Interleukin-34 permits Porphyromonas gingivalis survival and NF-κB p65 inhibition in macrophages.

Interleukin-34 (IL-34) is a cytokine that supports the viability and differentiation of macrophages. An important cytokine for the development of epidermal immunity, IL-34, is present and plays a role in the immunity of the oral environment. IL-34 has been linked to inflammatory periodontal diseases, which involve innate phagocytes, including macrophages. Whether IL-34 can alter the ability of macrophages to effectively interact with oral microbes is currently unclear. Using macrophages derived from human blood monocytes with either the canonical cytokine colony-stimulating factor (CSF)1 or IL-34, we compared the ability of the macrophages to phagocytose, kill, and respond through the production of cytokines to the periodontal keystone pathogen Porphyromonas gingivalis. While macrophages derived from both cytokines were able to engulf the bacterium equally, IL-34-derived macrophages were much less capable of killing internalized P. gingivalis. Of the macrophage cell surface receptors known to interact with P. gingivalis, dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin was found to have the largest variation between IL-34- and CSF1-derived macrophages. We also found that upon interaction with P. gingivalis, IL-34-derived macrophages produced significantly less of the neutrophil chemotactic factor IL-8 than macrophages derived in the presence of CSF1. Mechanistically, we identified that the levels of IL-8 corresponded with P. gingivalis survival and dephosphorylation of the major transcription factor NF-κB p65. Overall, we found that macrophages differentiated in the presence of IL-34, a dominant cytokine in the oral gingiva, have a reduced ability to kill the keystone pathogen P. gingivalis and may be susceptible to specific bacteria-mediated cytokine modification.

Salivary and serum inflammatory mediators among pre-conception women with periodontal disease.

BACKGROUND: There have been inconsistent conclusions regarding the levels of inflammatory mediators in saliva and serum among people with or without periodontal disease. Although pre-conception has been put forward as the optimal time for the periodontal treatment in order to improving pregnancy outcomes, few studies have been conducted to examine inflammatory mediators in saliva and serum among pre-conception women. METHODS: Pre-conception women were recruited between January 2012 and December 2014. Women were provided with an oral health examination to detect periodontal disease. Salivary and serum samples were collected at the same of examination. Inflammatory mediators includinginterleukin-1 beta (IL-1ß), IL-6, tumor necrosis factor alpha (TNF-α) and beta-glucuronidase (ß-glucuronidase) were tested and analyzed among women with overall periodontal disease (n = 442) or moderate/severe periodontal disease (n = 247). Results were compared to that in women with a healthy periodontium (n = 91). RESULTS: Significantly increased concentrations of inflammatory mediators of IL-1ß, IL-6, TNF-α and ß-glucuronidase in saliva and IL-1ß, ß-glucuronidase and TNF-α in serum were found among pre-conception women with moderate/severe periodontal disease, compared with women without periodontal disease. Significantly increased levels were also found in all the above saliva inflammatory mediators and in serum IL-1ß and TNF-α among women with overall periodontal disease. The levels of all inflammatory mediators in saliva and almost all inflammatory mediators except IL-6 in serum significantly increased with severity of periodontal disease. CONCLUSION: Periodontal disease is highly associated with the elevated levels of inflammatory mediators in saliva and some mediators in serum among pre-conception women.

Vulvovaginal-gingival Lichen Planus: Association with Lichen Planopilaris and Stratified Epithelium-specific Antinuclear Antibodies.

Vulvovaginal-gingival lichen planus (VVG-LP) consists of a triad of symptoms: vulval, vaginal and gingival lichen planus lesions. The aim of this study was to analyse the prevalence of lesions in various anatomical locations in patients with VVG-LP. The study included 126 consecutive patients with lichen planus. Sixteen (12.7%) patients fulfilled the criteria of VVG-LP. In 12/16 (75%) patients with VVG-LP scalp lesions were also observed. Stratified epithelium-specific antinuclear antibodies (SES-ANA) and anti-ΔNp.3α antibodies were detected in 10/16 (75%) patients with VVG-LP and in 15/110 (13.6%) patients with other forms of lichen planus (p < 0.05). In conclusion, VVG-LP is frequently associated with lichen planopilaris. The new entity may be termed "vulvovaginal-gingival-pilar lichen planus" and our study indicates that SES-ANA is a marker of this type of lichen planus with extensive, severe and refractory-to-therapy involvement of the mucous membranes, skin and scalp.

