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M. Y. Desrosiers and S. J. Kilty
in COPD exists [6]. It has also been demonstrated
that the administration of aerosolized neutrophil
elastase in mice leads to rapid damage to the surface epithelium with loss of ciliated respiratory,
mucosa, and resultant mucosal hyperplasia [8].
8.6 Implication inCRS
As for lower respiratory tract disease, interest in
the inammation in CRS has focused mainly on
Th2-mediated inammation due to the postulated
importance of the eosinophil, and therapeutic
strategies have focused mainly on the Th2 axis.
However, an increasing body of work is emerging to suggest that the neutrophil may play a role
in the development of CRS in a subpopulation of
patients with this disorder.
The rst attention to neutrophils in CRS was
derived from reports of predominant neutrophilia
in nasal polyps from Asian subjects and in patients
with cystic brosis [9, 10]. However, later reports
have demonstrated pronounced heterogeneity in
these groups, with both high- neutrophil and lowneutrophil subgroups being present. Interestingly,
a focus on differences between Asian and
Caucasian neutrophils in polyps has identied the
existence of two groups, one roughly characterized by high IL-5 levels and the second by a predominantly Th1/Th17 activation pattern [11].
Work in our laboratory with cultured sinus epithelial cells harvested from CRS patients and controls without CRS has identied a molecular
signature with high spontaneous inammation
present in only a subgroup of CRS cells.
Interestingly, simultaneously obtained biopsy
specimens from patients where cultures were
obtained show similar levels of tissue eosinophilia
in both populations. However, neutrophilic inltrate is present in only the group with the highinammation molecular expression signature.
8.7 Therapeutic Implications
Implications for the importance of this nding
are characterized by recent studies outlining poor
prognosis and lesser response to steroid therapy
in individuals with “neutrophilic” CRS. In a
study from Brazil, [12]) report that high NFkB
activation, a characteristic feature of Th1 axis
activity, results in a poorer response to steroids
and a rapid recurrence of the disease.
The impact on response to therapy has also
potential importance, as a Chinese group recently
identied a lesser response to oral steroids in
individuals with neutrophilia on biopsy of their
nasal polyps. In a similar direction, Al-Mot etal.
[13] identied a predominant neutrophilia in the
sinus pathology of post-ESS patients who demonstrated a poor response to topical steroid irrigations, whereas patients whose polyps had a low
neutrophil level had a favorable response to topical steroid therapy.
8.8 Summary
Taken together, these ndings suggest that the
neutrophil may play an important role in the subgroup of patients with a “neutrophil” predominant
phenotype of CRS.New methods for recognizing
the presence of this disease will be important, as
this “neutrophil” phenotype is independent of
currently used clinical phenotypic markers, the
presence or absence of nasal polyposis. This may
require novel diagnostic approaches to tailor therapy to individual disease status.
Lastly, recognition of the potential importance
of this subgroup may require a different therapeutic
approach than has been employed to date for “routine” CRS, possibly requiring the use of alternative,
nonsteroid-based anti-inammatory treatments for
the management of disease in these individuals.
References
1. Brinkmann V, Zychlinsky A.Neutrophil extracellular
traps: is immunity the second function of chromatin?
J Cell Biol. 2012;198:773–83.
2. Hager M, Cowland JB, Borregaard N. Neutrophil
granules in health and disease. J Intern Med.
2010;268:25–34.
3. van den Berg JM, Kuijpers TW. Educational paper:
defects in number and function of neutrophilic
granulocytes causing primary immunodeciency. Eur
J Pediatr. 2011;170:1369–76.
4. Savic S, Dickie LJ, Battellino M, et al. Familial
Mediterranean fever and related periodic fever
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syndromes/autoinammatory diseases. Curr Opin
Rheumatol. 2012;24:103–12.
5. Gibson PG, Simpson JL, Saltos N.Heterogeneity of
airway inammation in persistent asthma*: evidence
of neutrophilic inammation and increased sputum
interleukin-8. Chest. 2001;119(5):1329–36.
6. Moore WC, Meyers DA, Wenzel SE, et al.
Identication of asthma phenotypes using cluster
analysis in the severe asthma research program. Am J
Respir Crit Care Med. 2010;181:315–23.
