Modulation of olfactory signal detection in the olfactory epithelium: focus on the internal and external environment, and the emerging role of the immune system.

Detection and discrimination of odorants by the olfactory system plays a pivotal role in animal survival. Olfactory-based behaviors must be adapted to an ever-changing environment. Part of these adaptations includes changes of odorant detection by olfactory sensory neurons localized in the olfactory epithelium. It is now well established that internal signals such as hormones, neurotransmitters, or paracrine signals directly affect the electric activity of olfactory neurons. Furthermore, recent data have shown that activity-dependent survival of olfactory neurons is important in the olfactory epithelium. Finally, as olfactory neurons are directly exposed to environmental toxicants and pathogens, the olfactory epithelium also interacts closely with the immune system leading to neuroimmune modulations. Here, we review how detection of odorants can be modulated in the vertebrate olfactory epithelium. We choose to focus on three cellular types of the olfactory epithelium (the olfactory sensory neuron, the sustentacular and microvillar cells) to present the diversity of modulation of the detection of odorant in the olfactory epithelium. We also present some of the growing literature on the importance of immune cells in the functioning of the olfactory epithelium, although their impact on odorant detection is only just beginning to be unravelled.

Olfactory dysfunction and autoimmunity: pathogenesis and new insights.

Olfaction plays an important role in the perception of our environment. Smell impairment is known to be a manifestation of several autoimmune diseases. Similarities between the olfactory and immune systems and previously published human studies and animal models of autoimmune diseases account for the accumulating evidence for this observation. In this review, we will present the current literature concerning olfactory dysfunction in autoimmune diseases, discuss clinical aspects and provide new insights regarding pathogenesis and possible mechanisms.

Role of olfactory reactions, nociception, and immunoendocrine shifts in addictive disorders.

BACKGROUND AND OBJECTIVES: Addictive pathology is associated with nervous, immune, and endocrine shifts. Meanwhile, the nature of intersystemic relationship lying beneath addictive disorders remains unclear. The purpose of the study was to identify neuroimmunoendocrine markers of addictive disorders in male subjects defining the nature of their interaction. METHODS: The study enrolled 69 subjects aged 18-43 years: 59 males and 10 females divided into those with addictive disorders (n = 39) and conditionally healthy subjects (n = 30). EEG testing with olfactory stimulation, olfactometric, and pressure algometric examinations was carried out. Multiplex technique was applied to determine mitogen-induced production of cytokines IL-10, IL-1, IL-1RA, IL-2, IFN-gamma, TNF-alpha. ELISA method was applied to measure serum cortisol and testosterone levels. RESULTS: Olfactory responses to isopropanol with open eyes in addicted patients manifested as increase in alpha-rhythm and beta1-rhythm, with closed eyes presentation of this odorant was accompanied by increase of theta-rhythm in opioid-addicted patients. Male subjects with addictive disorders showed reduced alpha-rhythm in terms of olfactory stimulation with modified emotional evaluation of the odorant, deficient mitogen-induced production of IFN-gamma, and reduced pain sensitivity. Male subjects with opioid addiction had reduced beta1-rhythm in terms of olfactory stimulation, mitogen-induced production of IFN-gamma, and elevated testosterone level. CONCLUSIONS: The findings obtained verify potential involvement of nociception, olfaction, and cytokine production in addiction pathogenesis evidencing their various roles depending on the range of psychoactive substances (PAS) and pathology progression. SCIENTIFIC SIGNIFICANCE: The data obtained may provide background for unification of reward circuit and inhibitory control concepts in regulation of addictive behavior. (Am J Addict 2017;26:640-648).

Of volatiles and peptides: in search for MHC-dependent olfactory signals in social communication.

