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H. Kawauchi
non-specic phagocytic and cytolytic leukocytes, and cytokines, such as the antiviral active
interferons.
Defensins
Defensins are already introduced in this chapter,
but the details why defensins inhibit viral infection. They are produced by immune cells and
skin and mucosal epithelial cells and are consequently present on epithelia and in body uids.
Defensin genes can be induced by viral infection
[37]. Their most common antimicrobial function
is the formation of destructive pores in membranes of pathogens, including enveloped viruses.
Defensins can, however, also block infection by
enveloped and non-enveloped viruses alike by
aggregating the particles, blocking receptor binding, inhibiting virus entry, particle uncoating or
intracellular trafcking, interfering with essential
cell signaling, or viral gene expression. Moreover,
besides these direct antiviral activities, defensins
were shown to attract immune cells and modulate
adaptive immune responses.
Complement System
Complement activation is mediated by specic
receptors recognizing pathogens or immunocomplexes. Three different pathways are distinguished: the classical pathway (triggered by
antigen–antibody complexes), the mannanbinding lectin pathway (triggered by lectin
binding of pathogen surfaces), and the alternative pathway (triggered by complement factor
C3b- coated pathogen surfaces), respectively.
They all activate a cascade of reactions involving more than 20 soluble and cell-bound proteins, resulting in a rapid and massive response.
The complement system is able to tag infected
cells for destruction by phagocytic cells (opsonization), prime humoral immune responses,
and perforate membranes of infected cells by
the membrane attack complex [38]. In response
to those defense mechanisms, viruses have
evolved effective counter weapons, such as
incorporation of cellular complement regulatory
proteins into particles or expressing specic
inhibitors in infected cells.
Interferons
Interferons and innate and adapted antiviral
immune response interferons (IFNs) are a group
of signaling proteins made and released by host
cells in response to the infection or presence of
several viruses. In a typical scenario, a virusinfected cell will release interferons, causing
nearby cells to upregulate their antiviral activity.
Interferons are originally named for their ability
to “interfere” with viral replication by protecting
cells from virus infections. And, IFNs have various functions. They activate immune cells, such
as natural killer cells and macrophages. And they
increase host defenses by upregulating antigen
presentation by virtue of increasing the expression of major histocompatibility complex (MHC)
antigens. More than 20 distinct IFN genes and
proteins have been identied in animals and
human beings. They are typically divided among
three groups, namely, Type I IFN (IFN-alpha and beta), Type II IFN (IFN-gamma), and Type III
IFN. In general, type I and II interferons are
responsible for regulating and activating the
immune response.
Type I interferons are produced by a variety of
immunocompetent cells and exert inhibition of
viral replication and cell proliferation. Those also
enhance natural killer cell activity to lyse virusinfected host cells. Natural killer cells represent a
different lymphocyte lineage that recognize and
lyse virally infected cells. They are mainly effective during an early stage of viral infection, since
there is no lag phase of clonal expansion for NK
as occurs with T and B lymphocytes. Specic
immune antiviral mechanisms are both humoral
and cellular [39]. Specic antibodies protect
against viral infections and play an important role
in antiviral immunity, mainly during the early
stage of the infection. The most effective antiviral
antibodies are neutralizing antibodies which bind
to the viral envelope or capsid proteins and block
the virus from entering host cell. The main effec-
29 Nasal Defensive Proteins: Distribution andaBiological Function
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377
tors involved in specic antiviral immunity are
CD8+ cytotoxic T lymphocytes (CTL). These
cells recognize viral antigens presented at the cell
surface associated with class I MHC molecules.
CTL response is not always benecial, since the
tissue destruction caused by CTL is sometimes
greater than the damage done by the virus.
