This Article Abstract Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Sugerman, P.B. Articles by Bigby, M. Search for Related Content PubMed PubMed Citation Social Bookmarking                         What's this?

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 this window] [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 this window] [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).

Critical Reviews in Oral Biology & Medicine, Vol. 13, No. 4, 350-365 (2002)
DOI: 10.1177/154411130201300405


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?