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M. Jorissen and M. Jaspers
b
c
d
e
Fig. 3.3 (a) Drawing (left) and Transmission Electron
Microscopy (TEM) photo (right) of a longitudinal section
of a ciliary axonema; (b) longitudinal section of the tip
and (c) until (g) are cross-sections such as those can be
seen at the indicated levels namely (c) near the tip, (d) in
f
a
the ciliary shaft, (e) just above the footplate and (f) in the
upper part of the basal body; the image of Fig.3.2 is a
cross- section of the main central part of the axonema. 1
bers, 2 basal foot, 3 rootlets
g
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a
b
33
Fig. 3.4 The dynein motor unit or heavy chain consists
of six tandemly linked AAA ATPase domains, which form
a ring [8], with the linker emanating from AAA1 and the
coiled-coil stalk with the microtubule (MT)-binding
domain located between AAA4 and AAA5 (a). Following
ATP hydrolysis, the AAA rings of the dynein motor units
force through an ATP-driven temporary interaction with an adjacent doublet B tubule and a tail
domain that is stably xed to the outer doublet A
tubule (Fig.3.4).
3.1.4 Structural Abnormalities
Up to 5% abnormalities is normal.
In healthy persons, more than 95% of the cilia
are ultrastructurally completely normal. Only in a
minority of transverse section of cilia abnormalities are found. The percentage of abnormalities
may increase as a result of inammation, infection, and exposure to toxic agents. This is called
secondary ciliary dyskinesia (SCD) to distinguish from the inherited abnormalities: primary
ciliary dyskinesia (PCD).
were observed to move 8nm toward the distal end of the
axoneme [9]. As the motor is connected temporarily to the
adjacent B tubule via the MT-binding domain, located at
the tip of the coiled-coil stalk, this would result in the B
tubule being dragged distally (b)
Dynein deciency remains the most frequent
ultrastructural abnormality in PCD.In up to 1/3,
no ultrastructural abnormality is found.
Primary (genetic) defects in the structure and
function of sensory and motile cilia result in
multiple ciliopathies. The most prominent genetic
abnormality involving motile cilia (and the respiratory tract) is primary ciliary dyskinesia (PCD). PCD
reects abnormalities in the structure and function
of motile cilia. The most common ultrastructural
defects related to PCD are the total or partial
absence of dynein arms and absence or dislocation
of central tubules. Besides, a signicant number of
PCD patients have cilia with normal ultrastructure
but abnormal ciliary mobility (CBF and coordination). Based on the structural abnormalities found in
PCD, patients can be classied into different subgroups (see also Figs.3.5 and 3.6):
34
23%
17%
central ecc
peripheral
a
cd
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Fig. 3.5 Distribution of
different ultrastructural
subgroups in PCD based
on a series of 312
patients in the UZ
Leuven database
a b
central absent
8%
+ IDD
11%
ODD + IDD
2,5%
microt abn
0,5%
ODD
M. Jorissen and M. Jaspers
normal
35%
aplasi
3%
partial
ODD
Fig. 3.6 Ultrastructural abnormalities in PCD: (a) dynein deciency, (b) absent central pair, (c) eccentric central pair,
and (d) eccentric central pair + transposition
• Outer dynein arms deciency (ODD).
• Partial outer dynein arms deciency (part
ODD).
• Outer + inner dynein arms deciency
(ODD+IDD).
peripheral microtubular abnormalities, blebs of
the axonemal membrane, excess cytoplasm,
absence of the axonemal membrane, and ciliary
disorientation of the central pair microtubules
(see Fig.3.7).
• Eccentric central pair + inner dynein
deciency.
• Central pair of microtubules absent.
3.1.5 Genetic Heterogeneity ofPCD
• PCD with normal ultrastructure.
• Ciliary aplasia (no cilia and no basal bodies).
The genetic heterogeneity of PCD is predicted by
the complexity of the ciliary structure and the dif-
In the majority of patients, these abnormalities
can be differentiated from the acquired abnormalities: secondary ciliary dyskinesia (SCD).