In response to virus infection, plasmacytoid
dendritic cells (pDCs) are particularly equipped
to synthesize and secrete IFN-a/b, but in principle all nucleated cells can do it. In autocrine and
paracrine manner, IFNs trigger a signaling chain
leading to the expression of genes for potent antiviral proteins which limit further viral spread. In
addition, IFNs initiate, modulate, and enhance
the adaptive immune response. The signaling
events which culminate in the direct IFNdependent restriction of virus growth can be
divided into three steps, namely, (1) transcriptional induction of IFN synthesis, (2) IFN signaling, and (3) antiviral mechanisms.
Interferon Induction
Nucleic acids are main pathogen-associated
molecular patterns (PAMPs) of viruses, being
recognized by a number of pattern recognition
receptors (PRRs) to initiate induction of IFN
genes. Virus-triggered PRRs classes can be
divided into the endosomal Toll-like receptors
(TLRs) and various intracellular (mostly cytoplasmic) receptors. It is thought TLRs can be
activated by viral nucleic acids that had been
released from virus particles. Major PAMPs are
double-stranded RNA (dsRNA), single-stranded
RNA (ssRNA), 5′-tripho-sphorylated RNAs, and
double-stranded DNA (dsDNA). dsRNA is an
almost ubiquitous by-product of virus infection
that is recognized by a number of PRRs. In the
endosome, it is recognized by the TLR3, and in
the cytoplasm by the RNA helicases RIG-I and
MDA-5 during genome transcription and replication. Viral ssRNAs can be recognized in the
endosome by TLR7 and TLR8.
In addition to nucleic acids, some viral proteins can provoke a TLR response, such as envelope protein of respiratory syncytial virus and
measles virus by activating TLR4 and TLR2,
respectively.
All PRRs are triggering signaling chains which
culminate in activation the IFN regulatory factor
(IRF)-3, the general immune regulatory transcription factor NF-kB, and the stress activated transcription factor AP-1. In a cooperation, they
upregulate IFN gene expression. This leads to a
“rst wave” of IFN production (IFN-beta and IFNarupha4in mice) which triggers expression of the
transcription factor IRF-7. IRF-7 is a master regulator of IFN gene expression cooperating with
IRF-3 for full activity. IRF-7 can be activated in the
same way as IRF-3 and is responsible for a positive
feedback loop that initiates the synthesis of several
IFN-alpha subtypes as the “second wave” IFNs.
While cells with a nucleus are thought to be
equipped with the set of intracellular PRRs,
expression of TLRs is more restricted to epithelial
and immune cells. Myeloid dendritic cells (mDCs),
for example, can recognize dsRNA by the classical intracellular RLR pathway and, in addition, by
TLR3. pDCs recognize the presence of viral
ssRNA or dsDNA by TLR7, TLR8, and TLR9 to
transcriptionally activate multiple IFN- alpha
genes. IRF-7 is further upregulated in response to
IFN and generates a positive feedback loop for
high IFN-alpha and IFN-beta production.
Furthermore, TLR7 and TLR9 are retained in the
endosomes of pDCs to allow prolonged IFN
induction signaling.
Type IIFN Signaling
IFN-beta and multiple IFN-alpha subspecies activate a common type I IFN receptor signaling to
the nucleus through the so-called JAK–STAT
pathway [40, 41]. The signal transducer and activator of transcription (STAT) proteins are latent
cytoplasmic transcription factors, which become
phosphorylated by the Janus Kinases JAK1 and
TYK2. Phosphorylated STAT1 and STAT2
recruit a third factor, IRF9, to form a complex
known as IFN-stimulated gene factor 3 (ISGF3),
which translocates to the nucleus and binds to the
IFN-stimulated response element (ISRE) in the
promoter region of ISGF.
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H. Kawauchi
Direct andIndirect Antiviral Eects
ofType IIFNs
Type I IFNs activate the expression of several
hundred STAT-dependent ISGs of which only a
fraction has been studied in great detail. IFNalpha and IFN-beta bind to the type I IFN receptor (IFNAR) and activate the expression of
numerous ISGs via the JAK/STAT pathway [42].
