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.

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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.

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