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The function and regulation of LFA-3 in oral mucosal inflammation

Kirby, Alun C.; (1999) The function and regulation of LFA-3 in oral mucosal inflammation. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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The adhesion molecule lymphocyte function-associated antigen 3 (LFA-3), the major ligand of the T lymphocyte receptor CD2, is involved in cellular adhesion, activation and functional modulation. However, the role of LFA-3 and regulation of LFA-3 expression in oral mucosal and other diseases is poorly understood. The role of LFA-3 was investigated in the inflammatory disease oral lichen planus (OLP). Expression of LFA-3 was found to be up-regulated in OLP lesions compared with healithy oral tissues. Two distinct expression patterns were identified in OLP lesions - intracellular LFA-3 was localised within a population of infiltrating cells, and a 'soluble' form of LFA-3 (sLFA-3) was apparent within affected tissues. In contrast with the increased lesional expression of LFA-3, systemic sLFA-3 levels were not significantly altered in the sera of OLP patients compared with control subjects. RT-PCR of mRNA from OLP, other oral mucosal diseases and healthy oral mucosa revealed LFA-3 mRNA isoform expression to be neither tissue- nor disease-specific. However, a novel in vivo isoform of LFA-3 mRNA was detected. This mRNA isoform was cloned, sequenced and identified as LFA-3 AD2. Possible mechanisms for LFA-3 regulation and sLFA-3 generation in vivo were investigated in vitro. An intracellular pool of LFA-3 was demonstrated to be present within a range of cell lines. Although both surf ace and intracellular LFA-3 expression were relatively unaffected by inflammatory cytokines, the release of sLFA-3 from these cells was susceptible to cytokine-mediated modulation. Differential susceptibility to cleavage of surface LFA-3 by a phospholipase C (PLC) was demonstrated. PLC-mediated LFA-3 cleavage, a possible mechanism of sLFA-3 generation, was found to be associated with an increase in intracellular LFA-3 followed by replacement of LFA-3 at the cell surface. Finally, the in vivo role of LFA-3 in OLP was examined by adaptation of the Stamper-Woodruff adhesion assay. The results of these antibody blockade studies suggest that LFA-3 may be of equivalent importance to intercellular adhesion molecule 1 (ICAM-1) for lymphocyte adhesion within the OLP inflammatory infiltrate, and may be a potential therapeutic target for the control of OLP.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The function and regulation of LFA-3 in oral mucosal inflammation
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Lymphocyte function-associated antigen
URI: https://discovery.ucl.ac.uk/id/eprint/10114340
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