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9 Eosinophils inRhinologic Diseases
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105
mation, which was in contrast to ALT.However,
when ALT was combined with ASP and HDM,
the intensity of eosinophilia more than doubled
compared ALT alone. Thus, other allergens were
not able to initiate an eosinophilic inammation
like ALT did, but when combined with ALT, they
intensied the ALT-induced eosinophilia [91].
The critical involvement of IL-33 in ILC-2
cells in CRS with eosinophilia (ECRS) was then
strengthened by showing signicant elevation of
IL-33in patients with eosinophilia compared to
patients without tissue eosinophils [92, 93], and
showing that the ILC-2 cells are responsive to
the IL-33 stimulus by releasing IL-13, which
controls eosinophil recruitment from the vasculature into the tissue [94].
It was again Alternaria identied as a trigger,
which signicantly stimulated the release of
IL-33 from cultured nasal epithelial cells from
ECRS patients, compared with no IL-33 release
from non-ECRS patients and other control subjects [95].
A secreted enzyme from Alternaria, which
was a serine protease, was identied as a potential molecular culprit to mediate the IL-33dependent eosinophilic inammation [96].
Even more importantly, ALT was found to
cause a processed version of IL-33 to be released
by epithelial cells, which is cleaved and has only
a molecular weight of 19KDa, which is signicantly less than the 30KDa of the natural, full
length form [97]. The clinical signicance is that
the cleaved 19KDa long processed version is
about 30 times as potent than the natural 30KDa
form [97]. Thus, the ALT stimulus causes a signicantly more potent version of the crucial
IL-33 to be released by epithelial cells.
It was interesting that, while the initial innate
response to ALT was mediated by ILC-2 cells,
mice exposed to the Alternaria dominated allergen cocktail had developed a CD4+ mediated
acquired immune response after 4weeks of continuous exposure [91].
Thus, their immune system appears to have
shifted from a solely innate, ILC-2-mediated initial immunity triggering the eosinophilic inammation, to a CD4+ Th-2 type immunity which is
mediating the long-term IL-5, -13 and -33 cyto-
kine production, which in turn is mediating the
eosinophilic inammation. Importantly, while
ALT was the essential trigger, other allergens
such as ASP and HDM were able to contribute to
ALT-induced inammation, without being able
to incite the eosinophilia itself [91].
9.7 Initiation ofIgE Production
If Alternaria alternata exposure or stimulation is
able to induce Th-2 shifting in mouse models,
shifting naïve mammals toward a Th-2 hypersensitivity (allergic) subtype, how would IgEmediated allergy and aspirin sensitivity t in?
When naïve mice were exposed intranasally
to Ovalbumin (OVA), a very strong allergen, for
8weeks, they did not respond with an IgE production to OVA.However, when OVA was combined with Alternaria alternata (ALT), mice
started to produce IgE to OVA.Other combinations, like OVA + Aspergillus (ASP), or OVA +
House dust mites (HDM), did not trigger any
OVA specic IgE production. However, if ALT,
ASP, HDM, and OVA were combined, the OVAspecic IgE production was over 700% higher
compared to ALT + OVA alone [91].
In a follow-up study, JH
−/−
(B cell) knock out
mice showed and attenuated response, suggesting
that B cells are necessary to mediate this
Alternaria-induced pathway to IgE production
[98].
This suggests that inhaled allergens work
synergistically to trigger IgE production allergens, in this case OVA, with again Alternaria
being the key and necessary ingredient for the
development of an IgE-mediated allergy to
another allergen.
9.8 Aspirin-Exacerbated
Respiratory Disease (AERD)
It is clinically well known that certain patients react
after Aspirin (ASS) intake with an exacerbation of
their asthma symptoms, and the triad of CRS with
nasal polyposis, asthma, and aspirin intolerance is
named after Samter, who rst described it in 1968.
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It is now understood that arachidonic acid is metabolized to prostaglandins in a cyclooxygenase (CoX
1+2) dependent pathway. However, if that pathway
is blocked by CoX inhibitors, such as Aspirin, the
arachidonic acid is metabolized through the
5-Lipooxygenase pathway instead, producing leukotrienes, which signicantly magnify existing
eosinophilia, but cannot induce the eosinophilia by
themselves. Human Th2 cells (in contrast to Th1
cells) selectively express the high-afnity Cysteinyl
leukotriene receptor 1 (CysLT1R), which is the
receptor for leukotriene D4 (LTD4), and stimulation of Th2 cells with leukotrienes-induced chemotaxis of eosinophils, and IL-13 production that was
dependent on CysLT1R [99].
