The oral mucosa: A barrier site participating in tissue-specific and systemic immunity.

In the oral cavity, the immune system is constantly exposed to unique tissue-specific signals, including a rich community of commensal microbes and their metabolites, continuous tissue damage from mastication, and antigens from food and airborne particles. How this unique combination of signals participates in the training of specialized immunity at this site is not well understood, yet imbalance of local responses is linked to tissue-specific disease susceptibilities with the prototypic disease being periodontitis. However, the oral mucosa is also well recognized as a site where systemic inflammatory and autoimmune diseases often manifest, indicating that systemic immune deregulation is reflected in the function of the oral immune system. This commentary will discuss both aspects of compartmentalized and systemic immunity at the oral mucosa.

IL-17: overview and role in oral immunity and microbiome.

Interleukin-17 (IL-17) is a multifaceted cytokine with diverse roles in both immune protection and also immunopathology. IL-17 has a well-recognized role in immune surveillance at mucosal and barrier surfaces, but also has been increasingly implicated as a driver of immunopathology in settings of autoimmunity and chronic inflammation. The current review introduces basic aspects of IL-17 biology and examines the protective and pathogenic roles of IL-17 with a focus on oral mucosal immunity and inflammation. Specific emphasis is given to the role of the IL-17 response as a catalyst in 'shaping the microbiome at the oral barrier'.

Plasmin-Mediated Fibrinolysis in Periodontitis Pathogenesis.

The hemostatic and inflammatory systems work hand in hand to maintain homeostasis at mucosal barrier sites. Among the factors of the hemostatic system, fibrin is well recognized for its role in mucosal homeostasis, wound healing, and inflammation. Here, we present a basic overview of the fibrinolytic system, discuss fibrin as an innate immune regulator, and provide recent work uncovering the role of fibrin-neutrophil activation as a regulator of mucosal/periodontal homeostasis. We reason that the role of fibrin in periodontitis becomes most evident in individuals with the Mendelian genetic defect, congenital plasminogen (PLG) deficiency, who are predisposed to severe periodontitis in childhood due to a defect in fibrinolysis. Consistent with plasminogen deficiency being a risk factor for periodontitis, recent genomics studies uncover genetic polymorphisms in PLG, encoding plasminogen, being significantly associated with periodontal disease, and suggesting PLG variants as candidate risk indicators for common forms of periodontitis.

Establishment and Stability of the Murine Oral Microbiome.

Commensal microbiomes exert critical functions at barrier sites. In particular, establishment of the commensal microbiome after birth dictates immune functionality and tissue homeostasis at mucosal surfaces. To investigate the establishment and stability of the oral mucosal microbiome in mice, we evaluated oral microbiome communities shortly after birth, through adulthood, and up to 1 y of life in a controlled manner, using sequential oral samples from the same mice over time. We further evaluated transmissibility of oral microbiomes from parents and during cohousing experiments and evaluated susceptibility to oral inflammatory disease in mice harboring distinct microbiomes. Our work reveals basic principles in the establishment and stability of a health-associated oral microbiome after birth and provides insights that may be important for host-microbiome experimentation in animal models.

Lack of efficacy of etanercept in Sjögren syndrome correlates with failed suppression of tumour necrosis factor alpha and systemic immune activation.

OBJECTIVE: To provide insight into the clinical failure of the tumour necrosis factor alpha (TNFalpha) inhibitor, etanercept, in primary Sjögren syndrome (pSS), an extensive analysis of the systemic immune profile of patients with pSS was carried out and the effect of etanercept treatment on these immune parameters monitored. METHODS: Peripheral blood mononuclear cells of patients with pSS and healthy controls were compared by flow cytometry to determine differences in distribution of specific cell populations (T cells, B cells, monocytes), and to determine their expression of activation markers (CD25, HLA-DR), TNF receptors and chemokine receptors (CXCR1, 2) before and after treatment. Systemic cytokine levels were measured by multiplex ELISA assay in plasma and in lipopolysaccharide-stimulated whole blood from healthy controls and from patients with pSS before and after etanercept treatment. Baseline cytokine levels were correlated with clinical markers of disease. RESULTS: Before treatment, salivary gland inflammatory focus scores did not correlate with circulating TNF levels. Furthermore, consistent with the lack of evidence of significant clinical benefit, enhanced markers of immune activation, frequency of cell subpopulations and aberrant cytokine profiles were not restored to normal levels by etanercept treatment. Remarkably, the levels of circulating TNFalpha were significantly increased after treatment. CONCLUSION: Etanercept is an ineffective therapeutic agent in pSS consistent with the absence of suppression of TNFalpha and other indicators of immune activation in this patient population. These data suggest that TNFalpha may not be a pivotal cytokine in the pathogenesis of pSS, impelling continued molecular characterisation of disease parameters to define appropriate intervention targets.