However, there may be considerable overlap, and
in PCD patients, frequently SCD abnormalities
are found, because of inammation and infections. The most frequent ultrastructural abnormalities in SCD are the compound cilia,
ferent structural component affected. Cilia consist of more than 250 proteins and thus many
genes are involved in ciliary structure and function. Currently, mutations in more than 40 different genes coding for axonemal proteins have
been described, which explain about 70% of
PCD [10, 11]. Mutations in one of these genes
known to be associated with PCD (ARMC4,
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a b c
d ef
Fig. 3.7 Ultrastructural abnormalities in SCD: (a) compound cilia, (b) and (c) peripheral microtubular abnormalities,
(d) blebs of the axonemal membrane, (e) excess cytoplasm, and (f) absence of the axonemal membrane: naked cilium
CCDC103, CCDC114, CCDC151, CCDC39,
CCDC40, CCDC65, CCNO, CFAP298,
CFAP300, DNAAF1, DNAAF2, DNAAF3,
DNAAF4, DNAAF5, DNAH11, DNAH5,
DNAH8, DNAH9, DNAI1, DNAI2, DNAJB13,
DNAL1, DRC1, GAS8, HYDIN, LRRC56,
LRRC6, MCIDAS, NME8, OFD1, PIH1D3,
RPGR, RSPH1, RSPH3, RSPH4A, RSPH9,
SPAG1, SPEF2, STK36, TEKT1, TTC25,
ZMYND10) underlie specic ciliary ultrastructural defects identied by transmission electron
microscopy. For instance, DNAH5, DNAI1, and
DNAI2 cause outer dynein arm (ODA) defects
[12–14], while mutations in radial head spoke
proteins (RSPH9, RSPH4A) and the coiled-coil
domain-containing proteins (CCDC39, CCDC40)
are linked to central pair defects [15, 16].
However, mutations in some genes such as
DNAH11 do not result in a detectable
ultrastructural defect on transmission electron
microscopy [17].
Half of PCD families with ODA defects har-
bored DNAH5 mutations. DNAH5 encodes a
heavy chain of the ODA. The prevalence of
DNAI1 mutations is 10–13% in PCD patients
with dened ODA defects, but only 2–4% in the
whole cohort of PCD patients. All these genes
combined explain approximately 70% of PCD
cases; therefore, more genes need to be identied
[10, 11, 18].
3.2 Ciliary Movement
3.2.1 Ciliary Beat Cycle
The ciliary beat cycle consists of an effective and
a recovery stroke.
Respiratory cilia have a rhythmical beating
pattern and beat in a synchronous waveform.
Every beat cycle consists of two active components: an effective stroke, during which the fully
extended cilium moves in a plane perpendicular
to the cell surface, and a recovery stroke, during
which the bended cilium moves more parallel to
the cell surface sideward and backward to its
starting position; see Fig.3.8. The duration of a
recovery stroke is two to three times that of an
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Fig. 3.8 Ciliary beat. The cilium performs an effective
stroke (white cilium, thin arrow) and stays thereafter for
some time in a resting position. The recovery stroke (black
cilium, dotted arrow) is the start of a new cycle and takes
place in a third dimension (courtesy of TESAV)
effective stroke. After the effective stroke, there
is a short resting phase before the cilium starts its
recovery stroke. The direction of the stroke
depends on the orientation of the central microtubules [6].
As mentioned above, the bending of the cilia
is produced by sliding the outer microtubule doublets against one another comparable to the actinmyosin system in muscles. The energy needed
for the ciliary beat is produced by hydrolysis of
ATP by the ATPase domains of the dynein arms.
The velocity of the sliding movements and the
frequency of the ciliary beat are correlated with
the number of dynein arms and the concentration
of ATP [19, 20].
A ciliated cell has approximately 200 cilia that
beat in a coordinated way, and cilia on adjoining
ciliated cells (unit of ciliated cells) are beating
simultaneously. Ciliary beating is coordinated by
calcium signaling between epithelial cells
through gap junctions. Besides the regulatory
effect of calcium on the ciliary beat, calcium is
also involved in synchronizing the beat among
cilia of one single cell as well as between cilia in
different cells [21, 22]. Ciliary beat frequency
increases from the more peripheral parts of the
respiratory tract to the more central parts. In
larger airways like the nose, trachea, and main
bronchi, the frequency is 13–27Hz; in smaller
airways like the middle ear, small bronchi, and
M. Jorissen and M. Jaspers
bronchiole, the frequency is 7–12Hz. The beat
frequency increases with temperature and
decreases with a reduction in relative humidity of
the air.
Regulation of cilia that play a role in mucociliary clearance is complex, and any disturbance
can lead to disease.
3.2.2 Factors Inuencing Ciliary
Activity
Several factors inuencing the ciliary beat frequency have been described, including temperature, pH, and osmolarity [23]. A constant medium
temperature is essential for the accurate measurements, since CBF is temperature-dependent.
Ingels etal. [23] demonstrated a linear relationship between CBF and temperature in the range
from 22.5 to 40°C.Changes in pH and osmolarity do not inuence CBF when kept within a certain range. A pH change from 7.5 to 6.5 did not
affect CBF, below a pH of 6.5 CBF decreases.
