The Role of Oral Organs in Local Immunity with Elements of Morphology of Lingual Glands.

In postnatal ontogeny, the topographic relationships of the tongue glands and lymphoid structures in the thickness of the tongue have clear age-related features. In this article, we discuss the features of the glandular-lymphoid relationship in the thickness of the tongue, which is of particular scientific and practical importance for more precise understanding of the mechanisms providing local immunity in the oral cavity.

Langerin+ DCs regulate innate IL-17 production in the oral mucosa during Candida albicans-mediated infection.

The opportunistic fungal pathogen Candida albicans frequently causes diseases such as oropharyngeal candidiasis (OPC) in immunocompromised individuals. Although it is well appreciated that the cytokine IL-17 is crucial for protective immunity against OPC, the cellular source and the regulation of this cytokine during infection are still a matter of debate. Here, we directly visualized IL-17 production in the tongue of experimentally infected mice, thereby demonstrating that this key cytokine is expressed by three complementary subsets of CD90+ leukocytes: RAG-dependent αß and γδ T cells, as well as RAG-independent ILCs. To determine the regulation of IL-17 production at the onset of OPC, we investigated in detail the myeloid compartment of the tongue and found a heterogeneous and dynamic mononuclear phagocyte (MNP) network in the infected tongue that consists of Zbtb46-Langerin- macrophages, Zbtb46+Langerin+ dendritic cells (DCs) and Ly6C+ inflammatory monocytes. Of those, the Langerin+ DC population stands out by its unique capacity to co-produce the cytokines IL-1ß, IL-6 and IL-23, all of which promote IL-17 induction in response to C. albicans in the oral mucosa. The critical role of Langerin+ DCs for the innate IL-17 response was confirmed by depletion of this cellular subset in vivo, which compromised IL-17 induction during OPC. In conclusion, our work revealed key regulatory factors and their cellular sources of innate IL-17-dependent antifungal immunity in the oral mucosa.

IL-1 Coordinates the Neutrophil Response to C. albicans in the Oral Mucosa.

Mucosal infections with Candida albicans belong to the most frequent forms of fungal diseases. Host protection is conferred by cellular immunity; however, the induction of antifungal immunity is not well understood. Using a mouse model of oropharyngeal candidiasis (OPC) we show that interleukin-1 receptor (IL-1R) signaling is critical for fungal control at the onset of infection through its impact on neutrophils at two levels. We demonstrate that both the recruitment of circulating neutrophils to the site of infection and the mobilization of newly generated neutrophils from the bone marrow depended on IL-1R. Consistently, IL-1R-deficient mice displayed impaired chemokine production at the site of infection and defective secretion of granulocyte colony-stimulating factor (G-CSF) in the circulation in response to C. albicans. Strikingly, endothelial cells were identified as the primary cellular source of G-CSF during OPC, which responded to IL-1α that was released from keratinocytes in the infected tissue. The IL-1-dependent crosstalk between two different cellular subsets of the nonhematopoietic compartment was confirmed in vitro using a novel murine tongue-derived keratinocyte cell line and an established endothelial cell line. These data establish a new link between IL-1 and granulopoiesis in the context of fungal infection. Together, we identified two complementary mechanisms coordinating the neutrophil response in the oral mucosa, which is critical for preventing fungal growth and dissemination, and thus protects the host from disease.

Neuroinflammation is induced by tongue-instilled ZnO nanoparticles via the Ca2+-dependent NF-κB and MAPK pathways.