Comparison of Levels of Salivary Cytokines in Diabetic and Nondiabetic Puerto Rican Children: A Case-control Pilot Study.

PURPOSE: The oral health status of children with type 1 diabetes and its relationship to salivary cytokines have been researched in only one known study. The purpose of the present study was to evaluate the association between levels of salivary cytokines and gingival disease in diabetic and nondiabetic Puerto Rican children. METHODS: A matched case-control study with a convenience sample of 25 children with type 1 diabetes (cases) and 25 nondiabetic children (controls) were evaluated by a calibrated dentist for oral health indices. A five-ml stimulated saliva sample was taken from each subject and analyzed to determine cytokine levels (IL-6, IL-17, IP-10, TNF-alpha, MMP-2, MMP-9, CRP). Descriptive statistics, chi-square tests, and t tests were used. RESULTS: Diabetic children are observed to have more plaque than control children (P=.007), more calculus (P=.06), and more bleeding on probing (P=.001). Only the level of the mediator IL-17 (P=.002) was higher in diabetic children than in nondiabetic children, but no significant differences were observed in the levels of other cytokines between the two groups. However, for each salivary mediator evaluated, diabetic children had higher levels of the respective mediator. CONCLUSION: Salivary cytokines levels were higher in diabetic type 1 children than in nondiabetic children.

Oral mucosal lesions and immune status in HIV-infected Indian children.

OBJECTIVE: Pediatric HIV is growing at an alarming rate in developing countries. Due to their compromised immune status, children infected with HIV are prone to a number of opportunistic infections. Oral manifestations are the first signs of the disease in many of them. To assess the oral mucosal status of Indian children with HIV, based on their CD4 cell counts. METHODOLOGY: Two hundred and twenty one HIV infected children aged 6-18 years from various HIV centers, were divided into three groups, based on their CD4 cell counts; Group 1: ≥500, Group 2: 201-499 and Group 3: ≤200 cells. The children in each group were further considered as 'prior to antiretroviral treatment (ART)' and 'on ART'. Oral mucosal examination was done based on presumptive criteria given by Ramos-Gomez for diagnosis of oro-facial lesions commonly associated with HIV infection in children. Data obtained was subjected to statistical analysis. RESULTS: Angular cheilitis and pseudomembranous candidiasis were the frequently seen oral lesions. Children with CD4 cell count ≥500 had significantly fewer oral lesions each. CONCLUSION: A high percentage of HIV-infected children were affected with oral mucosal lesions. There was a significant association between immune status and frequency of oral lesions.

Lipoproteins of Actinomyces viscosus induce inflammatory responses through TLR2 in human gingival epithelial cells and macrophages.

Actinomyces viscosus has been suggested to be associated with periodontal disease. However, the pathogenicity of this bacterium is not known. In this study, we examined inflammation-inducing activity by A. viscosus. Whole cells and a lipophilic fraction of A. viscosus ATCC19246 induced production of interleukin-8 and tumor necrosis factor alpha from both human oral epithelial cells and human monocytoid cells. This cytokine production was blocked by lipoprotein lipase treatment of the lipophilic fraction. In addition, anti-Toll-like receptor 2 antibody blocked the cytokine production. These results suggest that lipoprotein of A. viscosus triggers inflammatory responses in periodontitis by activation of Toll-like receptor 2.

Ocular and oral mucous membrane pemphigoid (cicatricial pemphigoid).

