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THE PATHOGENESIS OF ORAL LICHEN PLANUS

¹ AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA; ² Oral Biology and Pathology, The University of Queensland, St Lucia, Brisbane, Queensland, Australia, ³ Department of Dermatology, Beth Israel Deaconess Medical Center, Brookline, MA, USA

View larger version (32K): [in a new window]   Figure 1. Hypothesis for antigen presentation and T-cell activation in OLP. Initially, the CD8+ T-cell antigen receptor engages a specific foreign antigen (Ag 1) in the context of MHC class I on the basal keratinocyte target cell in OLP [1]. The CD8+ T-cell may then seek CD4+ T-cell confirmation by expressing the hypothetical "request cytotoxic activity" (RCA) cell surface molecule [2]. The CD4+ T-cell expresses the hypothetical "RCA receptor" (RCA R) [4], but only following CD4+ T-cell antigen receptor engagement of a related foreign antigen (Ag 2) in the context of MHC class II on the antigen-presenting cell (basal keratinocyte or Langerhans cell in OLP) [3]. Ligation between RCA and RCA R in combination with co-stimulatory signals from the MHC class II+ antigen-presenting cell (e.g., CD40, CD80, and IL-12 binding CD154, CD28, and IL-12 R, respectively, on the CD4+ T-cell) initiates Th1 differentiation of the CD4+ T-cell that then secretes IL-2 and IFN- [5]. Receptors for IL-2 and IFN- are expressed by the CD8+ T-cell, but only following (i) specific engagement of the CD8+ T-cell antigen receptor in the context of MHC class I and/or (ii) ligation between RCA and RCA R. The CD4+ Th1 cytokines (IL-2 and IFN-) are detected by the CD8+ T-cell and interpreted as confirmation to proceed with target cell (basal keratinocyte) lysis. Keratinocyte activation by (i) the CD4+ or CD8+ T-cell following receptor-antigen-MHC trimerization or (ii) exogenous agents such as viral infection, bacterial products, mechanical trauma, systemic drugs, or contact sensitivity up-regulates keratinocyte cytokine and chemokine secretion [6] that promotes lymphocyte extravasation and directs lymphocyte migration into the site of the developing OLP lesion.

View larger version (43K): [in a new window]   Figure 2. Unifying hypothesis for the pathogenesis of OLP. (A) A lichen planus antigen is expressed in association with MHC class I molecules on basal keratinocytes at the OLP lesion site [1]. Antigen-specific CD8+ cytotoxic T-lymphocytes (CTLs) are activated in the OLP epithelium (possibly with help from Th1 CD4+ T-cells, as shown in Fig. 1) and trigger keratinocyte apoptosis via secreted TNF- binding the TNF- receptor (TNF-R1) [2], although roles for granzyme B and Fas cannot be excluded at this stage. TNF- may be activated and released from the CTL surface by lesional MMPs. (B) Activated T-cells undergo intra-lesional clonal expansion and release RANTES and other cytokines [3] that up-regulate mast cell CCR1 expression and stimulate intra-lesional mast cell migration and degranulation [4]. Degranulating mast cells release TNF-, which up-regulates endothelial cell adhesion molecule expression for lymphocyte adhesion and extravasation [5]. Mast cell TNF- also up-regulates RANTES [6] and MMP-9 [7] secretion by OLP lesional T-cells. Activated lesional T-cells (and possibly keratinocytes) secrete chemokines that attract extravasated lymphocytes toward the OLP epithelium [8]. Degranulating mast cells release chymase that damages the epithelial basement membrane directly [9] or indirectly via activation of MMP-9 secreted by OLP lesional T-cells [10]. Epithelial basement membrane disruption facilitates the passage of lymphocytes into the OLP epithelium [11] and denies keratinocytes a cell survival signal, resulting in further keratinocyte apoptosis [12]. (A) Represents the boxed area in (B).