BACKGROUND: The extensive biological applications of zinc oxide nanoparticles (ZnO NPs) in stomatology have created serious concerns about their biotoxicity. In our previous study, ZnO NPs were confirmed to transfer to the central nervous system (CNS) via the taste nerve pathway and cause neurodegeneration after 30 days of tongue instillation. However, the potential adverse effects on the brain caused by tongue-instilled ZnO NPs are not fully known. METHODS: In this study, the biodistribution of Zn, cerebral histopathology and inflammatory responses were analysed after 30 days of ZnO NPs tongue instillation. Moreover, the molecular mechanisms underlying neuroinflammation in vivo were further elucidated by treating BV2 and PC12 cells with ZnO NPs in vitro. RESULTS: This analysis indicated that ZnO NPs can transfer into the CNS, activate glial cells and cause neuroinflammation after tongue instillation. Furthermore, exposure to ZnO NPs led to a reduction in cell viability and induction of inflammatory response and calcium influx in BV2 and PC12 cells. The mechanism underlying how ZnO NPs induce neuroinflammation via the Ca2+-dependent NF-κB, ERK and p38 activation pathways was verified at the cytological level. CONCLUSION: This study provided a new way how NPs, such as ZnO NPs, induce neuroinflammation via the taste nerve translocation pathway, a new mechanism for ZnO NPs-induced neuroinflammation and a new direction for nanomaterial toxicity analysis.

Bioluminescent imaging reveals novel patterns of colonization and invasion in systemic Escherichia coli K1 experimental infection in the neonatal rat.

Key features of Escherichia coli K1-mediated neonatal sepsis and meningitis, such as a strong age dependency and development along the gut-mesentery-blood-brain course of infection, can be replicated in the newborn rat. We examined temporal and spatial aspects of E. coli K1 infection following initiation of gastrointestinal colonization in 2-day-old (P2) rats after oral administration of E. coli K1 strain A192PP and a virulent bioluminescent derivative, E. coli A192PP-lux2. A combination of bacterial enumeration in the major organs, two-dimensional bioluminescence imaging, and three-dimensional diffuse light imaging tomography with integrated micro-computed tomography indicated multiple sites of colonization within the alimentary canal; these included the tongue, esophagus, and stomach in addition to the small intestine and colon. After invasion of the blood compartment, the bacteria entered the central nervous system, with restricted colonization of the brain, and also invaded the major organs, in line with increases in the severity of symptoms of infection. Both keratinized and nonkeratinized surfaces of esophagi were colonized to a considerably greater extent in susceptible P2 neonates than in corresponding tissues from infection-resistant 9-day-old rat pups; the bacteria appeared to damage and penetrate the nonkeratinized esophageal epithelium of infection-susceptible P2 animals, suggesting the esophagus represents a portal of entry for E. coli K1 into the systemic circulation. Thus, multimodality imaging of experimental systemic infections in real time indicates complex dynamic patterns of colonization and dissemination that provide new insights into the E. coli K1 infection of the neonatal rat.

CX3CR1 is dispensable for control of mucosal Candida albicans infections in mice and humans.

Candida albicans is part of the normal commensal microbiota of mucosal surfaces in a large percentage of the human population. However, perturbations of the host's immune response or bacterial microbiota have been shown to predispose individuals to the development of opportunistic Candida infections. It was recently discovered that a defect in the chemokine receptor CX3CR1 increases susceptibility of mice and humans to systemic candidiasis. However, whether CX3CR1 confers protection against mucosal C. albicans infection has not been investigated. Using two different mouse models, we found that Cx3cr1 is dispensable for the induction of interleukin 17A (IL-17A), IL-22, and IL-23 in the tongue after infection, as well as for the clearance of mucosal candidiasis from the tongue or lower gastrointestinal (GI) tract colonization. Furthermore, the dysfunctional human CX3CR1 allele CX3CR1-M280 was not associated with development of recurrent vulvovaginal candidiasis (RVVC) in women. Taken together, these data indicate that CX3CR1 is not essential for protection of the host against mucosal candidiasis, underscoring the dependence on different mammalian immune factors for control of mucosal versus systemic Candida infections.

Preparation of polyclonal antibody against porcine beta defensin 2 and identification of its distribution in tissues of pig.