7. Foreman MG, Campos M, Celedon JC.Genes and
chronic obstructive pulmonary disease. Med Clin
North Am. 2012;96:699–711.
8. Voynow JA, Fischer BM, Malarkey DE, et al.
Neutrophil elastase induces mucus cell metaplasia
in mouse lung. Am J Physiol Lung Cell Mol Physiol.
2004;287(6):L1293–302.
9. Rowe-Jones JM, Shembekar M, Trendall-Smith N,
et al. Polypoidal rhinosinusitis in cystic brosis: a
clinical and histopathological study. Clin Otolaryngol
Allied Sci. 1997;22:167–71.
10. Wen W, Liu W, Zhang L, et al. Increased neutrophilia in nasal polyps reduces the response to oral
corticosteroid therapy. J Allergy Clin Immunol.
2012;129:1522–8.
11. Ba L, Zhang N, Meng J, et al. The association
between bacterial colonization and inammatory pattern in Chinese chronic rhinosinusitis patients with
nasal polyps. Allergy. 2011;66(10):1296–303. https://
doi.org/10.1111/j.1398- 9995.2011.02637.x.
12. Cardoso Pereira Valera F, Queiroz R, Scrideli C, etal.
NF-κβ expression predicts clinical outcome for nasal
polyposis. Rhinology. 2010;48:408–14.
13. Al-Mot S, Filali-Mouhim A, Rousseau S, et al.
Molecular signatures as a new classication scheme
for CRS. Otolaryngol Head Neck Surg. 2011;145(2
Suppl):P125.
Eosinophils inRhinologic Diseases
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JensPonikau, MaryTwarog, DavidSherris,
andHirohitoKita
9
Core Messages
• Eosinophils are the key effector cells in
chronic rhinosinusitis (CRS) and also play an
important role in allergic rhinitis.
• Eosinophils degranulate in CRS the mucus
and not in the tissue.
• Eosinophil granular proteins, especially
major basic protein (MBP), mediate the epithelial damage in CRS.
• Secreted protein(s) from the airborne fungus
Alternaria alternata have been identied as a
trigger for the eosinophilic inammation and
degranulation in CRS patients.
9.1 Introduction
The eosinophil granulocyte, although likely rst
observed by Wharton Jones in 1846in unstained
preparations of peripheral blood, was so named
by Paul Ehrlich in 1879 because of the intense
staining of its granules with the acidic dye eosin
[1]. Since that time the eosinophil has been the
subject of extensive investigation. Its occurrence
J. Ponikau (*) · M. Twarog · D. Sherris
Department of Otorhinolaryngology, Gromo Institute
and Sinus Center, Jacobs School of Medicine and
Biomedical Sciences, University at Buffalo, The State
University of New York, Buffalo, NY, USA
e-mail: jponikau@buffalo.edu
H. Kita
Department of Medicine and Immunology, Mayo
Clinic Scottsdale, Scottsdale, AZ, USA
in such disparate conditions as parasitic infections, presumably for the benet of the human
host, and hypersensitivity diseases, perhaps to
the detriment of the patient, although paradoxical, has become better understood as a consequence of newer information. Eosinophils are
resident and non-pathologic in various organs
such as gastrointestinal tract and mammary
glands, and they may play roles in the tissue and
immune homeostasis of these organs.
However, eosinophils are strikingly absent in
the nose and paranasal sinuses in healthy individuals, which is in contrast to their presence in
three distinct rhinologic diseases:
1. Chronic rhinosinusitis (CRS).
2. Allergic rhinitis (AR).
3. Upper respiratory viral infection (common
cold).
In addition, nonallergic rhinitis with eosinophilia (NARES) has been described as a syndrome. However, it is poorly dened only as a
lack of detectable IgE combined with evidence
of eosinophils present in the nasal cavity.
Coupled with the understanding that CRS is not
limited to the sinuses but usually also involves
the nasal cavity (and consequently the terminology change from chronic sinusitis to chronic rhinosinusitis), and the similarity of symptoms, no
evidence exists to distinguish NARES from a
mild or early stage of CRS, and for the purpose
of this chapter, is assumed as such.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
Ö. Ö. Celebi, T. M. Önerci (eds.), Nasal Physiology and Pathophysiology of Nasal Disorders,
https://doi.org/10.1007/978-3-031-12386-3_9
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In the above immune responses, eosinophils
are recruited into the sites of inammation where
they produce an array of cytokines and lipid
mediators, and release toxic granule proteins.