Unique Tailoring of Th17 at the Gingival Oral Mucosal Barrier.

Our recent work highlights unique requirements for the induction of Th17 cells at the oral/gingival mucosal barrier. Unlike other barrier sites, such as the skin and gastrointestinal tract, we found that Th17 cells can develop at the gingiva independently of commensal microbiota colonization. Instead, we identified that damage, which occurs physiologically due to mastication, promotes induction of Th17 cells and tones homeostatic immunity at the gingiva.

Differential mucosal susceptibility in HIV-1 transmission and infection.

HIV infection occurs primarily through mucosal surfaces, indicating that protection at mucosal sites may be crucial in prevention and treatment. The host innate and adaptive immune elements provide a level of protection, which differs between mucosal compartments, and appears to be most successful in the oral environment, where transmission is rare. In addition to the distinct oral mucosal architecture and cellular constituents, oral fluids, unlike other mucosal secretions, are rarely a vehicle for HIV infection. Multiple soluble factors may contribute to this antiviral activity, including neutralizing antibodies, secretory leukocyte protease inhibitor (SLPI), antiviral peptides such as defensins and cystatins, glycoproteins including thrombospondin and lactoferrin, and complement components. Understanding the antiviral activities of these and other potential resistance factors is becoming increasingly important in attempts to design treatments in the era of HAART resistance. In this regard, the mechanism of anti-HIV action of SLPI has recently been further elucidated by the discovery of its binding protein/receptor, which plays a key role in the infection of macrophages and may consequently be a novel therapeutic target. Continued elucidation of the unique features of mucosal HIV immunology is essential for understanding HIV pathogenesis and for developing effective vaccines and therapeutics.

Inborn errors in immunity: unique natural models to dissect oral immunity.

In recent years, the study of genetic defects arising from inborn errors in immunity has resulted in the discovery of new genes involved in the function of the immune system and in the elucidation of the roles of known genes whose importance was previously unappreciated. With the recent explosion in the field of genomics and the increasing number of genetic defects identified, the study of naturally occurring mutations has become a powerful tool for gaining mechanistic insight into the functions of the human immune system. In this concise perspective, we discuss emerging evidence that inborn errors in immunity constitute real-life models that are indispensable both for the in-depth understanding of human biology and for obtaining critical insights into common diseases, such as those affecting oral health. In the field of oral mucosal immunity, through the study of patients with select gene disruptions, the interleukin-17 (IL-17) pathway has emerged as a critical element in oral immune surveillance and susceptibility to inflammatory disease, with disruptions in the IL-17 axis now strongly linked to mucosal fungal susceptibility, whereas overactivation of the same pathways is linked to inflammatory periodontitis.

Matriptase promotes inflammatory cell accumulation and progression of established epidermal tumors.

Deregulation of matriptase is a consistent feature of human epithelial cancers and correlates with poor disease outcome. We have previously shown that matriptase promotes multi-stage squamous cell carcinogenesis in transgenic mice through dual activation of pro-hepatocyte growth factor-cMet-Akt-mTor proliferation/survival signaling and PAR-2-Gαi-NFκB inflammatory signaling. Matriptase was congenitally and constitutively deregulated in our prior studies, and therefore it was unclear if aberrant matriptase signaling supports only initiation of tumor formation or if it is also critical for the progression of established tumors. To determine this, we here have generated triple-transgenic mice with constitutive deregulation of matriptase and simultaneous inducible expression of the cognate matriptase inhibitor, hepatocyte growth factor inhibitor (HAI)-2. As expected, constitutive expression of HAI-2 suppressed the formation of matriptase-dependent tumors in 7,12-Dimethylbenz(a)anthracene-treated mouse skin. Interestingly, however, the induction of HAI-2 expression in already established tumors markedly impaired malignant progression and caused regression of individual tumors. Tumor regression correlated with reduced accumulation of tumor-associated inflammatory cells, likely caused by diminished expression of pro-tumorigenic inflammatory cytokines. The data suggest that matriptase-dependent signaling may be a therapeutic target for both squamous cell carcinoma chemoprevention and for the treatment of established tumors.