Genes of the major histocompatibility complex (MHC), which play a critical role in immune recognition, are considered to influence social behaviors in mice, fish, humans, and other vertebrates via olfactory cues. As studied most extensively in mice, the polymorphism of MHC class I genes is considered to bring about a specific scent signature, which is decoded by the olfactory system resulting in an individual-specific reaction such as mating. On the assumption that this signature resides in volatiles, extensive attempts to identify these MHC-specific components in urine failed. Alternatively, it has been suggested that peptide ligands of MHC class I molecules are released into urine and can elicit an MHC-haplotype-specific behavioral response after uptake into the nose by sniffing. Analysis of the urinary peptide composition of mice shows that MHC-derived peptides are present, albeit in extremely low concentrations. In contrast, urine contains abundant peptides which differ between mouse strains due to genomic variations such as single-nucleotide variations or complex polymorphisms in multigene families as well as in their concentration. Thus, urinary peptides represent a real-time sampling of the expressed genome available for sensory evaluation. It is suggested that peptide variation caused by genomic differences contains sufficient information for individual recognition beyond or instead of an influence of the MHC in mice and other vertebrates.

Olfactory immunology: the missing piece in airway and CNS defence.

The olfactory mucosa is a component of the nasal airway that mediates the sense of smell. Recent studies point to an important role for the olfactory mucosa as a barrier to both respiratory pathogens and to neuroinvasive pathogens that hijack the olfactory nerve and invade the CNS. In particular, the COVID-19 pandemic has demonstrated that the olfactory mucosa is an integral part of a heterogeneous nasal mucosal barrier critical to upper airway immunity. However, our insufficient knowledge of olfactory mucosal immunity hinders attempts to protect this tissue from infection and other diseases. This Review summarizes the state of olfactory immunology by highlighting the unique immunologically relevant anatomy of the olfactory mucosa, describing what is known of olfactory immune cells, and considering the impact of common infectious diseases and inflammatory disorders at this site. We will offer our perspective on the future of the field and the many unresolved questions pertaining to olfactory immunity.

Antigen-induced changes in odor attractiveness and reproductive output in male mice.

Modulation of social signals by antigen-induced immunoenhancement is a significant component of behavioral and reproductive adaptations of a host population to parasitic pressure. To investigate this concept, we studied odor attractiveness and reproductive output of ICR male mice treated with keyhole limpet hemocyanin (KLH) as an antigenic stimulus. We collected urine samples for olfactory preference tests (control vs. KLH administration) on different days following treatment. We found that the differences in odor attractiveness between control and immunized males, which were observed on the 3rd day, disappeared soon afterwards. Odor attractiveness of male mice positively correlated with their immunoresponsiveness, which was assessed by the sum of anti-KLH IgG1 and anti-KLH IgG2a titers. According to the hypothesis of terminal investment, antigen-treated males had higher reproductive output in comparison with control males and produced more progeny as a result.

Subconscious olfactory influences of stimulant and relaxant odors on immune function.

Brain and immune system are linked by bidirectional pathways so that changes of the central nervous system may influence various immune functions. The olfactory system may be involved in this interaction. In most odor studies subjects are aware of an odor exposure, using frequently high odor concentrations or long-term exposures without controls. In this pilot study, the potential immune effects of short-term odor exposure were examined in 32 blinded subjects (16 male, 16 female). Subjects were exposed without their knowledge either to a stimulant essential oil (grapefruit, fennel, pepper), a no-odor control or a relaxant essential oil (lavender, patchouli, rose) during a set of psychological questionnaires for 30 min at three separate visits. Activity of neutrophil granulocytes (CXCL8 release, CD16) and peripheral blood concentrations of mainly neutrophil-related immunological markers were measured. We tested the triple of stimulant odor, control and relaxant odor for every subject in a model which assumed opposite effects of the stimulant and the relaxant odor. This hypothesis was falsified by our experimental data, as no significant effect was observed for the parameters tested. The human immune functions tested in our study are not modulated by short-term odor exposure in blinded subjects. Further studies should directly dissect possible differences between long-term and short-term exposures of non-blinded subjects versus blinded subjects.

The genetic basis of individual-recognition signals in the mouse.

