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

Abstract

Objective. Acinar 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, ␣6␤4 integrin, and cytokeratin-18, for their expression levels, localization, and ability to form hemidesmosome adhesion complexes.Methods. Eighteen 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.Results. In 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, ␣6␤4 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.Conclusion. The 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.Severe alterations in acinar cells and the extracellular matrix (ECM) are recurrent observations in the labial salivary glands (LSGs) of patients with primary Sjögren's syndrome (SS) (1-4). LSG epithelial cells are linked to the basal lamina (BL) through several transmembrane protein complexes that have important functions in adhesion and cell signaling (5). These adhesion complexes include ␣6␤1 and ␣6␤4 integrins as a central

Increased production of soluble TLR2 by lamina propria mononuclear cells from ulcerative colitis patients

“…We found that expression of total TLR2 was significantly increased in intestinal mucosa from UC patients in comparison to CD and controls, although the expression of TLR2 mRNA was not significantly different among groups. While this finding may appear contradictory, similar observations were reported in Sjögren Syndrome for BP230 protein levels (Gonzalez et al 2011). According to these studies, in Saccharomyces, a difference between relative transcription and translation efficiency has been documented (Tuller et al 2007), suggesting that the cell preserves a global equilibrium between the processes.…”

Aberrant localization of fusion receptors involved in regulated exocytosis in salivary glands of Sjögren’s syndrome patients is linked to ectopic mucin secretion

“…LSGs were obtained as previously described [17]. Following surgery, samples were split into two portions.…”

Sjögren's syndrome and the epithelial target: A comprehensive review

“…An MMP/TIMP expression ratio greater than 1 was taken to indicate that degradative activity was increased. For laminin and collagen IV changes in immuno staining intensity were apparent in the basal lamina and ducts of acini, while no such changes were detected in capillaries situated in close proximity of these structures [104,105]. These observations indicated that salivary glands from SS-patients produced enzymes that destroyed their own basal lamina, which did not diffuse through the ECM.…”

“…This integrin is crucial to the organization of adhesion complexes called hemidesmosomes, which are responsible for cell anchorage to the basal lamina. Changes in a6b4 integrin and other components of this basal adhesion complex detected in SS-patients have been reviewed extensively elsewhere [105,107].…”