Again, the fungus Alternaria alternata was
found to induce CysLT1R expression on both
innate lymphocyte cells type-2 (ILC-2) as well
as Th2 cells, potently induced CysLT1R dependent IL-5, and IL-13, as well as the associated
eosinophilia. Additionally, LTD4 then potentiated Alternaria induced eosinophilia and ILC-2
proliferation and accumulation [100].
In a follow-up study, airway challenges with the
parent leukotriene C4 (LTC4) potentiated the effect
of IL-33 to naive wild-type mice, and led to synergistic increases in airway IL-13 and IL-5 cytokines
and resulting eosinophilia, compared to IL-33
alone. This immune response was mediated by
innate lymphocyte cells type 2 (ILC-2), independent of the acquired immune system. The synergistic effect of LTC4 with IL-33 was again completely
dependent upon CysLT1R.CysLT1R
−/−
(knockout)
mice had reduced lung eosinophils and ILC2 cytokine responses (IL-13/IL-5) after exposure to
Alternaria alternata, which again induced a robust
eosinophilic airway inammation via the Th2 cytokine pathway. Thus, CysLT1R promotes LTC4 and
Alternaria-induced ILC2 activation and eosinophilic airway inammation [101].
9.9 Eosinophil-Mediated
Damage inCRS, But Not
inAllergic Rhinitis
CRS patients exhibit severely damaged epithelium and thickened basal membrane, features of
airway remodeling seen as also seen in asthma,
which is in contrast to the absence of airway
remodeling in AR.It has been demonstrated that
eosinophilic MBP is capable to produce those
changes, and indeed MBP has been localized
with the epithelial damages found in CRS [51,
80]. Interestingly, toxic MBP levels have mea-
sured in CRS, but free MBP could not be measured in AR mucus, explaining the damage in
CRS, and its absence in AR [102]. This suggest
that MBP is released in the mucus in CRS but
not in AR.
Two prospectively designed histologic studies of tissue and mucus obtained during CRS
surgery used extra caution to preserve the
mucus. While eosinophils were intact in the tissue and in the epithelium, eosinophilic-rich
mucus with clusters of aggregated eosinophils
was found in 96% (97/101) and 94% (35/37) of
consecutive CRS patients [103, 104]. Another
study demonstrated that eosinophils released
their toxic MBP in the mucus within these clusters, and not in the tissue [51]. Estimated concentrations of MBP within the clusters, based
on digital analysis of the intensity of the MBP
staining, were as high as 2mM and far exceeded
those capable of mediating epithelial damage.
Overall, the clusters of eosinophils and intense
eosinophil degranulation in the mucus suggest
that eosinophils merely travel through the CRS
tissue to the mucus where they degranulate and
release their toxic proteins (Fig.9.2a, b).
These invivo observations explain the patterns of damage in CRS, where only the outer
layers of tissue are damaged (Fig.9.3a), suggesting that the damage to the epithelium is
inflicted from the outside (luminal side). This
epithelial damage may predispose CRS
patients to be susceptible for the secondary
bacterial infections, leading to acute exacerbations, which are observed clinically, and
absent in AR (Fig. 9.3b). Because bacteria
always elicit a neutrophilic inflammation in
hosts, these acute exacerbations of CRS are
presumed to be of bacterial origin. However,
bacteria are not known to elicit an eosinophilic
inflammation that predominates in CRS,
which suggests a nonbacterial etiologic mechanism for CRS.
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107
a
c
Fig. 9.2 (a) CRS tissue and attached eosinophilic mucin
show massive eosinophilic migration of eosinophils from
the tissue (left side of the image) into the mucus (right
side of the image). The white arrows mark the eroded epithelium typical in CRS.The mucus contains large sheets
(clusters) of eosinophils and eosinophilic debris (original
magnication ×800, HE). (b) Serial section of 2a with
immunouorescent staining with an antibody against
MBP reveals intact eosinophils in the tissue (left side of
the image) and free eosinophil granules. In contrast, once
the eosinophils have reached the mucus, MBP is diffusely
b
released in toxic concentrations. Note that MBP staining
reaches brightness in the mucus exceeding the one inside
the intact tissue eosinophils, indicating continuous deposition of free MBP into the same eosinophilic clusters in
the mucus. (original magnication ×800, anti-MBP).