A 17-year old patient with DOCK8 deficiency, severe oral HSV-1 and aggressive periodontitis - a case of virally induced periodontitis?

We present a 17-year old girl with DOCK-8 deficiency, severe untreated oral HSV-1 infection and associated aggressive periodontitis. DOCK-8 deficiency is a primary immunodeficiency, caused by biallelicloss-of-function mutations in the DOCK8 gene, often leading to severe viral and fungal mucocutaneous infections. Nevertheless, to date DOCK8 has not been associated with severe periodontitis and inflammatory bone loss around teeth. Understanding whether DOCK8 deficiency or severe HSV-1 infection underlies susceptibility to periodontitis is central to this case and may provide insights into susceptibility factors for periodontitis in the general population. Our clinical and microbiological data suggest that severe HSV-1 infection is the driver of periodontal inflammation in this case.

[Effectiveness and safety of using cyclosporin A in the treatment of primary Sjögren's syndrome]. / Effektivnost' i bezopasnost' primeneniia tsiklosporina A pri lechenii pervichnogo sindroma Shegrena.

We used oral cyclosporine-A (CyA) (5 mg/kg/day) initially in a double blind study for 6 mos. 10 patients received CyA and 10 placebo. At the end of this study it was observed that CyA improved subjective xerostomia, while subjective xerophthalmia, parotid gland enlargement, Schirmer-I-test and parotid flow rate did not show any significant differences in the two study groups. 9 of 10 patients who had received CyA for 6 mos and 9 of 10 in the placebo group continued in an open trial (CyA at the same dose) for an additional 6 mos. At the end of the study the only efficacy of CyA observed was improvement of subjective xerostomia. The side-effects observed were hypertrichosis (14 persons), mild hypertension (4), infections (5) and 3 dropped out because of nausea, tremor, paresthesias and infections. In conclusion, small doses of CyA for 12 mos are rather ineffective for Sjogren's syndrome.

[Monoclonal cryoglobulins in primary Sjögren's syndrome]. / Monoklonal'nye krioglobuliny pri pervichnom sindrome Shegrena.

Cryoglobulins were studied in the sera of 40 unselected pSS patients. The nature of the cryoglobulins was defined using a very fast and sensitive resolution electrophoresis technique combined with immunofixation. Thirty-five per cent of SS patients were shown to have circulating IgMk mixed monoclonal cryoglobulins. On the contrary, all the other tested cryoprecipitates were found to be mixed polyclonal, with the exception of one patient with SLE. The presence of cryoglobulins in the sera of SS patients correlated with extraglandular disease and with autoantibodies to Ro (SSA) cellular antigen and rheumatoid factor. Patients with cryoglobulins had lower serum C4 levels compared to patients without cryoglobulins. These findings suggest that SS in addition to polyclonal B-cell hyperreactivity expresses a monoclonal process preceding the development of lymphoid neoplasia. Extraglandular manifestations of the syndrome may be associated with an immune complex mediated pathology.

Immunological consequences of thalidomide treatment in Sjögren's syndrome.

OBJECTIVE: To study the immunological consequences of systemic thalidomide treatment in patients with Sjögren's syndrome. METHODS: Cytokine (tumour necrosis factor alpha (TNFalpha), interleukin (IL) 6) and soluble receptor (sIL2R) levels were measured in patient and control plasma (n = 7), before and after thalidomide treatment. Peripheral blood mononuclear cells were examined by FACS analysis for potential changes in specific cell populations (T cells, B cells, monocytes), and for the expression of activation markers (CD25, HLA-DR), costimulatory molecules (CD40, CD40L), TNF receptors, chemokine receptors, and adhesion molecules (L-selectin (L-sel)). RESULTS: Owing to adverse effects of thalidomide, the treatment interval was limited. None the less, statistically significant changes in markers of cell activation were recorded in the four treated patients. Before treatment, HLA-DR, TNFRI, CXCRI, and CXCRII were raised in the patients compared with healthy controls (p<0.05) and their expression was down regulated after treatment. B cell numbers and expression of the adhesion molecule L-sel also declined with thalidomide. CONCLUSION: Significant changes in measures of cell activation were detected during thalidomide treatment within this limited study, which upon further investigation may offer insight into the underlying immunoregulatory pathways of thalidomide.