We have reported that Sjögren's syndrome (SS) patients with enlarged exocrine glands (EEG) formerly referred to as Mikulicz's disease were defective with Fas-ligand (FasL) expression in PBL and lacrimal glands (LGs). To investigate the mechanisms of reduced FasL expression in SS patients with EEG, FasL mRNA expression level was determined using real-time PCR. The FasL gene promoter region (from -1197 to -3) was also amplified using PCR and specific primers. Expression of the FasL mRNA in the LGs and PBLs of three SS patients with EEG was significantly decreased. Direct sequencing revealed a heterozygous point mutation (-259T/C) in the FasL gene promoter region in one SS patient with EEG. A luminescent β-galactosidase (β-gal) reporter assay using a pβgal Enhancer Vector demonstrated that β-gal activity from the vector including the mutant (-259C) FasL (pβgal/mFasL) gene promoter region (735±42) was similar (p = 0.13) to that from a pβgal Enhancer Vector without the gene promoter region (603±66). On the other hand, the β-gal activity was significantly lower (p<0.0001) than that from a vector including the wild-type (-259T) FasL (pbeta;gal/wFasL) (3226±148). In conclusion, the down-regulation of FasL in SS patients with EEG may be due to transcriptional regulation, and the point mutation at -259T/C in the FasL gene promoter region may lead to the down-regulation of FasL mRNA expression and the lymphoproliferative process observed in SS patients with EEG.
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