Mucous membrane pemphigoid, a heterogeneous group of autoimmune blistering diseases, affects primarily the mucous membranes. Although oral and ocular mucosae can both be affected in a given patient, patients with involvement restricted to oral mucosae tend to have a benign outcome, whereas those with ocular disease commonly face treatment resistance, resulting in scarring and blindness. Diagnosis requires direct immunofluorescence microscopy to demonstrate a linear deposition of immunoglobulin (Ig) G or IgA, or complement component 3 (C3), at the epithelial basement membrane. Although the target antigens vary, subsets of patients affected exclusively by oral and ocular mucosal diseases have autoantibodies targeting α-6 and ß-4 integrins, respectively.

Oral eosinophilic ulcer, an Epstein-Barr virus-associated CD30+ lymphoproliferation?

Eosinophilic ulcer of the oral mucosa is a benign lesion of unclear pathogenesis mostly affecting the tongue. It has been suggested to represent a reactive pattern to several stimuli. We report on a 12-year-old boy who presented with a painless infiltrating ulcer on the gingiva of the lower jaw, which was covered by necrotic yellowish slough. There were no pathologic features of the jawbones or regional lymph nodes. Histopathological, immunohistochemical and gene rearrangement studies were in agreement with eosinophilic ulcer with predominant oligoclonal CD3+ and CD30+ T lymphocytes expressing the Epstein-Barr virus membrane protein. The ulcer resolved within 4 weeks and follow-up for 3 years revealed no evidence of recurrence. Epstein-Barr virus may have played a role in triggering this reactive lymphoproliferative disorder.

Comparison of oral manifestations with CD4 count in HIV-infected patients.

AIM AND OBJECTIVE: This study was carried out with the primary aim of correlating oral changes and general changes of HIV-infected patients with their CD4 count. MATERIALS AND METHODS: 124 patients were selected, and after taking their informed consent, they were subjected to detailed history taking and thorough clinical examination. Specific oral lesions and general physical changes were recorded. Every patient was subjected to laboratory investigation for CD4 count. All these findings were tabulated. The clinical observation and laboratory findings were subjected to critical analysis and correlated. Statistical test, i.e. Student's " t" test, was applied and objective conclusions were drawn. RESULT: Out of 124 patients, 40 had oral candidiasis, 6 had oral hairy leukoplakia, 12 had periodontal disease, 20 had xerostomia, 30 had melanin pigmentation, while 4 had HSV2, and atypical ulceration. Out of 40 patients with oral candidiasis, 28 patients had CD4 count <200 (group A), 10 patients were in group, B (CD4 count 200-500 cell/mm 3 ) and 2 patients in group C(CD4 >500 cell/mm 3 ). Oral hairy leukoplakia occurred in equal proportions in group A and B. These periodontal diseases were more commonly in group B; xerostomia and melanin pigmentation was equally seen in group A and B. CONCLUSION: Oral candidiasis, oral hairy leukoplakia, linear gingival erythema, necrotizing ulcerative gingivitis, and necrotizing ulcerative periodontitis are specific oral indicators which will definitely suggest to the dental surgeon that the disease is running a rapid downhill course and due to this the oral physician is in a position to raise a suspicion and alert the general physician regarding the declining immune status of patient.

MAGE-A antigens in lesions of the oral mucosa.

Oral squamous cell carcinoma develops continuously out of predamaged oral mucosa. For the physician and pathologist, difficulties arise in distinguishing precancerous from cancerous lesions. MAGE-A antigens are tumor antigens that are found solely in malignant transformed cells. These antigens might be useful in distinguishing precancerous from cancerous lesions. The aim of this study was to verify this assumption by comparing MAGE-A expression in benign, precancerous, and cancerous lesions of the oral mucosa. Retrospectively, biopsies of different oral lesions were randomly selected. The lesions that were included are 64 benign oral lesions (25 traumatic lesions (oral ulcers), 13 dental follicles, and 26 epulis), 26 oral lichen planus, 123 epithelial precursor lesions (32 epithelial hyperplasia found in leukoplakias, 24 epithelial dysplasia found in leukoplakias, 26 erythroplasia with oral epithelial dysplasia, and 41 carcinomas in situ in erythroleukoplakias). The lesions were immunohistochemically stained with the poly-MAGE-A antibody 57B, and the results were compared. Biopsies of oral lichen planus, oral ulcers, dental follicles, epulis, and leukoplakia without dysplasia showed no positive staining for MAGE-A antigens. Leukoplakia with dysplasia, dysplasia, and carcinomata in situ displayed positive staining in 33%, 65%, and 56% of the cases, respectively. MAGE-A antigens were not detectable via immunohistochemistry in benign lesions of the oral mucosa. The staining rate of dysplastic precancerous lesions or malignant lesions ranged from 33% to 65%. The MAGE-A antigens might facilitate better differentiation between precancerous and cancerous lesions of the oral mucosa.