Several ISGs contribute in a more indirect manner to the enhancement of both innate and adaptive immune responses. Type I IFNs can directly
enhance clonal expansion and memory formation
of CD8+ T cells. IFNs promote NK cell- mediated
cytotoxicity and trigger the synthesis of other
cytokines, such as IFN-gamma or IL-15. These
cytokines modulate the adaptive immune
response, enhance NK cell proliferation, and support CD8+ T cell memory. Moreover, by upregulating TLRs, MHCs, and costimulatory
molecules, IFNs enable APCs (most prominently
DCs) to become competent in presenting viral
antigens and stimulating the adaptive immune
response.
Type II IFN
IFN-gamma categorized type II interferon is a
cytokine that is essential and critical for innate
and adaptive immunity against viral, some bacterial, and protozoan infections [43]. IFN-gamma
is an important activator of macrophages and
inducer of major histocompatibility complex
class II molecule expression. Aberrant IFNgamma expression is associated with a number of
autoinammatory and autoimmune diseases. The
importance of IFN-gamma in the immune system
stems in part from its ability to inhibit viral replication directly, and most importantly from its
immunostimulatory and immunomodulatory
effects. IFN-gamma is produced predominantly
by natural killer (NK) cells and natural killer T
(NKT) cells as a part of the innate immune
response, and by CD4 Th1 and CD8 cytotoxic T
lymphocyte (CTL) effector T cells once antigenspecic immunity develops as part of the adap-
tive immune response. IFN-gamma is also
produced by non-cytotoxic innate lymphoid cells
(ILCs), a family of immune cells rst discovered
in the early 2010s.
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Olfaction
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HuartCaroline, PhilippeEloy, andPhilippeRombaux
30
Core Message
• This chapter reviews the physiology and the
pathology of the olfactory system. The aim is
to provide adequate information to clinicians
in order to improve their understanding about
olfaction and its troubles and to promote adequate management of patients with olfactory
disorders.
30.1 Introduction
Olfaction is one of the most ancient senses.
Nevertheless, the eld of olfaction has received
far less attention as compared to other sensory
modalities. This is notably due to the technical
challenge of working with odorous stimuli and
the difculties of measuring brain activity
induced by a chemosensory stimulus.
H. Caroline (*) · P. Rombaux
Department of Otorhinolaryngology, Cliniques
universitaires Saint-Luc, Brussels, Belgium
Institute of Neuroscience, Université catholique de
Louvain, Brussels, Belgium
e-mail: caroline.huart@saintluc.uclouvain.be
P. Eloy
Department of Otorhinolaryngology, Cliniques
universitaires Saint-Luc, Brussels, Belgium
Department of Otorhinolaryngology, CHU DinantGodinne (Site Godinne), Yvoir, Belgium
e-mail: philippe.rombaux@uclouvain.be
Although a majority of people consider it as
one of the less important senses, this sense plays
a major role in our interaction with the environment. Not only olfactory system acts for the
detection of potential danger in the environment,
such as smoke or gas, but also it inuences our
nutrition, social behavior, well-being, and memory processes.
This chapter proposes a global view of human
olfaction. First we will extend on physiology of
olfaction, paying a particular interest to olfactory
pathways. Then, we will study pathological situations associated with olfactory dysfunction.
More particularly, we will see into detail postinfectious olfactory loss, post-traumatic olfactory
loss, and sinonasal-related olfactory disorder.
30.2 Physiology
30.2.1 Embryology
The olfactory placode is induced at the end of the
fourth week of pregnancy when the local ectoderm makes direct contact with the prosencephalic vesicle. Some cells of the olfactory placode
will differentiate into primary neurosensory cells,
further constituting the olfactory neuroepithelium. At the end of the fth week, these cells will
develop axons, reaching the neurons from the
anterior wall of the prosencephalon, which
becomes the telencephalon. This will induce the
© 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_30
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development of the olfactory bulb which begins
to differentiate from the telencephalon. At the
seventh week, the olfactory bulb individualizes at
the tip of each hemisphere. It will then lengthen
and come to lie on the cribriform plate of the ethmoid bone at the 12th week of pregnancy.