(c) Serial section of 2a with immunouorescent staining
with an antibody against Alternaria alternata. Note the
absence of fungal antigens in the mucus. The red arrows
mark some examples of fungal hyphae in cross-section;
however, disseminated fungal debris is also visible (blue
arrows, original magnication ×800, anti-ALT)
Fig. 9.3 (a) Tissue from CRS patient shows intact tissue
eosinophils (blue arrows) and eosinophils traveling
through the severely damaged epithelium (yellow arrows).
Note the missing upper layers of epithelial cells and missing cilia, suggesting that the damage is inicted from the
luminal side. The white arrow highlights the thickened
ba
basal membrane. (original magnication ×1000, HE). (b)
Tissue from AR patient reveals intact epithelium including cilia and scattered eosinophils (white arrow). Note
also the absence of basal membrane thickening (original
magnication ×400, Hematoxylin Eosin)
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J. Ponikau et al.
9.10 What Causes Eosinophil
Degranulation?
In a recent study, eosinophils from healthy
people that were incubated with Alternaria
alternata antigens released signicant amounts
of eosinophil- derived neurotoxin (EDN) and
Major Basic Protein (MBP), the latter known
to mediate epithelial damage and basal membrane thickening, being part of airway remodeling in CRS.
When eosinophils from patients with asthma
or allergies were used, they even released about
70% more EDN compared to the healthy controls. The fraction from Alternaria alternata,
which induced the degranulation, had a molecular weight of ≈60kDa, was highly heat labile,
and worked protease-dependent through a G
protein- coupled receptor, identied as the
beta2- integrin of the CD11b receptor [71].
Other fungal antigens, including Aspergillus,
Cladosporium, and Candida, did not induce
eosinophil degranulation, nor did neutrophils
respond to Alternaria extracts, suggesting the
presence of a fungal species and cell type specic novel innate immune response to certain
fungi in human.
Another study from India identied also
Aspergillus Flavus as a trigger for MBP
release, demonstrating that other fungi besides
Alternaria alternata (tenuis) can also induce
MBP release [72].
Those studies have signicance, since no
other triggers (except fungal organisms) for
eosinophilic MBP release from inhaled allergens
or microorganism (bacteria) are known.
However, CRS patients have large and toxic
amount of MBP in their nasal and paranasal cavity (Fig.9.2b), especially where fungal antigens
can be detected (Fig.9.2c).
Thus, both innate and acquired immune
responses to environmental fungi, such as
Alternaria alternata may increase production of
the cytokines and provide cellular activation signals necessary for the robust eosinophilic inammation in CRS patients.
9.11 Summary andFuture
Directions
Eosinophils fulll distinctive and different function in CRS versus AR, although frequently
overlapping clinically. Those differences presumably result in two different pathophysiological mechanisms, mainly distinguishable through
the clustering of eosinophils and the subsequent
release of the eosinophil specic toxic major
basic protein (MBP) into the mucus in CRS.In
contrast, in allergic rhinitis, the eosinophils
appear to follow more a process of a controlled
cell death, without the release of toxic Major
Basic Protein (MBP), and without the subsequent epithelial damage. This difference in the
degranulation patterns explains the different
clinical and pathophysiologic presentation
between CRS and AR.
The fungus Alternaria alternata (ALT) has
emerged as a key trigger for the eosinophilic
inammation. Its antigens induce epithelial cells
to release a cleaved version of IL-33, which is
about 30 times as potent as the natural occurring
IL-33, and which cause the activation of the
innate immune system via ILC-2 cells to not
only produce crucial IL-13 (eosinophil recruitment) and IL-5 (eosinophil activation and life
prolongation), but also shift a naïve immune system toward a Th2-type, allergic subtype, including the initiation of IgE-mediated allergy to
other airborne allergens.
ALT also allows other allergens to act synergistic, worsening the eosinophilic inammation,
which they cannot do by themselves alone. This
initial innate immunity (ILC-2) appears to be
replaced after continuous challenge by the
acquired immune system and mediated by CD4+
lymphocytes, resulting in chronicity of airway
inammation. Last by not least, Alternaria alter-
nata induces activation and degranulation,
including the detrimental MBP release, of human
eosinophils.