Porcine ß-defensin 2 (pBD2) is an antimicrobial peptide in pigs that plays an important role in the immune system by preventing bacterial invasion. To produce an anti-pBD2 antibody, which is not commercially available, we expressed and purified a soluble, his-tagged version of pBD2 (his-pBD2). Purified pBD2 was injected into New Zealand white rabbits to generate polyclonal antiserum. Anti-pBD2 antibodies were purified by ammonium sulfate precipitation, followed by diethylaminoethyl cellulose ion-exchange chromatography. The purified polyclonal antibody showed high sensitivity, with a titer as high as 204,800 by enzyme-linked immunosorbent assay, and it also showed high specificity for both his-pBD2 and native pBD2, as assessed by western blotting. Furthermore, immunohistochemistry analysis using the purified antibody revealed that pBD2 protein is distributed in the tongue, liver, kidney, small intestine, and large intestine of pigs. These results indicate that the prepared polyclonal antibody will be a useful tool for further studies of the function and mechanism of pBD2.

Lupus-like oral mucosal lesions in mercury-induced autoimmune response in Brown Norway rats.

BACKGROUND: Administration of mercury at nontoxic doses induces systemic autoimmune disease in Brown Norway (BN) rats. The pathogenesis of lupus-like oral mucosal lesion by mercury-induced autoimmunity is still unclear, even though the oral mucosa is observed to be commonly affected in mercury-treated BN rats. In this study, we investigated the immunopathology of lupus-like oral mucosal lesions in a model of mercury-induced systemic autoimmunity. METHODS: Brown Norway male rats were injected subcutaneously with either phosphate-buffered saline (control) or mercury at a dose of 1.0 mg per kilogram of body weight on days 0, 3, 5, and 7. Blood, kidney, and tongue samples were taken at various timepoints for evaluation by immunohistochemistry, RT-PCR, and lupus band test (LBT). RESULTS: Oral mucosal lesions were classified according to three consecutive temporal phases on the basis of infiltration of immunocompetent cells as follows: (phase I) infiltration of MHC class II+ dendritic cells (DC) and macrophages; (phase II) addition of ED1+ macrophage infiltrates; and (phase III) focal infiltration of pan T cells following increased infiltration of DC and macrophages. Dense infiltration of DC and macrophages was observed in the basement membrane (BM) zone of the oral epithelium. Tissue expression of IL-4 mRNA was detected in early lesions (phase I), suggesting that locally produced IL-4 may be responsible for Th2-mediated immune response. A linear and continuous smooth pattern of fluorescence was observed in the oral epithelial BM in addition to renal glomeruli, indicating immune complex deposits. CONCLUSIONS: Local autoimmune responses are involved in the pathogenesis of mercury-induced lupus-like lesions of the oral mucosa.

[Transition from pemphigus vulgaris to pemphigus foliaceus: a case report]. / Transition phénotypique d'un pemphigus vulgaire en pemphigus superficiel.

BACKGROUND: Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are the two main subtypes of auto-immune pemphigus, each having different clinical, histological and immunopathological features. We report the case of a patient initially with typical PV who relapsed within 2years, presenting clinically, histologically and immunologically typical PF. PATIENTS AND METHODS: A 47-year old man presented in March 2008 with clinically, histologically and serologically typical PV and treated with systemic corticosteroids alone (prednisone: 1mg/kg per day) then combined with a cycle of rituximab, which resulted in complete remission. After discontinuation of therapy (duration: 26months), he relapsed 6 months later with PF presenting clinical, histological and serological characteristics typical of this condition. DISCUSSION: This is a rare case of complete transition from PV to PF in clinical, histological and serological terms, and the first case occurring after initial treatment with rituximab.

Graft-versus-host disease-related cytokine-driven apoptosis depends on p73 in cytokeratin 15-positive target cells.