A novel vaccine targeting Fusobacterium nucleatum against abscesses and halitosis.

An abscess in a gum pocket, resulting from bacterial infection, is a common source of chronic halitosis. Although antibiotics are generally prescribed for abscesses, they require multiple treatments with risks of creating resistant bacterial strains. Here we develop a novel vaccine using ultraviolet-inactivated Fusobacterium nucleatum (F. nucleatum), a representative oral bacterium for halitosis. A gum pocket model, established by continuous inoculation of F. nucleatum, was employed to validate the vaccine potency. Mice immunized with inactivated F. nucleatum effectively minimized the progression of abscesses, measured by swollen tissues of gum pockets. Most notably, the immunized mice were capable of eliciting neutralizing antibodies against the production of volatile sulfur compounds of F. nucleatum. The novel vaccine inducing protective immunity provides an alternative option to conventional antibiotic treatments for chronic halitosis associated with abscesses.

Hyper IgE (Job's) syndrome: a primary immune deficiency with oral manifestations.

Autosomal dominant hyper IgE (HIES or Job's) syndrome is a rare primary immune deficiency characterized by eczema, recurrent skin and lung infections, extremely elevated serum IgE, and a variety of connective tissue and skeletal abnormalities. Individuals with HIES share a characteristic facial appearance and many oral manifestations including retained primary dentition, a high arched palate, variations of the oral mucosa and gingiva, and recurrent oral candidiasis. Mutations in STAT3 account for the majority, if not all, of the cases of autosomal dominant HIES, but the pathogenesis of the many varied features remains poorly understood. In this review, we discuss the clinical phenotype of HIES including immunologic and non-immunologic features, the genetics of HIES, and treatment.

Oral manifestations as predictors of immune suppression in a HIV-/AIDS-infected population in south India.

The objectives of the study are to evaluate the relationship between common HIV-related oral lesions and absolute CD4+ count, age, gender, and medication used and to assess the sensitivity, specificity, positive and negative predictive value of oral manifestations for low absolute CD4+ counts. HIV-positive patients, 200, from south India were selected, whose absolute CD4+ counts were determined within 2 weeks of oral examination. Sociodemographic data was obtained using a structured questionnaire. Oral manifestations were diagnosed according to presumptive criteria of EEC-clearinghouse classification (1993). Four or more concurrent oral lesions were statistically significant with low CD4+ counts <200 cells/mm3 (P = 0.005). The highest and lowest mean CD4+ cell counts were seen in individuals with linear gingival erythema (LGE; 172.5 cells/mm(3)) and pseudomembranous candidiasis (PC; 87 cells/mm(3)), respectively. Smoking, age (<35 years), and males had a positive association with oral hairy leukoplakia (OHL; P < 0.05). Patients with CD4+ counts < 200 cells/mm(3) were associated with 15 times greater risk of PC and four times at greater risk for occurrence of any oral manifestation. Concurrent oral manifestations (>or=4) were good predictors (80-100%) of severe immune suppression. In most resource poor countries where facilities for undertaking CD4+ counts are not available, the presence of concurrent oral manifestations may be used as an indicator of deteriorating immune status.

Mucous membrane pemphigoid: a retrospective study.

