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Tumor necrosis factor (TNF)-alpha is a pro-inflammatory cytokine and crucial mediator in many aspects of immunity. Although several studies have shown that recurrent aphthous ulcers (RAU) can be prevented by treatment that prevents the synthesis of endogenous TNF-alpha little is known about the location and distribution of TNF-alpha-expressing cells at disease sites. The aim of the present work is, therefore, to investigate TNF-alpha and its cellular distribution in RAU lesions compared with those in induced oral traumatic ulcers (TUs). Twelve biopsies of RAU lesions of oral mucosa were obtained from 12 patients with RAU. They were compared to a control group consisting of ten samples of induced TUs. All samples were analyzed for TNF-alpha expression by using monoclonal mouse anti-human TNF-alpha antibody in avidin-biotin-peroxidase complex (ABC) staining. Results were quantified by a semi-automatic VIDAS image analysis system. TNF-alpha immunoreactivity was contained mainly in monocyte/macrophages and lymphocytes within the mononuclear inflammatory infiltrates. TNF-alpha was often seen in mast cells and vascular endothelial cells in connective tissue lateral to the inflammatory infiltrates. Interestingly, 32%-60% of the mononuclear cells were found to be TNF-alpha immunoreactive in RAU lesions. TNF-alpha containing cells were more numerous in aphthae (188+/-46 cells/0.2 mm2) compared with controls (52+/-14 cells/0.2 mm2, P<0.001). These findings suggest that RAU lesions are characterized by high expression of TNF-alpha. Because such expression occurred in the mononuclear inflammatory cells, mast cells and vascular endothelial cells, TNF-alpha, which is a major inflammatory mediator, may contribute to the activation and recruitment of leukocytes that are found in RAU lesions.

Abstract— Tissue lesions from eight patients with recurrent oral ulcers (ROU) were subjected to detailed immunohistopathologic studies. In five patients, a specimen of an unaffected area from the opposite site was obtained. The main inflammatory cells in situ were CD3 positive T lymphocytes, with CD4 cells forming approximately half (range 30‐60%) and CD8 cells 20% (range 10‐30%) of all cells. CD19 positive B lymphocytes formed 5‐12% of all cells. Furthermore, 45% (range 15‐65%) of all lymphoid cells had signs of previous antigenous contact and had helper/inducer CDw29 type. Suppressor/inducer CD45R cells formed only about 20% (range 7‐50%) of all cells. Although this observation suggests involvement of antigen as a causative and/or triggering stimulus, elements of a non‐specific inflammatory response were observed as well. Endogenous peroxidase‐positive neutrophils were present at the ulcer site, and were occasionally observed intravascularly and in th extracellular matrix in areas characterized by inflammatory mononuclear cell infiltrates. Although the proportion of endogenous peroxidase‐positive, recently recruited monocytes was low, CD11b and nonspecific esterase‐positive mature tissue macrophages formed about 14% (range 5‐35%) of all inflammatory cells in situ, particularly at the periphery of the lymphoid cell infiltrates. Mast cells were also observed in all samples studied, forming 2‐5% of inflammatory cells in the richly vascularized connective tissue beneath the basement membrane. In the specimens from clinically unaffected areas, inflammatory cells were rare. Our observations stress the multifaceted nature and participation of multiple effector systems in the local tissue pathogenesis of ROU.

Tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine, can stimulate matrix metalloproteinase synthesis and osteoclastic bone resorption. We hypothesized that elevated expression of TNF-alpha and its p55 and p75 receptors (TNF-R) in gingival tissue might associate with periodontitis. Immunohistochemistry was used for the study of the localization of TNF-alpha and its p55 and p75 TNF-R in adult periodontitis (AP) gingival tissue, in comparison with that in healthy control specimens. TNF-alpha and p55 TNF-R were detected in sulcular epithelial basal cells and in monocyte/macrophages, fibroblasts, and endothelial cells in the AP gingival tissue specimens, but mainly in fibroblasts and endothelial cells in control specimens. P75 TNF-R was occasionally found in monocyte/macrophage-like cells in gingival tissue specimens. The percentage of TNF-alpha-containing cells was not increased in AP compared with controls (13.2%+/-6.1% vs. 12.8%+/-7.6%), but, due to the increased cellularity of AP samples, the number of TNF-alpha positive cells/mm2 was clearly increased (1621+/-663 vs. 664+/-191, p > 0.001). Thus, AP gingival tissue has an elevated expression of TNF-alpha and especially its p55 receptor, suggesting that TNF-alpha may contribute to tissue degradation in periodontitis.

Healthy oral epithelial cells are equipped with H4 R, which displays a uniform staining pattern in a MC-independent fashion. In contrast, in OLP, increased numbers of activated MCs associate with increasing loss of epithelial H4 R. Cell culture experiments suggest a rapid H4 R stimulation-dependent receptor internalization and a slow cytokine-driven decrease in H4 R synthesis. H4 R may be involved in the maintenance of healthy oral mucosa. In OLP, this maintenance might be impaired by MC degranulation and inflammatory cytokines.

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Hayrirten-Immonen R: Immune-activation in recurrent oral ulcers (ROU). Scand J Dent Res 1992: 100: 222-7. Tissue specimens from eight patients with recurrent oral ulcers (ROU) were analyzed for possible signs of active lymphocyte involvement. A total of 13 specimens were analyzed, eight (8) taken at the ulcer site and five (5) from clinically unaffected mucosa at a site opposite the ulcer. Monoclonal antibodies or heterologous antisera were applied using the avidin-biotin-peroxidase complex (ABC) or peroxidase-antiperoxidase complex (PAP) methods to visualize cell-activation-associated marker proteins. In specimens from the ulcer area, approximately 43 + 18% of all inOatTimatory cells were positive for the MHC locus II coded Ia antigen. Furthermore, markers for cycling cells, interleukin-2 (CD25, 13 + 6%) and transferrin (CD71, 23± 14%) receptors, were frequent in the specimens studied. Staining for CDl (5 + 2%) disclosed dendritic intraepithelial cells in diseased and in clinically unaffected mucosa. Mobilization of such cells is suggested by their presence in submucosa in ROU specimens, but not in clinically unaffected mucosa. The presence of CDl cells, presumably denoting their identity as potent antigen-presenting Lagerhans' cells, and the rich presence of Ia suggest that local conditions are favorable for induction of T-cell-mediated responses. The simultaneous presence in such infiltrates of activation marker positive T-cells suggests activation de facto. This together with the rarity of activated B-cells, i.e. plasmablasts/cells containing cytoplasmic immunoglobulin, suggests active involvement of the local cells of the Tlymphocyte lineage in the pathogenesis of ROU.

The records were analyzed of 106 patients with sports-related dental traumas treated in 1983 at the public oral surgery unit in Helsinki, Finland; 51 were examined six years after injury. The mean age was 11.8 years (range 7-24 years). The woman/man ratio was 1:3. In 39% of cases, the injuries had arisen from ice hockey or skating; 30% happened during school hours; 80% were uncomplicated crown fractures, concussions or subluxations. During the six-year follow-up, of 80 teeth in 51 patients, root resorption was found in 6 teeth (7.5%), periapical lesions were noted in 2 teeth (2.5%), and obliteration of the pulp was seen in 4 teeth (5%). Three teeth (3.7%) had suffered loss of vitality. The pulp had been extirpated in 13 of the traumatized teeth (16%). In all, 13.7% of the patients were found to have complications six years later. The results showed that long follow-up periods are needed after dental injury.