed to mitigate
the off-target effects of corticosteroids; drug
development has focused on creating inhaled
corticosteroid formulations with reduced
systemic availability and characterizing the
differences in tissue-specific gene expression
induced by steroid analogs. However, a subset of
asthma patients is either steroid-dependent or
unresponsive to steroid treatment, due to acquired
or inherited conditions.
Biologicals  Glucocorticoid unresponsiveness
bears significant therapeutic consequences and
strongly motivated efforts to search for alterna-
tive, better means to target T-cell dependent
events in allergic airways inflammation. The par-
adigm of Th2 polarization as being a central
driver of allergic inflammation in asthma has led
to several attempts to develop targeted monoclo-
nal antibody immunotherapies against Th2 cyto-
kine pathways. In 2003 for adults and in 2016
also for children above 11 years of age, the FDA
approved Omalizumab (Xolair; Genentech/
Roche and Novartis), a non-anaphylactogenic
monoclonal antibody against IgE for the treat-
ment of asthma. Omalizumab is a humanized
monoclonal antibody that specifically targets the
C. H. Flayer et al.
circulating immunoglobulin E, which in turn
impedes and reduces subsequent releases of the
proinflammatory mediators [260]. Omalizumab
inhibits the binding of IgE to FcεRI on mast cells
and basophils by binding to an antigenic epitope
on IgE that overlaps with the site to which FcεRI
binds. This is important because ordinary anti-­
IgE antibodies can cross-link cell surface FcεRI-­
bound IgE and induce mast cell and basophil
degranulation. Omalizumab, however, is steri-
cally prevented from crosslinking
FcεRI.  Interestingly, Omalizumab also inhibits
IgE binding to the low-affinity IgE receptor
(FcεRII), CD23 on B cells and many other cell
types and attenuates IgE-mediated allergic
responses. Even more intriguing that Omalizumab
has recently been found to be beneficial in non-­
allergic diseases mediated by mast-cell degranu-
lation [261]. The mechanisms of this effect are
not well understood and are under intensive
investigation [260–262].
Because of the prominence of eosinophilic
granulocytes in the pathogenesis of asthma,
monoclonal antibody blockade of IL-5 signaling
was believed to have the most potential as a
therapeutic due to the central role of IL-5 in the
initialization of eosinophilic airway inflammation.
However, the early clinical trials of anti-IL-5 and
anti-IL-5Ra immunotherapies did not result in
significant reductions in clinical asthma
exacerbations. More recent clinical trials have
met with better outcomes when patients were
selected using biomarkers. Mepolizumab was
approved in 2015 for the treatment of severe
eosinophilic asthma. Results of major clinical
trials in severe asthma (MENSA [263] and
SIRIUS [264] on the effects of an anti-IL-5
monoclonal antibody, mepolizumab and ZONDA
on benralizumab [265–271]) indicated that
exacerbation rates as well as oral steroid intake
was reduced by 50–75% in severe asthmatic
patients. These and other previously published
investigations [272, 273] shared important
clinical features: significant therapeutic effect
was demonstrated only in patients who had
persistent symptoms and frequent exacerbations
together with peripheral blood and sputum
Adaptive Immunity of Airway Inflammation in Asthma
eosinophilia despite high dose inhaled
corticosteroid treatment. Further characterization
of asthma patient subgroups benefitting from
biological treatment, however, is warranted by
the high variability of the data obtained so far and
additional patient clustering results [274].
Importantly, some of the placebo-treated
asthmatics in the trials showed a marked
improvement in symptoms. Thus, not all patients
need treatment with biologics. Given their high
cost, careful selection of patients who will best
benefit from this treatment is imperative. Future
studies need to provide a way to distinguish
patients with true glucocorticoid-resistant asthma
as candidates for treatment with biologics from
those with adherence/compliance problems or
difficulties with correct inhaler technique, in
whom conventional glucocorticoid-based therapy
would otherwise work effectively.
Other monoclonal antibodies, targeting differ-
ent cytokines (IL-13, IL-4, IL-17 and TSLP) are
still under evaluation, though the preliminary
results are encouraging. Tezepelumab for exam-
ple, was recently developed for blocking the epi-
thelial-cell-derived cytokine thymic stromal
lymphopoietin (TSLP) [122, 275], in patients
whose asthma remained uncontrolled despite
treatment with long-acting beta-agonists and
medium-to-high doses of inhaled glucocorti-
coids. Indeed, among patients treated with long-
acting beta-agonists and medium-to-­high doses
of inhaled glucocorticoids, those who received
tezepelumab had lower rates of clinically signifi-
cant asthma exacerbations than those who
received placebo, independent of baseline blood
eosinophil counts [35, 276–279]. Thus, targeting
inflammation upstream of adaptive immune
processes may be more effective in treating both
neutrophilic and eosinophilic asthma [276].
Recent clinical trials for anti-IL-33
immunotherapy that have been completed and
are awaiting publication, CNTO 7160 and AMG
282. Immunotherapies targeting the alarmin
cytokines are currently believed to be some of the
most promising drugs in development for asthma
treatment [280].
73
6 Conclusions
Clinical failures in drug treatment of allergic
asthma greatly contributed to our understanding of
the molecular and cellular players in the pathogen-
esis of this complex disease and drove the research
efforts that lead to recent advancements.
Recognition of the significance of airway inflam-
mation was followed by discoveries of the impor-
tance of T cells and adaptive immunity with the
Th2-polarization hypothesis. The past decade of
translational research has, however, largely chal-
lenged the Th2-polarization hypothesis and impli-
cated a greater role for airway epithelial and innate
immune cells in modulating the adaptive immune
response in asthma, than previously thought.
We  now understand asthma to be a syndrome
­encompassing diverse etiologies. The continued
and rigorous characterization of the molecular
determinants and mediators; both intrinsic and
extrinsic, that underpin the many endotypes of
asthma will lead to the exploration of new drug-
gable targets in the proteome, genome, and
beyond. It is possible that therapeutics which tar-
get pathways upstream of Th2 cells will have a
broad impact in the clinic and thus be more effec-
tive than the treatments that directly target IL-4,
IL-5, and IL-13. These studies are currently under-
way. Other therapeutic strategies may seek to
impair the transcription factor complexes required
to synthesize the molecular products of the
immune cells that contribute to asthma or remodel
the epigenetic architecture that programs inflam-
matory signaling pathways. In the era of precision
medicine, it seems likely that the most successful
novel asthma therapeutics will seek not to treat all
asthmatics, but rather all asthmatics of an endo-
type. The most effective drugs in practice will bal-
ance specificity with utility, targeting converging
elements of asthma pathophysiology. Without the
extensive work of many laboratories around the
world to define the basic molecular pathways in
asthma, the development of such therapeutics
would not be possible. The era of precision medi-
cine holds much promise for more effective asthma
therapeutics.
74 C. H. Flayer et al.

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