BACKGROUND: Mucous membrane pemphigoid (MMP) is a vesiculobullous, autoimmune disease that occurs primarily in older women. The objective of this study was to perform a retrospective analysis of the intraoral clinical signs, symptoms and diagnostic findings of MMP. STUDY DESIGN: The charts of 729 patients in a university-based dental referral practice were reviewed. RESULTS: Of 729 patients, a clinical diagnosis of MMP was rendered in 29 cases. Of these cases, 93 percent had only oral lesions at the time of presentation, whereas 7 percent had lesions at other sites in addition to the oral cavity. Sixty-eight percent were female and 83 percent of the patients were over 50 years at onset. Common sites of involvement were gingiva and buccal mucosa. Sixty-three percent exhibited erosive or ulcerative lesions. Thirty-five percent showed clinical evidence of epithelial separation. Eighty-eight percent of biopsied patients had histopathologic findings consistent with MMP. Seventy-seven percent of patients exhibited IgG and C3 in the basement membrane region, consistent with pemphigoid. Eighty-two percent of the 29 patients who had two or more lesions were treated with topical corticosteroids. CONCLUSIONS: The intraoral sites most commonly affected by MMP are the gingiva and buccal mucosa. Routine histopathologic evaluation is an effective diagnostic tool when used in conjunction with direct immunofluorescence.

Clinical and immunopathologic findings in oral lichen planus pemphigoides.

Lichen planus pemphigoides (LPP) is a rare, acquired, immunobullous disorder of skin that occasionally involves oral mucous membranes. Clinical, histologic, and immunopathologic findings of the oral manifestations of LPP are described. Clinical features are lichenoid striae, erosions, and ulcerations involving gingiva and buccal mucosae. Histopathologic features are similar to those of ora lichen planus. Direct immunofluorescence demonstrates linear deposits of immunoglobulin G and complement component C3 along the basement membrane with fibrillar deposits of fibrin at the epithelial/lamina propria junction. Fluorescence overlay antigen mapping and laser scanning confocal microscopy of the biopsy specimen exhibits colocalization of in situ antibodies with beta4 integrin, a marker of the keratinocyte basal plasma membrane and upper lamina lucida, consistent with the location of the bullous pemphigoid antigens. This case report describes a case of LPP that presented exclusively as an oral condition. Lichen planus pemphigoides should be considered in the clinical differential diagnosis of vesiculoerosive oral mucosal diseases.

Metallic pigmentation of human teeth and gingiva: morphological and immunological aspects.

The composition of metallic pigmentations in gingiva and dental roots was determined by means of transmission electron microscopy with energy dispersive x-ray microanalysis. The systemic immune response to the metals found in the oral cavity was evaluated in 10 patients by using a modified lymphocyte proliferation test. Immunological results were compared with a group of five controls without metallic materials and pigmentation. Dense particles of various shapes and sizes, as well as of diverse extracellular and intracellular localization patterns, were detected in the pigmented lamina propria gingivae. Metallic deposits consisted predominantly of silver accompanied by selenium or sulfur or both. Besides, Ag, Au, Cr, Ni, Fe, Hg, Cu, and Ti were identified in dentinal tubules of teeth reconstructed with dental alloys. Nine patients with metallic pigmentations had a positive lymphocyte proliferative response to one or more metals present in their own metal reconstructions. Results of this study thus indicated that dental alloys-by virtue of their corrosion process-might pose a significant risk to immunologically susceptible patients.

Successful treatment of oral linear IgA disease using mycophenolate.

Linear IgA disease (LAD) is a rare acquired autoimmune bullous disorder, characterized by linear deposition of IgA along the dermoepidermal basement membrane zone. The clinical presentation of LAD consists of vesiculobullous lesions affecting the skin and mucosal surfaces. The present case report presents a rare presentation of this vesiculobullous disorder. Although more than 50% of LAD patients present with oral lesions, there are few reported cases of involvement of the mouth as the sole manifestation. A 79-year-old female presented with a sore mouth and erosions affecting the palate. The symptoms resolved following the provision of mycophenolate, an antiproliferative immunosuppressant which has not previously appeared to have been reported in the long-term successful management of linear IgA disease limited to the mouth. We found that mycophenolate is a useful adjunct to the successful treatment of oral linear IgA when the uses of other immunosuppressants are contraindicated.