The major histocompatibility complex (MHC) is widely assumed to be a primary determinant of individual-recognition scents in many vertebrates [1-6], but there has been no functional test of this in animals with normal levels of genetic variation. Mice have evolved another polygenic and highly polymorphic set of proteins for scent communication, the major urinary proteins (MUPs) [7-12], which may provide a more reliable identity signature ([13, 14] and A.L. Sherborne, M.D.T., S. Paterson, F.J., W.E.R.O., P. Stockley, R.J.B., and J.L.H., unpublished data). We used female preference for males that countermark competitor male scents [15-17] to test the ability of wild-derived mice to recognize individual males differing in MHC or MUP type on a variable genetic background. Differences in MHC type were not used for individual recognition. Instead, recognition depended on a difference in MUP type, regardless of other genetic differences between individuals. Recognition also required scent contact, consistent with detection of involatile components through the vomeronasal system [6, 18]. Other differences in individual scent stimulated investigation but did not result in individual recognition. Contrary to untested assumptions of a vertebrate-wide mechanism based largely on MHC variation, mice use a species-specific [12] individual identity signature that can be recognized reliably despite the complex internal and external factors that influence scents [2]. Specific signals for genetic identity recognition in other species now need to be investigated.

Functional endoscopic sinus surgery improved asthma symptoms as well as PEFR and olfaction in patients with nasal polyposis.

BACKGROUND: Nasal polyposis is a disease known to be associated with asthma. The management is anti-inflammatory, with topical and oral corticosteroids as the first-line treatment. The effect of surgical treatment on lower airway inflammation has not been sufficiently studied. AIM: The aim of this study is to investigate the effects of functional endoscopic sinus surgery (FESS) as well as fluticasone proprionate nasal drops (FPND) 400 microg b.i.d. on nasal and lower airway parameters in asthmatics with nasal polyposis. METHODS: This was a prospective 21-week study of 68 patients with asthma and nasal polyposis, on the benefits of FESS on nasal '(butanol test, subjective olfaction, peak nasal inspiratory flow, congestion, rhinorrhoea, and polyp score)', and on the lower airway parameters (dyspnea, cough, mean daily peak expiratory flow rate (PEFR), and lung function tests). It also included a randomized, double-blind, placebo-controlled 14 weeks phase on FPND. RESULTS: Functional endoscopic sinus surgery significantly improved mean asthma symptom scores and daily PEFR and all nasal parameters including subjective and objective olfaction tests. This is the first study that shows the benefits of FESS on butanol tests in patients with nasal polyposis. We found no significant difference between topical treatment with FPND or placebo in the nasal or lower airway variables. CONCLUSION: Functional endoscopic sinus surgery improved nasal and asthma symptoms in patients with nasal polyposis. Functional endoscopic sinus surgery could be considered early in the natural course of nasal polyposis with concomitant asthma, as well as a second-line treatment in nasal polyposis patients with a reduced sense of smell. The potential benefits of FPND 400 microg b.i.d. were probably overshadowed by FESS.

Parkinson's disease, autoimmunity, and olfaction.

Parkinson's disease (PD) is a common progressive neurodegenerative disorder, mainly classified as a movement disorder which manifests among others nonmotor symptoms such as olfactory dysfunction. The etiopathogenesis of this disease has yet to be elucidated, though it seems to be interconnected with a complex set of genetic, environmental, and immunological interactions. This review unfolds the immune alterations observed in PD patients by describing the increase in the innate immune components including complement and cytokines within their substantia nigra and cerebrospinal fluid (CSF). These alterations extended to the adaptive immune response with the elevation of T cells and autoantibodies (anti-alpha-synuclein and anti-GM1-ganglioside) in the peripheral blood and CSF of PD patients. Interestingly, another etiopathogenic triad has recently emerged linking PD to autoimmunity through olfactory dysfunction. Smell deficit is one of the earliest signs of PD and a unique observation suggesting olfactory declines to be a consequence of autoimmune mechanisms. Therefore, we considered several undisputed autoimmune diseases known for their olfactory consequences as template examples that may shed more light on the relationship between autoimmunity and PD. We hope that understanding the nature of this disease may lay the ground for successes in the quest to halt the progressive neurodegenerative process.