Acute graft-versus-host disease (GVHD), a major complication of allogeneic stem cell transplantation, involves cytotoxic soluble and cellular effectors that selectively induce apoptosis in normally apoptosis-resistant, cytokeratin 15 (K15)-expressing epithelial stem cells residing at the tips of rete ridges of human epidermis and in analogous rete-like prominences (RLPs) of murine dorsal lingual epithelium. The mechanisms whereby epithelial stem cells are rendered vulnerable to apoptosis during allostimulation are unknown. We hypothesized that GVHD-induced target cell injury may be related to pathways involving the p53 family that are constitutively expressed by epithelial stem cells and designed to trigger physiological apoptosis as a result of environmental danger signals. Among the p53 family members, we found that p73 protein and mRNA were preferentially expressed in K15(+) RLPs of murine lingual squamous epithelium. On in vitro exposure to recombinant TNF-α and IL-1 in an organ culture model previously shown to replicate early GVHD-like target cell injury, apoptosis was selectively induced in K15(+) stem cell regions and was associated with induction of phosphorylated p73, a marker for p73 activation, and apoptosis was abrogated in target tissue obtained from p73-deficient (p73(-/-)) mice. Evaluation of early in vivo lesions in experimental murine GVHD disclosed identical patterns of phosphorylated p73 expression that coincided with the onset of effector T cell infiltration and target cell apoptosis within K15(+) RLPs. This study is the first to suggest that paradoxical apoptosis in GVHD of physiologically protected K15(+) epithelial stem cells is explainable, at least in part, by cytokine-induced activation of suicide pathways designed to eliminate stem cells after exposure to deleterious factors perceived to be harmful to the host.

Molecular survey of Toxoplasma infection in sheep and goat from Fars province, Southern Iran.

Toxoplasmosis is a widespread zoonotic disease that causes significant morbidity and mortality in human fetus and in immunocompromised patients. Moreover, it becomes a major cause of abortion in sheep and goats. Since consumption of meat of infected lamb and goat is considered as the main sources of human infection in Iran, this study was undertaken to determine the prevalence of Toxoplasma infection in edible tissues of sheep and goats in Shiraz in 2008. Samples of brain, tongue, liver, and muscles of neck, intercostals, and femoral were taken from 56 sheep and 22 goats and tested by PCR. The total prevalence of Toxoplasma infection among animals was found to be 33.3%. Five out of 22 goats (22.7%) and 21 out of 56 sheep (37.5%) were infected by Toxoplasma. Differences between the prevalence rate of infection among females (nine out of 14 = 46%) and males animals (12 out of 45 = 29.5%) was significant (P = 0.013). Furthermore, a positive correlation was found between the age of animals and the rate of infection; animals greater than 2 years old showed a higher rate of infection (47%) in comparison with those less than 2 years old (25%, P = 0.04). The highest infected tissue was tongue (21.8%) followed by brain (19.2%) and femoral and intercostal muscles (17.9%). This study demonstrated a high level of Toxoplasma infection in slaughtered animals in Shiraz and these should be considered as the main sources of infection for human population in the region.

Differing Progression to Posterior Glottic Stenosis in Autoimmune and Idiopathic Subglottic Stenosis.

