Is the Immune System Involved in Aphthous Ulcers?
Yes, the immune system is fundamentally implicated in the pathogenesis of aphthous ulcers, with evidence demonstrating both innate and adaptive immune dysfunction driving the inflammatory process and tissue destruction.
Immune System Mechanisms in Aphthous Ulcer Development
Innate Immune System Dysfunction
The innate immune system plays a central role in aphthous ulcer pathogenesis through several mechanisms:
- Neutrophil hyperactivation occurs in patients with recurrent aphthous ulcers (RAU), characterized by increased reactive oxygen intermediate (ROI) production by both resting and stimulated neutrophils, indicating prior in vivo priming 1
- Elevated CD11b expression on neutrophils in RAU patients confirms previous in vivo stimulation and priming of these cells 1
- Decreased total antioxidant status in serum results from the increased ROI production by peripheral blood neutrophils, contributing to tissue damage 1
- Complement system activation is evident, with higher levels of C3c, C4, and increased hemolytic activity of the complement system in RAU patients compared to healthy individuals 1
Adaptive Immune System Alterations
The adaptive immune response shows significant abnormalities in aphthous ulcer patients:
- Reversed CD4:CD8 T cell ratios occur in peripheral blood of healthy subjects with RAU, indicating T cell dysregulation 2
- Increased T cell receptor-gamma delta+ cells are found in higher proportions in RAU patients 2
- Adhesion molecule upregulation includes strong expression of ICAM-1 and ELAM, which are involved in lymphocyte homing and may be critical in RAU pathogenesis 2
Cytokine-Mediated Inflammation
Inflammatory cytokines drive the ulcerative process:
- TNF-alpha production is increased in peripheral blood lymphocytes of RAU patients, contributing to tissue destruction 2
- Thalidomide effectiveness in treating RAU through TNF-alpha inhibition provides therapeutic evidence of this cytokine's pathogenic role 2
Clinical Context and Disease Severity
The immune system's role becomes more pronounced in immunocompromised states:
- HIV-associated RAU shows increased severity, with 66% of HIV+ patients developing the more severe herpetiform or major RAU forms, suggesting that HIV disease-related immune changes exacerbate the condition 2
- Serum TNF-alpha levels correlate with disease activity in patients with active HIV disease/AIDS who develop aphthous ulcers 2
Pathophysiologic Summary
The ultimate pathway involves inappropriate immune responses leading to epithelial destruction, with pain, recurrence, and self-limitation as consistent outcomes regardless of the specific triggering mechanism 3. While local trauma, stress, nutritional deficiencies, and genetic factors may precipitate attacks, the immune system mediates the actual tissue damage through both innate (neutrophils, complement) and adaptive (T cells, cytokines) mechanisms 3, 1.
Treatment Implications Based on Immune Pathogenesis
Given the immune-mediated nature of aphthous ulcers, treatment strategies target immune suppression:
- Topical corticosteroids (clobetasol 0.05% gel, dexamethasone 0.1 mg/ml rinse, betamethasone sodium phosphate) serve as first-line therapy by suppressing local immune responses 4
- Systemic immunosuppression with colchicine, corticosteroids (prednisone 30-60 mg or 1 mg/kg), or other immunosuppressive agents is reserved for refractory cases 4, 5
- TNF-alpha inhibitors may be considered in selected severe cases, based on the established role of this cytokine in pathogenesis 4, 2
Important Caveat
While the immune system is clearly implicated, no single principal cause has been identified 3. The condition likely represents a final common pathway of epithelial destruction triggered by multiple potential etiologies (genetic, microbial, nutritional, traumatic) but mediated through immune mechanisms 3, 1.