These molecules may regulate immune response,
cause tissue damage, and facilitate tissue repair.
Eosinophils can also present antigens to naïve
and memory T cells and initiate/amplify antigenspecic immune responses. This review summarizes the biological and immunological
properties of eosinophils and discusses the roles
of eosinophils applied in the eld of rhinology,
with a focus on chronic rhinosinusitis (CRS).
9.2 Eosinophils at Baseline
Condition
9.2.1 Eosinophils Are Resident
inSeveral Tissues at Baseline
Condition
The life cycle of the eosinophil is divided into
bone marrow, blood, and tissue phases.
Eosinophils are produced in bone marrow from
pluripotential stem cells. The stem cells differentiate into a progenitor, which is capable of giving
rise to mixed colonies of basophils and eosinophils, pure basophil colonies, or pure eosinophil
colonies. Among various hematopoietic factors,
those important for eosinophil proliferation and
differentiation are interleukin (IL)-3, granulocytemacrophage colony-stimulating factor (GM-CSF),
and IL-5. IL-3 and GM-CSF are relatively nonspecic and stimulate the proliferation of neutrophils, basophils, and eosinophils. In contrast, IL-5
potently and specically stimulates eosinophil
production [2].
Although the eosinophil is a formed element
of the peripheral circulation, it is primarily a
tissue- dwelling cell. In healthy individuals, most
eosinophils are found in the gut (but not in the
esophagus), mammary gland, uterus, thymus,
and bone marrow; the gastrointestinal eosinophil
is the predominant population of eosinophils [3].
At baseline conditions, eosinophils are present
in the gastrointestinal tract independent of adap-
tive immunity and enteric ora, and the eosinophil levels are regulated by the constitutive
expression of eotaxin-1 and eosinophil chemokine receptor, CCR3 [4, 5]. Eosinophils also
home into the thymus, mammary gland, and
uterus, as controlled by eotaxin-1 [6].
As mentioned above, the eosinophil is absent
in the nose and paranasal sinuses and only present in disease stages, suggesting a crucial role as
an effector cell in the above diseases.
9.3 Immunoregulatory Roles
ofEosinophils
Previously, eosinophils have been considered an
end-stage effector cell. However, accumulating
evidence suggest that eosinophils can perform
various immune regulatory functions likely
through presentation of antigens and production
and release a range of cytokines and other immunomodulatory molecules.
9.3.1 Eosinophils Present Antigens
Eosinophils possess the ability to internalize,
process, and present antigenic peptides within
the context of surface-expressed receptors. It
also has the capacity to provide costimulatory
signals to T cells through surface expression of
molecules such as CD80, CD86, and CD40, and
ability to physically interact with CD4+ T cells
[7]. Similarly, following airway allergen challenge of mice, eosinophils trafc to and accumulate within draining lymph node, where they
upregulate MHC II, CD86, and CD54 [8].
Murine eosinophils process and present antigen
to T cell clones and hybridomas [9] and to antigen-primed and naïve CD4+ T cells in vitro
[10]. In humans, although circulating eosinophils from healthy donors are generally devoid
of surface MHC II expression, they are induced
to express MHC II [11] and costimulatory molecules [12, 13] with appropriate cytokine stimulation and after transmigration through
endothelial cell monolayer [14].
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9.3.2 Production ofCytokines
andOther
Immunomodulatory
Molecules by Eosinophils
Eosinophils are a source of a number of regulatory or pro-inammatory cytokines and chemokines [15, 16]. For example, eosinophils produce
cytokines, which are able to act on eosinophils
themselves, the so-called “autocrine” cytokines,
including IL-3 and GM-CSF [17, 18].
Eosinophils from CRS patients with nasal polyps also express TGF-β1, suggesting that TGFβ1 synthesis by eosinophils may contribute to
the structural abnormalities of nasal polyps, such
as stromal brosis and basement thickening [19].