Secondary neurosensory cells will differentiate
inside the olfactory bulb and their dendrites synapse with axons of the primary neurosensory
cells. Axons of secondary neurosensory cells will
group to form the olfactory tract and synapse
with cortical olfactory areas of the entorhinal
paleocortex and archicortex [1, 2].
30.2.2 Olfactory Pathways
The olfactory system detects odorant molecules
dissolved in air and trapped in the airow passing
through the nasal cavity. Nasal turbinates will
guide the airow to the olfactory cleft, allowing
the odorant molecules to reach the olfactory
neuroepithelium.
30.2.2.1 The Olfactory
Neuroepithelium
The olfactory neuroepithelium is located in the
upper part of the nasal vaults. It covers the cribriform plate of the ethmoid bone, medially to the
middle turbinate and can extend to the superior
turbinate, the superior part of the septum, and the
middle turbinate [3]. In adult humans, its surface
area is 2.5cm2 per nasal fossa. The location of the
olfactory epithelium is dependent on individual
factors and is thought to change with age, resulting from a conversion of olfactory neuroepithelium to respiratory epithelium or due to loss of
olfactory neurons with age or from damages
(smoke, toxics, chemicals, chronic infection).
The olfactory neuroepithelium is a pseudostratied columnar epithelium covering a lamina propria. It is composed of (1) olfactory
receptor neurons (ORNs), (2) supporting cells,
(3) basal cells, some of which serve as ORN stem
cells for the regeneration of new olfactory sensory neurons throughout life, and (4) the duct of
the Bowman’s glands (which are located in the
lamina propia) (Fig.30.1).
The ORNs are bipolar cells, with their dendritic extensions directed toward the olfactory
cleft and carrying on its surface several cilia that
project into the mucus. Odorants are carried
through the mucus layer by olfactory binding
proteins, and bind to olfactory receptors located
on the ORNs. In 1991, Axel and Buck [4] discovered a family of approximately 1000 genes
that encode for an equivalent number of olfactory receptors, corresponding to the largest fam-
Fig. 30.1 Schematic
representation of
olfactory
neuroepithelium. The
olfactory
neuroepithelium is
composed by olfactory
receptor neurons,
supporting cells, and
basal cells. The dendritic
extension of olfactory
receptor neurons carries
on its surface several
cilia, where are located
the olfactory receptors.
The axons run through
the cribriform plate of
the ethmoid bone and
reach the olfactory bulb
where they synapse with
mitral cells in spherical
structures named
glomerulus
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383
ily of genes in the mammalian genome [5],
highlighting their important role in physiology.
In the majority of mammals most of these genes
are functional, but in primate the number of
functional genes decreases and is to about
350in humans [6]. Axel and Buck found that
each ORN possesses only one type of odor
receptor and each receptor is specialized for a
small number of odors. Hence, a given odorant
will bind a typical pattern of olfactory receptors.
The binding results in the activation of G proteins. The activation of G proteins stimulates the
formation of cyclic AMP. Increased levels of
cAMP open cyclic nucleotide-gated channels.
This causes the opening of the channels and
Ca2+ inux. This inux activates chloride channels, opening them up, causing Cl−leaves, and
nally depolarizing the ORN and generating the
action potential.
ORNs axons converge into the olfactory
nerves, passing through the cribriform plate of
the ethmoid bone and projecting directly to the
ipsilateral olfactory bulb where they synapse into
spherical structures known as the glomerulus.