Thus Alternaria alternata is thus far the only
trigger known to cause a concerted immune
response in epithelial cells and regulatory lympho-
9 Eosinophils inRhinologic Diseases
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109
cytes representing the innate and acquired immune
system. In addition, the eosinophils act as effector
cells themselves, with ALT causing their degranulation and toxic MBP release. ALT also links
together the development of IgE- mediated allergy,
Th2-shifting, and aspirin sensitivity, and gives new
insides into the mediating receptors.
Understanding the details of those mechanisms and the eosinophil’s function has now led
to the development and the approval of antiIL-13 antibody therapy for the treatment of CRS
with nasal polyposis, with Alternaria alternata
being the only known trigger thus far for IL-13
production in CRS patients. Thus, those novel
insides into the immunologic reaction produce
targets to further improve the care of patients
suffering from these chronic, eosinophil-mediated, inammatory diseases in rhinology.
Take Home Pearls
• Eosinophils show different behavior patterns
in chronic rhinosinusitis versus allergic rhini-
tis, resulting in different pathophysiologies.
• Anti-IL-13 antibody treatment is the rst
immunologic therapy for CRS with nasal
polyps.
• The fungus Alternaria alternata causes a con-
certed immune response, shifting the immune
system towards a Th2 subtype.
• Alternaria triggers a concerted immune
response, including epithelial cells, innate
and acquired lymphocytes, to activate and
recruit eosinophils.
• Alternaria triggers activation and degranula-
tion of eosinophils.
• Aspirin sensitivity and the development of IgE-
mediated allergy is inducible by Alternaria.
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Biologic Therapies forChronic
https://t.me/medicina_free
Rhinosinusitis
MichaelJ.Aw andShaunJ.Kilty
10
Core Points
• Chronic rhinosinusitis (CRS) is a complex
heterogeneous inammatory disease that is
characterized by type 1 and type 2 inammation, with type 2 inammation predominating
in patients with CRS with polyps.
• Despite the efcacy of current medical and
surgical therapies, there are many patients for
whom disease control remains elusive.
• Biologic therapies are biologically targeted
treatments that offer patients with recalcitrant
CRS disease, a new treatment option.
Chronic rhinosinusitis (CRS) is a complex multifactorial inammatory disease of the nose and
paranasal sinuses that impacts 5–12% of the
worldwide adult population [1–3]. Often diagnosed later in life, the onset of primary CRS occurs
generally between 40 and 60years of age [4]. The
diagnosis of CRS is based on both clinical symptoms and mucosal changes observed with either
endoscopy or computed tomography (CT) [2].
This disease is associated with signicant morbidity and has been associated with a substantially
reduced health-related quality of life [4]. In North
M. J. Aw
Faculty of Medicine, The University of Ottawa,
Ottawa, ON, Canada
S. J. Kilty (*)
Department of Otolaryngology-Head and Neck
Surgery, The University of Ottawa/The Ottawa
Hospital, Ottawa, ON, Canada
America, a majority of people with CRS report
facial pain (60–92%), nasal congestion (95–
100%), loss of olfaction (56–84%) and headache
(33–90%) [5]. The costs of managing CRS are not
insignicant, with the annual direct cost of CRS
treatment ranging from 5560 to 5955 USD per
patient, and annual indirect costs estimated at
10,077.07 USD per patient [6, 7]. The annual total
direct cost attributed to CRS treatment in the
United States has been previously estimated at
upwards of from 60.2 billion USD [6].
The commonly used treatments for CRS focus
on the control of inammation by either regulating mucosal inammation with topical or systemic corticosteroids, reducing planktonic
bacterial burden with antibiotics and the improvement of sinus ventilation and access for topical
therapies, with endoscopic surgeries. However,
despite medical and surgical therapy, a subset of
patients, often labelled as difcult-to-treat, do not
achieve adequate inammation, and subsequently, symptom control [8, 9]. The use of biologic therapies originally developed for other
inammatory diseases, such as asthma, have
demonstrated that they may have an important
role to play in CRS care, particularly for difcult-
to- treat patients. The signicant implications on
health and healthcare attributed to this prevalent
disease warrants the study of disease-modifying
agents to better control mucosal inammation to
reduce the burden of disease. Here, we discuss
recent advances in CRS treatments.
© 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_10
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