Indeed, eosinophil-derived TGF-β enhances proliferation and collagen synthesis of lung and dermal broblasts [20]. TGF-α produced by
cytokine- activated eosinophils increases mucin
production by airway epithelial cells [21]. Thus,
a number of evidences exist to demonstrate the
ability of eosinophils to inuence the tissue
cells, leading to remodeling of tissues and
changes in their physiological properties (e.g.,
hyperreactivity to exogenous stimuli).
By producing cytokines and chemokines,
eosinophils may modulate the functions of other
immune cells. Human eosinophils can produce
IL-4 [22, 23], and IL-4 protein has been localized to eosinophils in airway [24] and skin [22]
tissue specimens from patients with IgEmediated allergic diseases. Furthermore, when
stimulated with eotaxin (CCL11) or RANTES
(CCL5), human eosinophils rapidly release
stored IL-4 by vesicular transport to the local
milieu [25]. Thus, eosinophils can provide a
strikingly wide variety of cytokines and chemokines, suggesting that eosinophils are potentially
involved in diverse biological responses, from
tissue remodeling to activation of resident and
inltrating immune cells.
In addition to producing these cytokines,
eosinophils secrete mediators with the potential
to promote Th2-type immune responses. Another
immunomodulatory factor generated by human
eosinophils is one of their granule proteins,
namely eosinophil-derived neurotoxin (EDN)
(see below for more details). EDN is an RNase A
superfamily member and, in addition to its antiviral properties, EDN is a chemoattractant [26]
and activator [27] of dendritic cells (DCs). As a
consequence, EDN enhances Th2 responses
through a TLR2-dependent mechanism [28].
9.3.3 Immunoregulatory Functions
ofEosinophils InVivo
The immunomodulatory functions of eosinophils invivo are demonstrated in murine models
of allergen sensitization and challenge with ovalbumin (OVA) and helminth infection.
Eosinophils recruitment into the sites of Th2type inammation was considered previously a
result of activation of adaptive immune response
that produces IL-5 and eotaxin [29]. However,
invivo studies with helminth infection models
revealed that an early wave of eosinophil inux
into inammation sites precedes that of lymphocytes [30–32] and that it occurs even in mice
decient in adaptive immunity [33, 34]. Notably,
in IL-5/eotaxin double- knockout mice, in which
eosinophil numbers in both blood and tissues are
severely decreased, IL-13 production of Th2
cells in response to OVA challenge is attenuated.
This defect in Th2 cells was restored by eosinophil reconstitution [35], suggesting regulation of
adaptive Th2-type immune response by
eosinophils.
The roles of eosinophils in asthmatic airway
inammation were subsequently addressed
directly by using eosinophil-decient animals.
Both Lee etal. [36] (PHIL mice) and Yu etal.
[37] developed mice depleted of eosinophils
through different genetic alteration. When sensitized and challenged with OVA, Th2-type airway
inammation and asthma-like pathology (e.g.,
airway hyperreactivity, airway remodeling, and
mucus production) were attenuated in both
mouse models, and these responses were restored
by reconstitution of eosinophils alone [38] or a
combination of eosinophils and antigen-specic
T cells [39]. Likewise, airway production of Th2
cytokines and asthma-like pathology were
diminished and exposed intranasally to the prod-
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uct of fungus Aspergillus fumigatus [40]. This
demonstrates that eosinophils are necessary to
induce the pathophysiologic changes associated
with bronchial asthma.
9.4 Eector Functions
ofEosinophils
As summarized in the reviews [1, 15, 29], eosinophils contain numerous highly basic and cytotoxic granule proteins that are released upon
activation. They also produce an arsenal of
enzymes and lipid mediators, which are implicated in effector functions of eosinophils.
9.4.1 Granule Proteins
Human eosinophil granules contain major
basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and
eosinophil derived neurotoxin (EDN). Those
proteins are located in the characteristic secondary granules of the eosinophils (Fig.9.1a,
b). MBP is stored in a crystalline stage, form-
ing the characteristic rectangle core of the
granule, whereas the other proteins are stored
in the surrounding matrix of the granule
(Fig.9.1b). Its name is derived from the fact
that MBP is the most basic protein in the
humans with a pH of 11.3, and it makes up
over 50% of the entire granular protein load of
the eosinophil. Human MBP binds to and
directly damages and destroys the surfaces of
parasites [1], and is also directly toxic to tumor
cells and other mammalian cells by disrupting
the integrity of lipid bilayers [41].
