**6. Non-specific immune mechanisms in OLP pathogenesis**

Some of the T-cells in the T-cell dominant lymphocytic infiltrate so pathognomonic for OLP are not specific or targeted. Their presence may be due to pre-existing inflammation that favours the movement of such non-specific T-lymphocytes into the epithelium, which in turn, causes destruction of the keratinocytes. The mechanisms involved include: (1) basement membrane disruption; (2) increased presence of matrix metalloprotienases (MMP); (3) Chemokine (C-C motif) ligand 5 (CCL5) (previously termed RANTES - Regulated on Activa‐ tion, Normal T cell Expressed and Secreted) activity; and (4) Mast cell activation and degra‐ nulation. [14, 15]

**Basement Membrane Disruption:** Integrity of the epithelial basement membrane is main‐ tained by the keratinocytes, which release collagen IV and laminin V into the basement membrane zone, but the keratinocytes require a basement membrane-derived signal to prevent their apoptosis. Thus, the basement membrane is needed for keratinocyte survival and its integrity is maintained by the keratinocytes. Apoptosis of the keratinocytes by the CD8+ cytotoxic T-cells results in the loss of the maintenance function by performed the keratinocytes, leading to disruption of the basement membrane, thereby allowing the non-specific T-cell to infiltrate the epithelial cell layers. [14, 23] The disruption of the basement membrane also leads to apoptosis of the keratinocytes, due to the loss basement-membrane derived signal to prevent their apoptosis, and so on. This ongoing, self-perpetuating cycle may explain the chronicity of OLP.

**Matrix Metalloprotienases (MMPs):** MMP-9 concentrations have been found to be increased in culture supernatants taken from patients with OLP compared with normal controls. [25] MMP-9 is one member of a family of some 20 MMPs identified to date, which are all zinccontaining proteinases. [26] MMP-9 (together with MMP-2) are gelatinases that cleave collagen IV. Other MMPs can cleave collagen IV and laminin. The MMPs are inhibited by tissue inhibitors of metalloproteinases (TIMPs) that form stable complexes with MMPs or pro (precursor) MMP's. [27] T-cells release activators of MMP-9, resulting in disruption of the basement membrane.

**Chemokine (C-C Motif) Ligand 5 (CCL5 (RANTES)):** CCL5 is a key chemokine released by various cells including, activated T-lymphocytes, oral keratinocytes and mast cells and has a critical role in the recruitment of various immune and inflammatory cells, including lympho‐ cytes, monocytes, eosinophils, basophils and mast cells. CCR1, CCR3 to CCR5, and CCR9 and CCR10 are key cell surface receptors for CCL5 and have also been identified in lichen planus. [28] CCL5 attracts mast cells which degranulate, releasing TNF-α and chymase, which in turn up regulates OLP lesional T-cell release of CCL5, leading again to the development of a selfperpetuating cycle, that further contributes to the chronicity of OLP.

**Mast Cell Activation and Degranulation:** Mast cells are not only increased in numbers, but most are degranulated in OLP (compared with normal tissues). [14, 23, 28] Mast cell degra‐ nulation results in the release of variety of pre-inflammatory mediators, including TNF-α, chymase and typtase. TNF-α can up-regulate endothelial cell adhesion molecules required for the lymphocytes to adhere to luminal surfaces of blood vessels and their subsequent extrava‐ sation. Chymase, a mast cell protease, activates MMP-9, so contributing to basement mem‐ brane disruption. Both chymase and TNF-α can stimulate CCL5 secretion by lesional Tlymphocytes, which in turn can trigger further mast cell degranulation. [28]