Olfaction--a window to the mind.

Although our knowledge of the brain, the olfactory sense and autoimmunity continues to evolve, examining the olfaction ability is not yet routinely applied by clinicians in the process of diagnosis and treatment. Moreover, assessment of the sense of smell and olfactory impairments is usually overlooked by patients and their clinicians. Given the clinical data reviewed here, clinicians should be encouraged to screen for olfactory impairments, which can help in the early diagnosis of CNS diseases such as Parkinson, dementia and schizophrenia, as well as CNS-autoimmune diseases such as neuropsychiatric lupus.

How relevant is the impairment of smell for the quality of life in allergic rhinitis?

PURPOSE OF REVIEW: In the present review, the authors try to evaluate how relevant smell impairment is in patients suffering from allergic rhinitis and how it affects their quality of life. Smell dysfunction has a significant impact on the quality of life as it can lead to a wrong choice of food and intake, a reduction in appetite and eventually to weight loss, malnutrition, immunity reduction and worsening of medical illness. Patients with smell impairment are reported to use larger quantities of sugar and salt to highlight flavours, thus worsening their general health condition and increasing the risk of developing diabetes and hypertension. RECENT FINDINGS: Recent studies estimate that a complete loss of the sense of smell can be found in at least 1% of the US population, and that an impairment in the olfactory function can be highlighted in about 24% of individuals aged 53-97 years and 19% of individuals aged 20-92 years. Despite the high prevalence, subjective complaints do not accurately reflect the real disturbance experienced by the patient, and usually go unnoticed. SUMMARY: Current information in literature highlights the need for additional studies that concentrate on the impact of olfactory dysfunction on the quality of life of patients affected by allergic rhinitis.

[The influence of postradiation chemical signals of mice on the humoral immune response in recipients in different time relative to antigenic stimulus].

The influence of volatile urine chemosignals of irradiated (4 Gy) mice on the primary humoral immune response to sheep red blood cells in intact recipients was investigated. It was demonstrated that the direction of immunomodulatory effect is dependent upon the time at which the postradiation chemosignals was initially applied. The antibody response to antigen was markedly suppressed in mice that were exposed before antigen injection. When chemosignals applied immediately following inoculation of antigen the antibody response was unaffected. The immune response was increased when chemosignals was loadeded for 1-10 days after immunization. The possible mechanisms of immunomodulation are considered.

Odour learning and immunity costs in mice.

There is accumulating evidence that learning is metabolically costly. One way in which this may manifest itself is in trade-offs between learning effort and immune function, with learning increasing susceptibility to infection. We tested this idea in the context of odour learning using outbred (BKW) male laboratory mice. Mice were exposed to three experimental treatments in which they were required to learn different numbers of urinary odours. While treatment affected the extent to which mice habituated to test odours during training, differences were not a simple function of the number of odours. The fact that there was also no significant effect of treatment on the degree of preference for novel over familiar odours in subsequent tests suggests mice retained learned odour profiles equally well regardless of the number of odours. That subsequent infection with Babesia microti increased with the number of odours mice had to learn is then consistent with an increased cost to learning effort when more odours were presented. Analysis within treatments, and relationships with the change in corticosterone concentration over the period of the experiment, suggested that it was a failure to learn, rather than maintaining learning performance, in more difficult learning tasks that led to greater infection. As in a previous study of maze learning in the strain, there was no direct relationship between infection and measures of peripheral antibody (total IgG) titre. The results are discussed in relation to studies in other learning contexts and reported relationships between glucocorticoid hormones and learning outcomes.

The genome of the miiuy croaker reveals well-developed innate immune and sensory systems.