Human ECP is a basic neurotoxic protein,
with antiviral and antiparasitic properties; and
human EDN is a powerful neurotoxin that can
severely damage myelinated neurons in experimental animals [1]. EDN as well as ECP have
antiviral activities and decrease the infectivity in
RSV suspensions [42, 43]. When puried EDN
or ECP were added to RSV viral suspensions,
the viral titer are reduced, dependent on the ribonuclease activities of EDN and ECP [42].
Interestingly, ribonuclease A lacked this antiviral activity, suggesting that ribonuclease activity
is necessary but not sufcient for the anti-viral
effects of EDN and ECP.Furthermore, in guinea
pigs infected with parainuenza, pretreatment
with anti-IL-5 and reduction of eosinophils strikingly increased the viral content in the airways
[44], suggesting a potential role for eosinophils
in viral immunity and explaining the inux of
eosinophils in upper viral infections and the subsequent clinical relevant exacerbation of CRS
and asthma during common colds.
a b
Fig. 9.1 (a) Electron microscopy of tissue eosinophil in
CRS. Note the black arrow pointing to a characteristic
secondary granule (transmission electron microscopy,
original magnication ×7000). (b) Electron microscopy
of an eosinophil secondary granule with its characteristic,
rectangle crystal core, which is entirely made up of MBP
(transmission electron microscopy, original magnication
×55,000)
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EPO is a member of a mammalian peroxidase
family. EPO is a central participant in generating
reactive oxidants and radical species by activated
eosinophils [45]. Eosinophil activation invivo
shows oxidative damage of proteins through bromination of tyrosine residues [46]. Furthermore,
eosinophils are a major source of nitric oxidederived oxidants in specimens from patients with
severe asthma [47].
Considerable evidence exists to link these
eosinophil granule proteins and human diseases.
For example, the concentrations of MBP in the
bronchial alveolar lavage (BAL) uids from
patients with asthma and from monkeys are correlated with the severity of bronchial hyperreactivity [48, 49]. MBP has been localized to
damaged sites of bronchial epithelium in patients
with asthma and chronic rhinosinusitis [50, 51].
Instillation of human MBP and human EPO provokes bronchoconstriction, and MBP increases
airway responsiveness to inhaled methacholine
[50]. Interestingly, polyglutamic acid antagonizes MBP’s ability to increase respiratory resistance and bronchial hyperreactivity in
cynomolgus monkeys [52], suggesting that the
cationic nature of MBP contributes to the damage and physiologic changes. In vitro, MBP acts
as an antagonist for M2 muscarinic receptors.
Many eosinophils localized close to nerves with
extracellular MBP adhering to the nerves [53].
Finally, neutralization of endogenously secreted
MBP, either with a polyanionic peptide or with
antibodies to MBP, can prevent antigen-induced
bronchial hyperreactivity in guinea pigs [54].
Marked deposition of free EDN is also observed
in affected tissues from patients with eosinophilic esophagitis (EoE) [55]. Deposition of
EDN is reduced in certain patients with EoE who
are treated with anti-IL-5 antibody [56].
Several pro-inammatory enzymes have been
associated with the eosinophil [1]. Arylsulfatase
B is located predominantly in the small granules
of the eosinophil. β-glucuronidase activity in
eosinophils is about twice that in neutrophils,
and exposure of eosinophils to opsonized zymosan particles releases up to 24% of the total cellular β-glucuronidase.
9.4.2 Activation ofHuman
Eosinophils Takes Multiple
Stages
In early 1980s, increased number of unusual
human eosinophils with a specic gravity
<1.085 g/mL [57] was reported in peripheral
blood of patients with eosinophilic disorders,
such as hypereosinophilic syndrome [58] and
asthma [59]. These eosinophils, called
“hypodense eosinophils,” were highly reactive to
stimuli and showed increased survival, adhesion,
leukotriene synthesis, superoxide production
and antibody-dependent cytotoxicity as compared to “normodense eosinophils” [60, 61].
Thus, eosinophils in human blood are not a
homogenous population but represent various
magnitudes of activation. It was found later
eosinophil exposure to activating cytokines,
such as IL-3, IL-5, and GM-CSF, leads to development of the hypodense eosinophil.
