What is the pathophysiology of aphthous ulcers?

Updated: Feb 25, 2019
  • Author: Michael C Plewa, MD; Chief Editor: Russell W Steele, MD  more...
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The pathophysiology of aphthous ulcers remains incompletely understood. The primary disorder appears to be the result of activation of the cell-mediated immune system. Early lesions show a cluster of macrophages and lymphocytes (predominantly cytotoxic and natural-killer T cells) at the preulcerative base, followed by formation of an ulcer with a neutrophilic base and an erythematous lymphocytic ring.

Patients with recurrent aphthous ulcers (canker sores) have increased numbers of cytotoxic CD8+ cells and decreased numbers of helper CD4+ cells in peripheral blood. [1]  Antithyroid and antigastric antibodies may also play a role [2] since antibodies to gastric parietal cells, thyroglobulin and thyroid microsomes may be present in 13-19% of cases. [3]   Lesions have elevated levels of interferon gamma, tumor necrosis factor-alpha, interleukin (IL)-2, IL-4, and IL-5; [4] they have a functional deficit of IL-10. Some lesions have also had mast-cell activation and degranulation. In vitro cytotoxicity to oral keratinocyte targets is greater in patients with active recurrent aphthous ulcers (canker sores) than in control subjects or in patients with traumatic ulcers. As expected with this abnormal immunologic activity, corticosteroids are effective therapy.

Aphthous ulcers may have abnormalities in cell communication and epithelial integrity. Lesions have increased expression of an adhesion molecule termed vascular cell adhesion molecule-1 (VCAM-1), E selectin, and keratinocyte intercellular adhesion molecule-1 (ICAM-1). [5] Connexins (markers for the presence of gap junctions) are present in the oral mucosa of patients with recurrent aphthous ulcers (canker sores) in amounts similar to those present in normal mucosal tissue. Experimental treatment with irsogladine maleate, which reinforces gap junctional intercellular communication, is effective.

The oral flora likely plays a role in recurrent aphthous ulcers (canker sores), and a dysbiosis of the microbiota has been suggested. [6]  Helicobacter pylori may or may not be involved in aphthous ulcer formation. [7, 8, 9]

Factors predisposing patients to recurrent aphthous ulcers (canker sores) may include trauma, emotional stress [10] poor nutritional status, thiamine deficiency, [11] vitamin B12 and D deficiency, [12] zinc deficiency, [13]  malabsorption, celiac disease, regional enteropathy, menstruation, food hypersensitivity (eg, cow's milk), [14] allergic reaction, low antioxidant levels, [15, 16] and exposure to toxins (eg, nitrates in drinking water). Aphthous ulcers (canker sores) are more prevalent in nonsmokers and in smokers who quit but are diminished with nicotine replacement therapy.

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