OBJECTIVES/HYPOTHESIS: We sought to characterize rates of progression to posterior glottic stenosis (PGS) from autoimmune or idiopathic subglottic stenosis. STUDY DESIGN: This was a retrospective review. METHODS: Patients from a tertiary-care laryngology practice over a 10-year period with autoimmune or idiopathic subglottic stenosis (SGS) were included. Patients with a history of prolonged intubation or other causes of iatrogenic stenosis were excluded. PGS was confirmed on videostrobolaryngoscopy recordings by a fellowship-trained laryngologist. PGS type (1-4) was also recorded. Demographic information was recorded, and if applicable, autoimmune disease type was specified. Time until PGS was recorded along with the number of interventions. Chi-squared analysis was used to compare PGS in autoimmune and idiopathic SGS. RESULTS: A total of 77 patients were identified with autoimmune (32 patients) or idiopathic (45 patients) subglottic stenosis. Autoimmune pathologies included systemic lupus erythematosus, granulomatosis with polyangiitis (GPA), rheumatoid arthritis, relapsing polychondritis, and sarcoidosis, with GPA the most common (14/32). Patients with autoimmune SGS had a higher rate of PGS (10 of 32) compared to idiopathic subglottic stenosis (1 of 45) for an odds ratio of 20 (95% CI: 2.4-166.4, P = .006). Patients with idiopathic SGS were more likely to be female (all 45 compared to 29/32 autoimmune, P = .07) and older (mean 53 (range 29-75) compared to 46 (20-82), P = .02). CONCLUSIONS: In this large patient cohort, autoimmune SGS patients were found to have a higher likelihood of developing PGS compared to their idiopathic counterparts, suggesting that counseling for this progression may be warranted. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1816-1820, 2021.

Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling.

Oral mucositis (OM) is a treatment-limiting adverse side effect of radiation and chemotherapy. Approximately 80% of patients undergoing radiotherapy (RT) for head and neck cancers (HNC) develop OM, representing a major unmet medical condition. Our understanding of the immunopathogenesis of OM is limited, due in part to the surprising paucity of information regarding healing mechanisms in the oral mucosa. RNAseq of oral tissue in a murine model that closely mimics human OM, showed elevated expression of IL-17 and related immune pathways in response to head and neck irradiation (HNI). Strikingly, mice lacking the IL-17 receptor (IL-17RA) exhibited markedly more severe OM. Restoration of the oral mucosa was compromised in Il17ra-/- mice and components associated with healing, including matrix metalloproteinase 3, 10 and IL-24 were diminished. IL-17 is typically associated with recruitment of neutrophils to mucosal sites following oral infections. Unexpectedly, in OM the absence of IL-17RA resulted in excessive neutrophil recruitment and immunopathology. Instead, neutrophil activation was IL-1R-driven in Il17ra-/- mice. Blockade of IL-1R and depletion of neutrophils lessened the severity of damage in these mice. Overall, we show IL-17 is protective in OM through multiple mechanisms including restoration of the damaged epithelia and control of the neutrophil response. We also present a clinically relevant murine model of human OM to improve mechanistic understanding and develop rational translational therapeutics.

Prognostic Role of Tumor-Infiltrating Lymphocytes and Tumor Budding in Early Oral Tongue Carcinoma.

OBJECTIVES/HYPOTHESIS: Occult lymph metastasis is an important prognosticator for the treatment of early oral tongue squamous cell carcinoma (SCC). The objective of this study was to evaluate the prognostic significance of tumor-infiltrating lymphocytes (TILs) in early oral tongue SCC. The combination of the TIL subtype and intermediate- or high-grade budding scores was investigated as a prognostic marker for occult neck metastases. STUDY DESIGN: Retrospective study. METHODS: Specimens from 62 patients with early oral tongue SCC treated with only primary surgery were analyzed by immunohistochemistry for CD4+, CD8+, FoxP3+, and CD45RO+ T cells and CD163+ macrophages. The highest number of each TIL subtype was counted in two areas of parenchyma and stroma in the tumor (Tumor) and peripheral stroma of the invasion margin. RESULTS: Based on multivariate analysis, a high density of Tumor CD163+ macrophages served as the poorest prognostic factor for regional control (RC) and disease-free survival (DFS). Patients with both a high density of Tumor CD163+ macrophages and an intermediate- or a high-grade budding score had a poor prognosis for RC according to the log-rank test. CONCLUSIONS: In summary, each TIL subtype may use different mechanisms during early and advanced stages of oral tongue SCC. A high density of Tumor CD163+ macrophages was determined to be a risk factor for RC and DFS as well as an additional stratification factor for RC in patients with intermediate- or high-grade budding scores. Therefore, identifying TIL subtypes in daily clinical practice can help determine a more successful and individualized therapeutic approach for early oral tongue SCC. LEVEL OF EVIDENCE: Step 4 (Level 4) Laryngoscope, 131:2512-2518, 2021.