IL-3, IL-5, and GM-CSF, besides being
growth and maturation factors for eosinophils,
stimulate several functions of mature human
eosinophils. Among human peripheral blood
leukocytes, eosinophils are the only cells having
detectable levels of IL-5 receptors in agreement
with the specic action of IL-5 on human eosinophils [62, 63]. Other Th2 cytokines, such as
IL-4 and IL-13, also activate eosinophils. IL-4
upregulates the binding of eosinophils to IgA
[64]. IL-4 or IL-13 act synergistically with
TNF-α or IL-5 for increased expression of CD69.
9.4.3 Eosinophil Activation
inInnate Immunity
Fully activated human eosinophils appear to
defend against large, non-phagocytosable organisms, most notably the multicellular helminthic
parasites. Some of the mechanisms used by
eosinophils in host defense against these organisms may also produce detrimental effects on the
host. Several lines of evidence have indicated
that bacterial and/or viral infections may exacerbate allergic inammation. Direct activation of
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eosinophils by microbe-derived molecules may
explain the mechanism.
Importantly, eosinophils are activated by a
natural cysteine protease from mite allergens,
Der f 1, and release granule proteins [65].
Eosinophils also recognize the aspartate protease activity and cysteine protease activity that
are produced by fungus Alternaria alternata
[66] and cockroaches [67], respectively, and
they release granule proteins and cytokines.
Thus, human eosinophils are equipped with
machineries that recognize and respond to proteases, such as those found in microbes and at
allergic response sites, resulting in active
release of pro- inammatory mediators.
An association between fungal exposure and
asthma has been widely recognized [68].
Moreover, exposure to Alternaria is a risk factor
for respiratory arrest in patients with asthma
[69]. These airborne fungi and their products
may contribute to the development and exacerbation of allergic airway diseases. For example,
fungal products, e.g., proteases, induce immunologic and inammatory reactions, resulting in a
Th2- like cytokine response and the destruction
of mucosal barrier functions [70]. Extracts of
Alternaria alternata and Aspergillus avus
potently induces eosinophil degranulation [71,
72], as a matter of fact they are the only known
triggers to induce release of toxic eosinophil
Major Basic Protein (MBP) which is detectable
in toxic concentration in CRS mucus. Alternaria
also strongly induces other activation events in
eosinophils, including increases in intracellular
calcium concentration, cell surface expression of
CD63 and CD11b, and production of IL-8 [71].
Interestingly, Alternaria does not induce neutrophil activation, suggesting specicity for fungal
species and cell type. In addition, when human
eosinophils are exposed to live Alternaria alter-
nata fungus, eosinophils release their cytotoxic
granule proteins into the extracellular milieu and
onto the surface of fungal organisms and kill the
fungus in a contact-dependent manner [73].
Eosinophils do not express common fungus
receptors, such as dectin-1, but use their versatile
β2 integrin molecule, CD11b (see below for
more details), to recognize and to adhere to a
major cell wall component, β-glucan.
The role of IgE in mediating eosinophil activation is controversial. Eosinophils isolated
from patients with eosinophilia degranulated in
response to anti-IgE antibody or IgE-coated
parasites [74, 75]. Eosinophils can potentially
express three types of IgE receptors, the lowafnity IgE receptor, lectin-type IgE-binding
molecule [76], and high-afnity IgE receptor. It
has been claimed that the high-afnity IgE
receptor, FcεRI, is present on eosinophils from
patients with eosinophilia and that various
functions of eosinophils, including degranulation and parasite cytotoxicity, are mediated
through this receptor [77]. On the other hand,
the number of high-afnity receptors expressed
on the surfaces of eosinophils from patients
with allergic diseases or airway eosinophilia
was minimal or undetectable [78]; and the ligation of IgE FcεRI receptor did not result in
detectable eosinophil degranulation [79].
9.5 Dierences
intheEosinophilic
Inammation Between
Allergic Rhinitis andChronic
Rhinosinusitis
The events and the pathophysiology of allergic
rhinitis have been well understood. The inhalation of an allergen where an individual has produced corresponding, circulating IgE antibodies
will cause (within 10min) a crosslink of the IgE
FcεRI receptors situated on the mast cells. This
will result in an immediate degranulation and
histamine release from the mast cells, resulting
in histamine-mediated symptoms of sneezing,
clear anterior rhinorrhea, and nasal obstruction.