The miiuy croaker, Miichthys miiuy, is a representative Sciaenidae known for its exceptionally large otoliths. This species mainly inhabits turbid aquatic environments with mud to sandy mud bottoms. However, the characteristics of the immune system of this organism and its specific aquatic environment adaptations are poorly understood. Thus, we present a high-quality draft genome of miiuy croaker. The expansions of several gene families which are critical for the fish innate immune system were identified. Compared with the genomes of other fishes, some changes have occurred in the miiuy croaker sensory system including modification of vision and expansion of taste and olfaction receptors. These changes allow miiuy croaker to adapt to the environment during the long-term natural selection. The genome of miiuy croaker may elucidate its relatively well-developed immune defense and provide an adaptation model of the species thriving in turbid deep aquatic environments.

Theoretical accounts of Gulf War Syndrome: from environmental toxins to psychoneuroimmunology and neurodegeneration.

Non-specific illness includes a wide variety of symptoms: behavioural (e.g., reduced food and water intake), cognitive (e.g., memory and concentration problems) and physiological (e.g., fever). This paper reviews evidence suggesting that such symptoms can be explained more parsimoniously as a single symptom cluster than as a set of separate illnesses such as Gulf War Syndrome (GWS) and chronic fatigue syndrome (CFS). This superordinate syndrome could have its biological basis in the activity of pro-inflammatory cytokines (in particular interleukin-1: IL-1), that give rise to what has become known as the 'sickness response'. It is further argued that the persistence of non-specific illness in chronic conditions like GWS may be (in part) attributable to a bio-associative mechanism (Ferguson and Cassaday, 1999). In the case of GWS, physiological challenges could have produced a non-specific sickness response that became associated with smells (e.g., petrol), coincidentally experienced in the Persian Gulf. On returning to the home environment, these same smells would act as associative triggers for the maintenance of (conditioned) sickness responses. Such associative mechanisms could be mediated through the hypothalamus and limbic system via vagal nerve innervation and would provide an explanation for the persistence of a set of symptoms (e.g., fever) that should normally be short lived and self-limiting. We also present evidence that the pattern of symptoms produced by the pro-inflammatory cytokines reflects a shift in immune system functioning towards a (T-helper-1) Th1 profile. This position contrasts with other immunological accounts of GWS that suggest that the immune system demonstrates a shift to a Th2 (allergy) profile. Evidence pertaining to these two contrasting positions is reviewed.

Influenza vaccinations and chemosensory function.

BACKGROUND: Although influenza vaccines have saved millions of lives, some have been associated with extremely rare adverse effects such as Guillain-Barré syndrome, Bell's palsy, and optic neuritis. Despite the fact that olfactory loss after an influenza vaccination is noted in one case report, no quantitative olfactory testing was performed. Hence, it is unclear whether, in fact, olfactory dysfunction can be associated with such vaccinations. This study was designed to (1) identify patients from the University of Pennsylvania Smell and Taste Center who attributed their empirically determined chemosensory disturbances to influenza vaccinations and (2) determine whether influenza vaccinations add to the degree of olfactory or gustatory dysfunction due to other causes. METHODS: A retrospective analysis of self-reported etiologies of 4554 consecutive patients presenting to the University of Pennsylvania Smell and Taste Center with complaints of chemosensory dysfunction was performed. Those who reported dysfunction secondary to influenza vaccinations were identified. Additionally, in a subset of 925 patients for whom detailed inoculation histories were available, it was determined whether the number of lifetime inoculations added to the deficits due to other causes. RESULTS: Nine of the 4554 patients (0.19%) attributed olfactory disturbances to an influenza vaccination. None complained of taste dysfunction. All nine had abnormally low scores on the University of Pennsylvania Smell Identification Test (p < 0.001), with three being anosmic and six microsmic. Seven had elevated phenyl ethyl alcohol detection thresholds (p < 0.05). Two cases exhibited mild-to-moderate loss of whole mouth taste function. Of the 925 patients, no association was evident between the number of lifetime vaccinations and the chemosensory test scores. In accord with previous studies, age and sex were significantly related to the test scores. CONCLUSION: A very small percentage of the 4554 patients evaluated (0.19%) attributed their chemosensory dysfunction to a prior influenza vaccination. No influences of the number of lifetime influenza vaccinations on the test scores were evident in the subset of 925 patients whose dysfunction was due to other causes.