Concerning osmolarity, a gradient of 150–
225mM (0.9–1.35%) NaCl did not affect CBF
substantially. In hypotonic (0.45%) and hypertonic (1.5%) saline solutions, CBF decreases by
50% compared to the initial frequency [24],
while at 3% saline cilia are complete immotile.
Βeta-adrenergic inuences on the respiratory
mucosa are well known to cause enhancement of
ciliary activity and mucociliary clearance [25,
26]. However, considering that isoproterenol
stimulates secretory function in airways [27], the
question remained whether this increase in ciliary activity was due to a direct and specic action
on the ciliated cells. Verdugo etal. [28] demonstrated that isoproterenol directly stimulates the
activity of ciliated cells of the respiratory epithelium and that this effect was β-adrenergic specic
since the observed stimulation could be blocked
by propranolol. Toxins derived from bacterial
infections reduce ciliary activity of human nasal
epithelial cells [29, 30], and reduced ciliary activity can aggravate inammation. Mallants etal.
[31] found that after a toxin-induced decrease,
both bacitracin and clindamycin resulted in a
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37
complete recovery of CBF, suggesting that topical antibiotic treatment of nasal infections could
result in a dual positive effect, namely, treatment
of bacterial infection and recovery of the ciliary
activity.
3.2.3 Abnormal Beating Patterns
intheContext ofPCD
Recent studies have conrmed that the ciliary
beat pattern is associated with specic ultrastructural defects in PCD [32]. New high-resolution
digital high-speed video (DHSV) imaging has
allowed the precise beat pattern of cilia to be
viewed in three different planes in slow motion or
frame by frame. Using this technique, three patterns were identied and correlated with ultrastructural defects.
In the rst pattern, the cilia are virtually
immotile in large areas. Ciliary movement, when
present, is restricted to slow, low-amplitude, stiff
ickering motion. This is associated with either
an isolated outer dynein arm defect or a combined inner and outer dynein arm defect.
In the second pattern, the cilia have a very
abnormal stiff forward power stroke with a markedly reduced amplitude. This pattern is associated with an inner dynein arm defect or a radial
spoke defect.
In the third pattern, the cilia beat in a large
circular gyrating motion about the base of the
cilium. This pattern is associated with transposition defects.
3.3 Mucociliary Transport
3.3.1 Structural andFunctional
Organization
Ciliary organization comprises four levels.
Mucociliary transport is the nal result of the
functional and ultrastructural organization of the
cilia at different levels: single cilium, interciliary
coordination, metachronal waveform, and mucociliary pathways [33].
• First level: Single cilium.
A single cilium has a specic and well-
characterized ultrastructure: a 9+2 microtubular organization or axoneme. Morphological
investigation at this level is mostly done with
transmission electron microscopy (TEM).
Ciliary beat frequency (CBF) is the most frequently used parameter of a single ciliary
function. Other parameters are the beating
pattern, the amplitude, and the beat-to-beat
variation (signal consistency [23]; intracellular variability [34]).
• Second level: Ciliary orientation and
coordination.
Cilia have to beat in a coordinated way to
produce mucociliary transport, within one
ciliated cell and between different cells.
Ciliary activity is coordinated when all cilia
beat in phase and in the same direction. This
intra- and intercellular ultrastructural coordination can be studied using scanning electron microscopy (SEM) and transmission
electron microscopy (TEM): ciliary (dis)orientation. Ciliary orientation can be measured in TEM images of transverse sections
in which the two central microtubules could
be seen. A line is drawn through the central
microtubular pair of each transversely sectioned cilium. The angle between this line
and a reference line is measured for all cilia
seen in one photograph; see Fig. 3.9. The
standard deviation of all these measured
angles is the ciliary disorientation. A normal
value is 15°; >20° may be considered disorientation; and >35° corresponds to random
orientation [35–38].
• Third and fourth levels: Metachronal wave
form and mucociliary transport pathways.
Finally, the coordination results in the
metachronal wave form which can easily be
seen in scanning electron microscopy and
which is linked not only to the small phase difference between neighboring cilia within one
cell but also intercellularly to a whole surface
area. The metachronal waveform and the CBF
are regulated by different intraciliary, intracellular, and intercellular mechanisms [39].
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Fig. 3.9 Normal orientation with perfect alignment of all cilia (left) and random disorientation of the central pair in the
context of PCD (right)
M. Jorissen and M. Jaspers
At a macroscopical level, this is organized
in various streams that can only be measured
overall as mucociliary transport. Mucociliary
transport is the process by which ciliary activity causes the transport of a thin lm of mucus
from the upper and lower respiratory tracts
toward the digestive tract. Effective and coordinated ciliary beating is of the utmost importance for mucociliary transport.