About 2–8h after antigen challenge, eosinophils
enter the nasal tissue as part of the so-called late
phase allergic reaction (together with further
mast cells, B and T lymphocytes), leading to further nasal obstruction.
In contrast to allergic rhinitis, the early phase
immediate reaction is missing in CRS, explain-
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103
ing the lack of allergic rhinitis specic,
histamine- related symptoms (sneezing, anterior
clear rhinorrhea). Another clinical distinction
between CRS and AR is that CRS can occur with
or without nasal polyps, while AR never leads to
nasal polyposis. While some investigators follow
the notion that due to different severities in the
cytokine pattern, CRS with and without nasal
polys should be viewed as two different entities,
while others see it as a different spectrum of disease, with inammatory mucosal thickening on
one side of the spectrum, to gross nasal polyps
on the other side. The severity of the inammation can be easily overlooked if patients are
given systemic steroids or other anti-inammatory medication before harvesting the tissue for
examination, like pre-operatively. This distinctive eosinophilic inammation is also very heterogeneous, without eosinophilic inltration in
one area of a nasal mucosal tissue specimen, but
with intense eosinophilic inltration in another
area of the same specimen [80]. Thus, reports in
which only single biopsies are examined and in
which it was unclear whether patients had
received steroids before the biopsies were taken
need to be interpreted carefully regarding the
intensity of the eosinophilic inltrate.
The eosinophilic inammation in CRS occurs
independently of an IgE-mediated inammation,
as evident by the fact that more than 50% of CRS
patients have no detectable IgE-mediated allergies. This in return suggests non-allergic mechanism driving recruitment, migration activation
and degranulation. Indeed, very different mechanisms have been identied.
Central to the migration of eosinophils from
the vasculature into the tissue is the expression
of vascular cell adhesion molecule-1 (VCAM-
1), which has been identied in the vascular
endothelium in CRS patients [81]. This expression occurred independent of any IgE-mediated
allergy and explains the presence of eosinophils
in allergic as well as non-allergic patients with
CRS.VCAM-1 is known to specically bind to
the VLA-4 (very late-appearing antigen-4) on
eosinophils, thus causing selective adhesion and
migration of eosinophils from the vasculature to
the sinus and nasal tissue. VCAM-1 expression
is induced via either IL-4 or IL-13, which share
the same receptor on the endothelial cells. IL-4
is present and IL-13 is absent in allergic rhinitis,
which is in contrast to non-allergic CRS, where
only IL-13 is present in the tissue, but IL-4 is
absent [82]. In patients with CRS and allergies,
both IL-4 and IL-13 are present. This cytokine
pattern indicates that eosinophils are recruited
via two distinct cytokines, IL-4 in AR and
IL-13in CRS; however, both diseases can coexist as CRS with allergies (comorbidity), with
both IL-4 and IL-13 present.
Signicantly elevated levels of IL-5, the key
cytokine that mediates eosinophil differentiation, survival and activation, are present in tissue
specimens of CRS patients and AR patients, and
not in those of healthy controls [2, 83–85]. A
majority of the IL-5 staining cells are lymphocytes (68%), followed by eosinophils (18%) and
mast cells (14%) [83]. The exact combination of
source cells for IL-5in AR is not known.
The importance of IL-5, IL-13, and eosinophils in the CRS pathophysiology is emphasized though the rst approval of a therapeutic
monoclonal IL-13 antibody (dupilumab) for the
treatment of CRS with nasal polyps. In two
large phase 3 trials, dupilumab was efcacious
in reducing nasal symptoms including congestion, improved CT scans, and reduced nasal
polyp size [86].
In addition, IL-5 antibodies are already FDA
approved for eosinophilic asthma, and are currently in clinical trials for CRSwNP.
9.6 What Are theKnown
Triggers fortheCytokine
Response Leading
totheEosinophilic
Inammation?
While many different allergens can lead to the
release of IL-5in AR via the IgE-mediated pathway, any trigger for the non-allergic production
of IL-5 and IL-13in CRS (and other cytokines
leading to eosinophilia) was thus far unknown.
