Alterations in type I hemidesmosome components suggestive of epigenetic control in the salivary glands of patients with Sjögren's syndrome

Abstract

AbstractObjectiveAcinar cells in the salivary glands of patients with Sjögren's syndrome (SS) display severe alterations in anchorage to the basal lamina. Bioinformatics analysis of the BP230 gene sequence has revealed the presence of CpG islands that might be involved in epigenetic control of gene expression, and methylation of the BP230 promotor region may be implicated as an epigenetic control mechanism in salivary gland damage. Thus, the present study was undertaken to evaluate the protein BP230, as well as proteins BP180, α6β4 integrin, and cytokeratin‐18, for their expression levels, localization, and ability to form hemidesmosome adhesion complexes.MethodsEighteen patients with primary SS and 14 healthy control subjects were studied. Levels of messenger RNA (mRNA) and protein were measured by reverse transcription–polymerase chain reaction and Western blotting, respectively. BP230 methylation was determined by methylation‐sensitive polymerase chain reaction. Protein complexes were analyzed by immunoprecipitation and assessed for localization by immunofluorescence.ResultsIn patients with SS as compared with controls, BP230 mRNA levels were decreased while protein levels were increased, and the gene promotor region was hypermethylated. Augmented proteolysis of BP180 was detected, since levels of linear IgA disease fragment 1 were increased. The complex‐forming ability of BP230, BP180, α6β4 integrin, and cytokeratin‐18 was maintained in patients with SS, in contrast to that in controls. BP230 and BP180 colocalized at the basal membrane of acinar cells, and cleavage of BP180 coincided with a loss of colocalization.ConclusionThe decrease in BP230 mRNA levels may be explained by gene hypermethylation. We postulate that local epigenetic modifications of BP230 are produced in response to factors present in the damaged salivary glands of patients with SS. Additionally, the paradoxical increase in BP230 protein levels and the formation of both normal and altered adhesion complexes may help avoid cell death induced by the loss of anchorage.