30.2.2.2 The First Olfactory Structure:
TheOlfactory Bulb
The olfactory bulb is ovoid in shape and located
in the anterior cranial fossa, above the cribriform
plate of the ethmoid bone, and under the frontal
lobe. It contains a major structure that is considered as the rst olfactory structure: the glomerulus. The glomerulus is the only relay between the
periphery and the cortex. Each glomerulus collects ORN axons from the same type of odorant
receptor (Fig.30.2). ORNs axons and dendrites
of mitral cells synapse in the glomerulus.
The olfactory bulb has a multilayered cellular
architecture. It encompasses 6 different layers:
(1) the external layer is composed of ORNs
axons; (2) the glomerular layer is composed by
glomeruli wherein axons of ORNs synapse with
dendrites of mitral cells; (3) the external plexiform layer consists of dendrites of mitral and
Fig. 30.2 Basic schematic representation of odor coding
at the level of neuroepithelium and glomeruli. Odorant
molecules bind with specic olfactory receptor neurons.
Each olfactory receptor neuron possesses only one type of
odorant receptor. Olfactory receptor neurons carrying the
same type of receptor send their axon to the same glomerulus at the level of the olfactory bulb
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tufted cells; (4) the mitral and tufted cells layer
contains cell bodies of mitral and tufted cells
(second-order olfactory neuron); (5) the internal
plexiform layer; and (6) the granule cell layer
contains rows of mitral and tufted axons and
granule cells which are interneurons.
Axons of the mitral cells and tufted cells
coalesce to form the olfactory tract, located at the
base of the forebrain.
Centripetal information is secondary to neuronal activation, with glutamate as the principal
neurotransmitter.
30.2.2.3 The Second Olfactory
Structure: ThePrimary
Olfactory Cortex
As compared to all other senses, olfaction is
particular in that second-order olfactory neurons send information directly to primary olfactory cortex. In humans, the olfactory bulb is
connected to the primary olfactory cortex by
the bers of the lateral olfactory tract (LOT).
The LOT conveys olfactory information to a
wide number of brain areas within the frontal
lobe and the dorsomedial surface of the temporal lobe, often referred to primary olfactory
cortex.
The primary olfactory cortex comprises the piriform cortex, which covers the uncus, the entorhinal
cortex, the anterior olfactory nucleus, the periamygdaloid cortex, the olfactory tubercle, and nucleus.
These projections are mainly ipsilateral, but there
are also contralateral connections via the anterior
commissure [7–9]. Some of the structures of the
primary olfactory cortex then project to tertiary
highest cognitive centers of the brain. The major
projection of the piriform cortex is the thalamus,
but it will also project to the insular cortex, the orbitofrontal cortex (neocortex), and the hypothalamus.
The entorhinal cortex supplies afferent input to the
hippocampus, while the olfactory tubercle connects to the thalamus. The amygdala is the major
source of afferents to the hypothalamus (Fig.30.3).
Interestingly, there are many interactions between
the secondary olfactory structures: between the
anterior olfactory nucleus and the piriform cortex,
the piriform cortex and the olfactory tubercle, the
piriform cortex and the entorhinal cortex.
Fig. 30.3 Schematic diagram of major olfactory pathways
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30.2.2.4 The Tertiary Olfactory
Structures
The tertiary olfactory structures are the thalamus,
the hypothalamus, the amygdala, the hippocampus, the orbitofrontal cortex, and the insular
cortex.
The thalamus receives information from the
piriform cortex and the olfactory tubercle. The
hypothalamus, the orbitofrontal cortex, and the
insular cortex also receive afferent input from the
piriform cortex, while hippocampus is connected
to entorhinal cortex. We should also note that
there are also some interactions between these
tertiary olfactory structures. In this way, the thalamus connects to the orbitofrontal cortex and the
insular cortex. Therefore, the orbitofrontal cortex
and the insular cortex receive direct input from
the piriform cortex and indirect input via the
thalamus.
30.2.2.5 Centrifugal Information
Most secondary and tertiary structures have
numerous centrifugal bers leading to the olfactory bulb, with GABA and acetylcholine as principal neurotransmitter. The supposed aim of this
centrifugal information is to allow the brain to
control the incoming ow of olfactory signals.
