**4. Development of autoantibodies against self-antigens and the promotion of autoimmunity**

The autoimmune nature of OLP is evidenced by the chronic and protracted course of the disease, its later age of onset, its higher prevalence in women, its association with other autoimmune diseases, proven demonstration of the T-cell auto-reactivity and increased auto-cytoxicity against basal keratinocytes, its clinical, histological and immunological similarity to graft-versus host disease (GVHD) and the effectiveness of immunosuppres‐ sive therapies. Two theories have been advanced to explain the autoimmune nature of OLP, specifically the loss of self-tolerance of the basal keratinocytes: (1) impaired immunesuppression in OLP due to lack of Transforming Growth Factor-β1 (TGF-β1); and (2) loss of "immune-privilege" in OLP. [14, 20]

**Impaired Immune-Suppression in OLP (deficient TGF-β1):**TGF-β is believed to be important regulator of the immune system by inducing and increasing the differentiation of both Foxp3+ regulatory T cells (Tregs) (and Th17 cells). FOXP3 (forkhead box P3) also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator (transcription factor) in the development and function of regulatory T cells. [21, 22]

TGF-β also appears to block the activation of lymphocytes and monocyte derived phagocytes. TGF-β1 levels and/or activity may be deficient for some of the following reasons: insufficient numbers of TGF-β1-secreting Th3 regulatory T cells; blockage of TGF-β1secretion; secretion of defective, non-functional TGF-β1; defective or inadequate TGF-β1receptor expression; or defective intracellular downstream signalling from the TGF-β1 receptors. Local overproduc‐ tion of IFN-γ by Th1 CD4+ T cells in OLP lesions would down-regulate the immunosuppressive effect of TGF-β1and so up-regulate keratinocyte MHC class II expression and CD8+ cytotoxic T cell activity explaining the immune responses to antigens including self antigens and the chronicity of OLP.

**Loss of "Immune-Privilege" in OLP:** The normal oral epithelium, similar to the eye, testes and placenta, may represent an immune-privileged site, by being able to induce apoptosis of infiltrating T-lymphocytes. In these sites, the stromal cells possess Fas Ligand (CD95L) that can trigger the apoptosis of infiltrating inflammatory and immune cells that express Fas (CD95). [20] Keratinocytes themselves can also trigger T-cell apoptosis by the release of the cytokine TNF-α, which on binding the TNF-receptor-1 of T-cells triggers their apoptosis. Loss or impairment of either of these two mechanisms to induce T-cell apoptosis may have a role in the pathogenesis of OLP.

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

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**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

**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 self-

**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 T-

Genetic factors clearly must have a role in the pathogenesis of OLP. Recently, the identification of genetic polymorphisms of cytokine/receptor gene loci has been shown to act as clear-cut genetic risk factors for a number of autoimmune diseases. [29] Polymorphism of several cytokines has been shown to be associated with the clinical presentation of LP. [30] Genetic polymorphisms of the first intron of the promoter gene of interferon-γ and development of oral lesions of LP and an association between the –308A TNF-α allele and the development of cutaneous lesions of LP. [30] The occurrence of OLP has also been linked to MHC class II allele

perpetuating cycle, that further contributes to the chronicity of OLP.

lymphocytes, which in turn can trigger further mast cell degranulation. [28]

OLP.

basement membrane.

**7. Genetic factors**

Langerhans cells may also contribute to the loss of self-tolerance. Langerhans cells phagocytose the apoptotic bodies and debris of basal keratinocytes, but in doing so, may process and present to the CD4+ T helper cells a self-antigen derived from the remains of the basal keratinocyte. In turn, this may activate self-reactive CD4+ T cells that differentiate into Th1 or Th2 phenotypes and promote cell- or antibody-mediated autoimmune reactions against basal keratinocytes, including the stimulation of the cytotoxic T cells against the basal keratinocytes. [14]