3.3.2 Mucociliary Transport
Healthy airway surfaces are lined by ciliated epithelial cells and covered with an airway surface
liquid, which is composed of two layers: the periciliary layer and the mucus layer. The low viscosity periciliary layer approximates the height of
cilia and provides an optimal environment for
ciliary beating [40]. The protective mucus layer
on top of it is the secretory product of the goblet
cells and the submucosal glands. It is a nonhomogeneous, adhesive, viscoelastic gel composed of
water, carbohydrates, proteins, and lipids. This
mucus layer traps foreign particles like dust,
allergens, toxic substances, bacteria, and viruses
from the air. Mucus is transported from the respiratory tracts into the pharynx by mucociliary
clearance, where it is either swallowed or
expelled via coughing. Mucociliary clearance in
the airways is driven by the coordinated beating
of ciliated cells in the airway epithelium. The
permanent clearance of the mucus toward the
pharynx is the most important defense mechanism in the upper and lower respiratory tracts.
The velocity of mucus clearance is 10–24mm/
min in the trachea, 4.5–7 mm/min in the nose,
and 0.5–2 mm/min in the bronchioli. There is
great variability between individuals, but for each
individual, the clearance rates are fairly constant.
Airway diseases may inuence mucociliary
clearance by changes in the amount and in the
viscoelastic properties of the mucus and the periciliary uid and by changes in the number, the
structure, and the activity of the cilia. These
changes can be secondary and reversible or primary and nonreversible.
The mucociliary transport pathways are genetically dened and rather specic for each location. The different paranasal sinuses have specic
pathways as well as the ostiomeatal complex and
the nasal cavity.
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39
3.4 Conclusion
Cilia are extensions of the apical membranes.
The cilium itself is characterized by a 9+2 axonemal structure. An active, coordinated ciliary
beating is essential for mucociliary transport.
Ciliary beating depends on the ATPase activity
in the dynein arms and is characterized by a specic beating pattern. In healthy persons, 95% of
the cilia are ultrastructurally completely normal.
Ciliary abnormalities can be the results of external (secondary ciliary dyskinesia) or inherited
factors (primary ciliary dyskinesia). Ciliary
function and structure are organized at different
levels from the individual cilia, over interciliary
and intercellular interaction, to the macroscopic
level of the ciliated tapestry and mucociliary
transport.
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Functional Defense Mechanisms
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oftheNasal Respiratory
Epithelium
RobertC.Kern andJenniferR.Decker
4
Core Messages
• Sinonasal epithelium provides both a physical
and immunologic barrier to infection.
• Intracellular junctions, mucus composition,
and mucociliary clearance compose the
mechanical barrier to pathogen invasion.
• Innate and adaptive immune responses form
the immunologic barrier.
• Innate immunity provides the rst-line defense
to pathogens that circumvent the physical
mucosal barrier by recognizing conserved
pathogen-associated markers and activating a
nonspecic inammatory response.
• Adaptive immunity confers memory to particular pathogens, providing a faster response
to repeated infections.
• Sufcient stimulation of the innate immune
system results in activation of and directs the
type of subsequent adaptive immune response.
• Fungus and staphylococcal superantigens
appear to be disease modiers in chronic rhinosinusitis rather than the direct cause.
R. C. Kern (*)
Department of Otolaryngology– Head and Neck
Surgery, Northwestern Memorial Hospital,
Chicago, IL, USA
e-mail: r-kern@northwestern.edu
J. R. Decker
Department of Otolaryngology– Head and Neck
Surgery, Feinberg School of Medicine, Northwestern
University, Chicago, IL, USA
• Dysregulation in the adaptive immune
response is the key factor in the pathogenesis
of chronic rhinosinusitis.
• Understanding of host-specic sinonasal
immune defenses will inuence future therapies for CRS.
4.1 Overview
The sinonasal epithelium is an important biological point of interface with the external environment, clearing foreign materials without signicant
collateral tissue inammation. Multiple components carry out this task, and while they are typically considered separately, they are functionally
integrated. The rst component is mucus produced
by nasal glands and the epithelial goblet cells
which trap particulate matter to be swept into the
nasopharynx via mucociliary ow. The mucus also
contains tonic levels of host defense molecules
with antimicrobial properties, limiting microbial
survival and proliferation. The next anatomic barrier is the epithelial layer with cells bound together
via junctional complexes. Breaching these
mechanical barriers brings exogenous agents in
contact with receptors that activate the innate
response. Secretion of host defense molecules is
augmented, and chemokines and cytokines are
secreted. The latter initiates inammation and fosters the accumulation and activation of innate
effector cells. If the stimulus is sufciently strong,
© 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_4
41
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