30.2.2.6 Properties ofOlfactory
Pathways
The olfactory pathways are distributed to different brain structures that are involved in the determination of our personal and social behavior. For
example, the connections with:
1. Hippocampus and limbic system are thought
to inuence our memory system.
2. Amygdala system could act on emotional,
motivational and craving circuits.
3. Hypothalamus, that mediates feeding regula-
tion, could inuence our feeding behavior.
4. Orbitofrontal cortex mediates our conscious
perception of odors and could inuence our
preferences [10].
Hence, odor perception may affect our behavior and plays a major role in our interaction with
the environment.
The olfactory system present unique properties as compared to other sensory systems. They
are (1) the predominance of ipsilaterality of the
olfactory projections, (2) the conduction of odorevoked signals without an obligatory thalamic
relay, and (3) the intimate overlap with limbic
regions of the brain [11].
1. Odor processing remains principally ipsilat-
eral [7–9] all the way from the nasal periphery
to the primary olfactory cortex. This feature is
different for other sensory modalities, such as
the visual or auditory systems which, early in
the processing pathways, supply sensory
information in both hemispheres. This may
help the cortex better discriminate and make
bilateral odor comparisons and perhaps provide differential access to odor memories.
2. The absence of an obligatory thalamic relay is
also in contrast with other sensory modalities
in which an incoming signal undergoes
thalamic modulation prior to being delivered
to the sensory-specic cortex [11]. The
absence of thalamic sensory integration in the
olfactory pathways would seem to have an
evolutionary explanation [11].
3. The connections between the olfactory sys-
tem and the limbic system appear to be
involved in the emotional and memory background to odorant stimuli, our social behavior,
and the formation of novel stimulus- reinforced
associations [11].
30.2.3 Orthonasal andRetronasal
Olfaction
Paul Rozin noted that smell is unique in having a
“dual nature”—meaning that it can sense signals
originating outside (orthonasal) or inside (retronasal) the body [12].
Orthonasal olfaction refers to odorants originating outside and sniffed in through the nares to
reach the olfactory neuroepithelium. This route is
used to smell odors from the environment, such
as perfumes, food aromas, smoke, predator smell,
social odors, or pheromones. Orthonasal olfac-
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Fig. 30.4 Schematic representation of the central processing of orthonasal and retronasal olfaction. Orthonasal
olfaction is processed by the olfactory pathways. On contrast, retronasal olfaction is not only processed by olfac-
tion is processed by olfactory pathways and is
inuenced by the visual pathway.
Retronasal olfaction refers to odorants originating from the back of the mouth and reaching
the olfactory neuroepithelium via the nasopharynx. This retronasal stimulation occurs during
food ingestion. It is activated only when breathing out through the nose, between mastication
and swallowing [10, 13]. The retronasal olfaction, also termed as “avor,” account for an
important part of food identication. This
explains why a majority of patients suffering
from smell disorder also complain of “taste” disorder, although their sense of taste is intact. On
contrast to orthonasal olfaction, avor perception
is not only processed by olfactory pathways but is
also inuenced by almost all sensory modalities,
which are taste, touch, sound, and proprioception
tory pathways but is also inuenced by other sensory
modalities, which are taste, sound, vision and proprioception. These multisensory information are integrated in the
orbitofrontal cortex
(for a review see [10]). Indeed, the orbitofrontal
cortex receives connections from other sensory
neocortical areas (taste, hearing, touch, and
vision) [14] (Fig.30.4). Since it is receiving multisensory input and integrating these different
sensory information, the orbitofrontal cortex is
an important area to inuence our food preferences and choices.
30.2.4 Olfactory andTrigeminal
Interactions
The nasal fossa has double innervations from
olfactory and trigeminal afferents. Although
odorants are dened as volatile compounds having the ability to activate the olfactory system,
the vast majority of odorants will actually acti-
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