Clinicopathological correlation of tumor-stroma ratio and inflammatory cell infiltrate with tumor grade and lymph node metastasis in squamous cell carcinoma of buccal mucosa and tongue in 41 cases with review of literature.

INTRODUCTION: Several studies regarding tumor-stroma ratio (TSR) in colorectal, esophageal, breast, endometrial, and cervical carcinomas have been done in the past with significant results. OBJECTIVES: The objectives of this study were to (1) study and grade TSR in buccal mucosa and tongue squamous cell carcinoma (SCC), (2) grade inflammatory cell infiltrate surrounding the tumor, and (3) correlate the above two parameters with tumor grade, lymph node metastasis, lymphovascular invasion (LVI), and perineural invasion (PNI). MATERIALS AND METHODS: Totally, 25 patients of buccal SCC and 16 cases of tongue SCC were included in the study. TSR was assessed visually on the hematoxylin and eosin-stained tissue sections by two independent observers. Cases were categorized into two groups: One with high TSR >50% (stroma poor) and the other with low TSR <50% as the stroma-rich group. TSR was correlated with tumor size, lymph node metastasis, inflammatory cell infiltrate, LVI, and PNI. Data were analyzed by the Statistical Package for the Social Sciences version 16.0 (Chicago, IL, USA) for Windows. The Chi-square and Fischer's exact tests were applied in the analysis of categorical variable. RESULTS AND CONCLUSION: SCC of buccal mucosa showed a significant correlation between TSR and size of the tumor (P = 0.001). We found that smaller the tumor size ≤2 cm (Stage T1), lesser the TSR, and size >2 cm was found to be associated with higher TSR. Hence, higher TSR (stroma poor) was associated with an adverse pathological characteristic, i.e., advanced T significantly. There was no significant correlation between TSR and inflammatory infiltrate with grade of the tumor, lymph node metastasis, LVI, and PNI. In 16 cases of SCC of the tongue; no correlation was observed between TSR and inflammatory infiltrate with tumor size, grade of the tumor, lymph node metastasis, LVI, and PNI. TSR has been studied in various malignancies (mostly adenocarcinomas) including laryngeal SCCs; however, it has never been studied on oral SCCs.

Characterization of the immune profile of oral tongue squamous cell carcinomas with advancing disease.

We investigated whether a unique immune response was instigated with the development of oral tongue squamous cell carcinomas (OTSCC), with/without nodal involvement, with/without recurrent metastatic disease, or within tumor involved nodes. One hundred and ten formalin-fixed paraffin-embedded samples were collected from a retrospective cohort of 67 OTSCC patients and 10 non-cancerous tongue samples. Targets including CD4, CD8, FOXP3, PD-L1, and PD-1 were analyzed by immunohistochemistry. The Nanostring PanCancer Immune Profiling Panel was used for gene expression profiling. Data were externally validated in the The Cancer Genome Atlas (TCGA) head and neck (HNSCC), melanoma and lung squamous cell carcinoma (LSCC) cohorts. A 24-immune gene signature was identified that discriminated more aggressive OTSCC cases, and although not prognostic in HNSCC was associated with survival in other TCGA cohorts (improved survival for melanoma, P < .001 and worse survival for LSCC, P = .038). OTSCC exhibited concordant gene and immunohistochemical (IHC) features characterized by a TH-2 biased, proinflammatory profile with upregulated B cell and neutrophil gene activity and increased CD4, FOXP3, and PD-L1 expression (P < .001 for all by IHC). Compared to less advanced disease, nodal involvement and recurrent OTSCC did not induce a different immune response although recurrent disease was characterized by significantly higher PD-L1 expression (P = .004 by SP263, P = .013 by 22C3, P = .004 for gene expression). Identification of a gene signature associated with different prognostic effects in other cancers highlights common pathways of immune dysregulation that are impacted by the tumor origin. The significant immunosuppressive signaling in OTSCC indicates primary failure of immune system to control carcinogenesis emphasizing the need for early, combination therapeutic approaches.

