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.

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).

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.

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.

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.

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.

Effects of maternal immune activation on adult neurogenesis in the subventricular zone-olfactory bulb pathway and olfactory discrimination.

Maternal infection and maternal immune activation (MIA) during pregnancy increase risks for psychiatric disorders such as schizophrenia and autism. Many deficits related to psychiatric disorders are observed in adult offspring of MIA animal models, including behavioral abnormalities, morphological defects in various brain regions, and dysregulation of neurotransmitter systems. It has previously been shown that MIA impairs adult neurogenesis in the dentate gyrus of the hippocampus. In this study, we examined whether MIA affects adult neurogenesis in the subventricular zone (SVZ)-olfactory bulb (OB) pathway. Polyinosinic-polycytidylic acid (PolyI:C), a synthetic analog of double-stranded RNA mimicking viral infection, was injected into pregnant mice on gestation day 9.5 to activate immune systems. In the SVZ-OB pathway of adult offspring, different cell types of the neural stem cell lineage responded differently to MIA. Neural stem cells and neuroblasts were decreased. Cell proliferation of transit-amplifying cells was impaired. Consequently, newborn neurons were reduced in the OB. Olfactory deficiency has been suggested as a biomarker for schizophrenia. Here we found that olfactory discrimination was compromised in adult MIA offspring. Taken together, these findings show that MIA leads to defective adult neurogenesis in the SVZ-OB pathway, and the impairment of adult neurogenesis may lead to deficits in olfactory functions.

Olfactory imprinting is triggered by MHC peptide ligands.

Olfactory imprinting on environmental, population- and kin-specific cues is a specific form of life-long memory promoting homing of salmon to their natal rivers and the return of coral reef fish to natal sites. Despite its ecological significance, natural chemicals for olfactory imprinting have not been identified yet. Here, we show that MHC peptides function as chemical signals for olfactory imprinting in zebrafish. We found that MHC peptides consisting of nine amino acids elicit olfactory imprinting and subsequent kin recognition depending on the MHC genotype of the fish. In vivo calcium imaging shows that some olfactory bulb neurons are highly sensitive to MHC peptides with a detection threshold at 1 pM or lower, indicating that MHC peptides are potent olfactory stimuli. Responses to MHC peptides overlapped spatially with responses to kin odour but not food odour, consistent with the hypothesis that MHC peptides are natural signals for olfactory imprinting.

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.

Regulation of inflammation-associated olfactory neuronal death and regeneration by the type II tumor necrosis factor receptor.

BACKGROUND: Olfactory loss is a debilitating symptom of chronic rhinosinusitis. To study the impact of inflammation on the olfactory system, the inducible olfactory inflammation (IOI) transgenic mouse was created in which inflammation can be turned on and off within the olfactory epithelium. In this study, the type II tumor necrosis factor (TNF) receptor (TNFR2) was knocked out, and the effect on the olfactory loss phenotype was assessed. METHODS: IOI mice were bred to TNFR2 knockout mice to yield progeny IOI mice lacking the TNFR2 receptor (TNFR2(-/-) ). TNF-α expression was induced within the olfactory epithelium for 6 weeks to generate chronic inflammation. Olfactory function was assayed by electro-olfactogram (EOG), and olfactory tissue was processed for histology and immunohistochemical staining. RESULTS: Compared to IOI mice with wild-type TNFR2, IOI mice lacking the TNFR2 demonstrated similar levels of inflammatory infiltration and enlargement of the subepithelial layer. However, IOI-TNFR2(-/-) mice differed markedly in that the neuronal layer was largely preserved and active progenitor cell proliferation was present. Odorant responses were maintained in the IOI-TNFR2(-/-) mice, in contrast to IOI mice. CONCLUSION: TNFR2 is the minor receptor for TNF-α, but appears to play an important role in mediating TNF-induced disruption of the olfactory system. This finding suggests that neuronal death and inhibition of proliferation in CRS may be mediated by TNFR2 on olfactory neurons and progenitor cells. Further studies are needed to elucidate the subcellular pathways involved and develop novel therapies for treating olfactory loss in the setting of CRS.

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.

Brain-immune interactions and the neural basis of disease-avoidant ingestive behaviour.

Neuro-immune interactions are widely manifested in animal physiology. Since immunity competes for energy with other physiological functions, it is subject to a circadian trade-off between other energy-demanding processes, such as neural activity, locomotion and thermoregulation. When immunity is challenged, this trade-off is tilted to an adaptive energy protecting and reallocation strategy that is identified as 'sickness behaviour'. We review diverse disease-avoidant behaviours in the context of ingestion, indicating that several adaptive advantages have been acquired by animals (including humans) during phylogenetic evolution and by ontogenetic experiences: (i) preventing waste of energy by reducing appetite and consequently foraging/hunting (illness anorexia), (ii) avoiding unnecessary danger by promoting safe environments (preventing disease encounter by olfactory cues and illness potentiation neophobia), (iii) help fighting against pathogenic threats (hyperthermia/somnolence), and (iv) by associative learning evading specific foods or environments signalling danger (conditioned taste avoidance/aversion) and/or at the same time preparing the body to counteract by anticipatory immune responses (conditioning immunomodulation). The neurobiology behind disease-avoidant ingestive behaviours is reviewed with special emphasis on the body energy balance (intake versus expenditure) and an evolutionary psychology perspective.

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.

[Smell: integrating neurodegeneration and autoimmunity - a personal view]. / Olfacto: uma visão pessoal integrando neurodegeneração e autoimunidade.

Throughout human evolution, smell lost its important role to be replaced by other senses. Although, it retained a "role"in several "healing" practices. The aim of this review was to analyze the possible roles and influences of olfaction on higher brain functions, like mood and memory, and in contrast heightened the influence of pathologies such as Alzheimer's disease and schizophrenia on the olfactory function, based on recent animal and human data. In this neuro-psychiatric approach, the immune system could have a central role.

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.