This changed when certain molds were found
to induced the elevated production of IL-5in iso-
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J. Ponikau et al.
lated peripheral blood mononuclear cells
(PBMCs), which contained lymphocytes and
other cells that can serve as antigen-presenting
cells from 16 out of 18 CRS patients stimulated
with Alternaria antigens [87]. More importantly,
PBMCs from none of the 15 healthy controls did
release IL-5in response to Alternaria alternata.
PBMCs from allergic and non-allergic CRS
patients produced similar amounts of IL-5, indicating that this reaction is independent from an
IgE-mediated allergic reaction. In addition,
PBMCs from 33% of CRS patients stimulated
with Cladosporium and 22% of CRS patients
stimulated with Aspergillus antigens also show
increased production of IL-5; no response is
seen with stimulation with Penicillium antigen,
and none of the healthy control subject responded
to any fungal stimulus.
But not only IL-5 was produced by the CRS
patients’ immune cells in response to Alternaria.
The mold also induced the release of large
amounts of IL-13in all the CRS patients studied,
the cytokine triggering the recruitment of eosinophils from the vasculature into the tissue in
CRS.Again, none of the healthy controls were
producing any detectable IL-13 [87].
Furthermore, production of interferon-γαμμα
(IFN-γ), a Th-1 cytokine which facilitates
destruction of parasites by eosinophils, was 5.5
times higher in PBMCs from CRS patients stimulated with Alternaria antigen compared with
production by healthy control PBMCs [87].
When nasal secretions from nine healthy controls and nine CRS patients were examined,
there were no differences in their levels of total
Alternaria proteins, indicating that both groups
had similar levels of Alternaria in their nasal
mucus. This study was important since it was the
rst to demonstrate a non-allergic pathway in
CRS leading to the production of the crucial
cytokines for the eosinophilic inammation,
which was absent in healthy controls. In addition, it also showed a specic trigger for the
cytokine production, a common mold being
present in nose of every person tested.
Now that a trigger (Alternaria alternata
(ALT)) had been identied, two more breakthroughs were made: (1) the discovery of innate
Lymphocyte Cells Type 2 (ILC-2) and their crucial role in initiating the cytokine cascade leading to Th-2 shifting and eosinophil-mediated
immunity, and (2) the discovery of IL-33 as a
regulating cytokine which is produced the basal
layer of the airway epithelial cells.
When now mice were sensitized to Alternaria
alternata (ALT), and then challenged with ALT,
they produced severe airway eosinophilia,
including airway reactivity (asthma). Alternaria
challenge caused the release of IL-33 which
peaked after 1h, followed by the release of IL-5
and IL-13 which peaked after 6h; thus, IL-33
preceded the IL-5/-13 release [88, 89].
The next step was to knock out the IL-33
receptor (ST2
−/−
), which resulted in the elimination of IL-5/-13 release, and showed that IL-5/13 production was IL-33 dependent [89].
Surprisingly, the control group, which did not
get the ALT sensitization, but got only the ALT
challenge, produced a similar airway eosinophilia. To further investigate this, mice which
had the CD4+ acquired immunity knocked out
−/−
(Rag1
) where challenged with ALT, but
despite them having no CD4+ acquired immunity produced similar levels of Th2 cytokines
IL-5/-13/-33 [89]. Thus, the source for the cytokines had to be innate. Indeed, knocking out the
innate lymphocytes (Myd88−/−) completely
depleted the ALT-induced IL-5/-13/-33 cytokine
production. Thus, the initial source for the cytokines leading to airway eosinophilia was indeed
innate, and Alternaria alternata was a reliable
trigger [89].
Recently discovered innate lymphocyte cells
type 2 (ILC-2) were suspected to play a role.
Consequently, when ILC-2 knockout mice
−/−
(II7r
) where challenged with ALT the eosinophilic air way inammation did not occur.
However, when ILC-2 cells were isolated from
normal mice and transplanted into the ILC-2
knockout mice, the eosinophilia was back to full
strength, which demonstrated that ILC-2 cell
mediates the initial (innate) Th2 response to ALT
[90].
Other allergens by itself, such as Aspergillus
fumigatus (ASP), or house dust mites (HDM),
did not induce any eosinophilic airway inam-
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