Mapping of the lingual immune system reveals the presence of both regulatory and effector CD4+ T cells.

BACKGROUND: Sublingual immunotherapy (SLIT) is safe and reduces both symptoms and medication requirements in patients with type I respiratory allergies. Nonetheless, immune mechanisms underlying SLIT need to be further documented. OBJECTIVE: A detailed characterization of the lingual immune system was undertaken in mice, to investigate the presence of tolerogenic and pro-inflammatory mechanisms. METHODS: Immune cells were characterized in lingual tissues from BALB/c mice using immunohistology and flow cytometry. Resident CD4(+) T cells were sorted and toll-like receptor (TLR) expression profiles as well as functional characterization were assessed by RT-PCR, T cell suppressive assays and cytokine gene expression, respectively. RESULTS: Eosinophils and mast cells were only detected in submucosal tissues. No NK, NK-T, gamma/delta, CD8(+) T cells, nor B-lymphocytes were detected. Potential antigen presenting cells include various subsets of dendritic cells (CD207(+) Langerhans cells, CD11b(+)CD11c(+) myeloid cells and 120G8(+) plasmacytoid DCs) together with F4/80(+) macrophages. Noteworthy, both CD103(-) and CD103(+) CD4(+) T cells expressing TLR2 and TLR4 receptors are present along the lamina propria, in vicinity of myeloid CD11b(+)CD11c(+/-) dendritic cells. Such resident lingual CD4(+) T lymphocytes comprise both suppressive T cells as well as cells with memory/effector functions (i.e. expressing IFN gamma, IL4, IL10 and IL17 genes following stimulation), irrespective of the presence of the mucosal addressing marker CD103. CONCLUSION: The sublingual route is pertinent to induce antigen-specific tolerance, due to (i) limited numbers of pro-inflammatory cells, rather located in submucosal tissues, (ii) co-localization of APCs and resident CD4(+) T cells with regulatory functions. Since the oral immune system can also elicit pro-inflammatory effector responses, the cytokine milieu in which allergens are presented by sublingual APCs needs to be controlled during immunotherapy (e.g. with adjuvants) in order to favour tolerance over inflammation.

Attenuation of peripheral salt taste responses and local immune function contralateral to gustatory nerve injury: effects of aldosterone.

Dietary sodium restriction coupled with axotomy of the rat chorda tympani nerve (CTX) results in selectively attenuated taste responses to sodium salts in the contralateral, intact chorda tympani nerve. Converging evidence indicates that sodium deficiency also diminishes the activated macrophage response to injury on both the sectioned and contralateral, intact sides of the tongue. Because a sodium-restricted diet causes a robust increase in circulating aldosterone, we tested the hypothesis that changes in neurophysiological and immune responses contralateral to the CTX could be mimicked by aldosterone administration instead of the low-sodium diet. Taste responses in rats with CTX and supplemental aldosterone for 4-6 days were similar to rats with CTX and dietary sodium restriction. Responses to sodium salts were as much as 50% lower compared with sham-operated and vehicle-supplemented rats. The group-related functional differences were eliminated with lingual application of amiloride, suggesting that a major transduction pathway affected was through epithelial sodium channels. Consistent with the functional results, few macrophages were observed on either side of the tongue in rats with CTX and aldosterone. In contrast, macrophages were elevated on both sides of the tongue in rats with CTX and the vehicle. These results show that sodium deficiency or administration of aldosterone suppresses the immune response to neural injury, resulting in attenuation of peripheral gustatory function. They also show a potential key link among downstream consequences of sodium imbalance, taste function, and immune activity.