Fox smell abrogates the effect of herbal odor to prolong mouse cardiac allograft survival.

BACKGROUND: Herbal medicines have unique odors, and the act of smelling may have modulatory effects on the immune system. We investigated the effect of olfactory exposure to Tokishakuyaku-san (TJ-23), a Japanese herbal medicine, on alloimmune responses in a murine model of cardiac allograft transplantation. METHODS: Naïve or olfactory-dysfunctional CBA mice underwent transplantation of a C57BL/6 heart and were exposed to the odor of TJ-23 until rejection. Some naïve CBA recipients of an allograft were given olfactory exposure to Sairei-to (TJ-114), trimethylthiazoline (TMT), individual components of TJ-23, or a TJ-23 preparation lacking one component. Adoptive transfer studies were performed to determine whether regulatory cells were generated. RESULTS: Untreated CBA mice rejected their C57BL/6 allografts acutely, as did olfactory-dysfunctional CBA mice exposed to the odor of TJ-23. CBA recipients of a C57BL/6 heart given olfactory exposure to TJ-23 had significantly prolonged allograft survival, whereas those exposed to the odor of TJ-114, TMT, one component of TJ-23, or TJ-23 lacking a component did not. Secondary allograft recipients that were given, at 30 days after transplantation, either whole splenocytes, CD4+ cells, or CD4+CD25+ cells from primary recipients exposed to the odor of TJ-23 had indefinitely prolonged allograft survival. CONCLUSIONS: Prolonged survival of cardiac allografts and generation of regulatory cells was associated with exposure to the odor of TJ-23 in our model. The olfactory area of the brain may have a role in the modulation of immune responses.

Antibody-specific behavioral effects: intracerebroventricular injection of antiphospholipid antibodies induces hyperactive behavior while anti-ribosomal-P antibodies induces depression and smell deficits in mice.

This study compares the effects of human antiphospholipid (aPL) and anti-P-ribosomal (anti-P) IgG and control IgG on the brain. Intracerebroventricular (ICV) injected aPL mice (exAPS) displayed specific hyperactivity compared to anti-P-injected (exSLE) and control mice. In contrast ICV injected anti-P-injected mice specifically displayed depression-like behavior and olfactory impairment compared to the other 2 groups. Both anti-P and aPL injected mice were impaired in the passive avoidance test compared to controls. The distinct cognitive effects of the 2 pathogenic antibodies argue for a specific and differential direct action of these autoantibodies on the brain in clinical disease.

Brain-immune interaction accompanying odor-evoked autobiographic memory.

The phenomenon in which a certain smell evokes a specific memory is known as the Proust phenomenon. Odor-evoked autobiographic memories are more emotional than those elicited by other sensory stimuli. The results of our previous study indicated that odor-evoked autobiographic memory accompanied by positive emotions has remarkable effects on various psychological and physiological activities, including the secretion of cytokines, which are immune-signaling molecules that modulate systemic inflammation. In this study, we aimed to clarify the neural substrates associated with the interaction between odor-evoked autobiographic memory and peripheral circulating cytokines. We recruited healthy male and female volunteers and investigated the association between brain responses and the concentration of several cytokines in the plasma by using positron emission tomography (PET) recordings when an autographic memory was evoked in participants by asking them to smell an odor that was nostalgic to them. Participants experienced positive emotions and autobiographic memories when nostalgic odors were presented to them. The levels of peripheral proinflammatory cytokines, such as the tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), were significantly reduced after experiencing odor-evoked autobiographic memory. Subtraction analysis of PET images indicated that the medial orbitofrontal cortex (mOFC) and precuneus/posterior cingulate cortex (PCC) were significantly activated during experiences of odor-evoked autobiographic memory. Furthermore, a correlation analysis indicated that activities of the mOFC and precuneus/PCC were negatively correlated with IFN-γ concentration. These results indicate that the neural networks including the precuneus/PCC and mOFC might regulate the secretion of peripheral proinflammatory cytokines during the experience of odor-evoked autobiographic memories accompanied with positive emotions.