Severe alterations in expression and localisation of 6 4 integrin in salivary gland acini from patients with Sjogren syndrome (original) (raw)
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Arthritis and Rheumatism, 2006
ObjectiveTo investigate remodeling of the basal lamina of labial salivary glands (LSGs) from patients with Sjögren's syndrome (SS) by analyzing the expression of specific components that participate in its assembly and attachment to acinar and ductal cells.To investigate remodeling of the basal lamina of labial salivary glands (LSGs) from patients with Sjögren's syndrome (SS) by analyzing the expression of specific components that participate in its assembly and attachment to acinar and ductal cells.MethodsTwo groups of SS patients with similar levels of remnant glandular tissue but with low and high levels of interacinar fibrosis, respectively, were studied. The expression of laminin α1, α4, and γ2 chains and nidogens was examined at the messenger RNA (mRNA) and protein levels. Nidogens 1 and 2 were also studied in situ by immunohistochemistry.Two groups of SS patients with similar levels of remnant glandular tissue but with low and high levels of interacinar fibrosis, respectively, were studied. The expression of laminin α1, α4, and γ2 chains and nidogens was examined at the messenger RNA (mRNA) and protein levels. Nidogens 1 and 2 were also studied in situ by immunohistochemistry.ResultsIncreases in the amount of mRNA and protein for both the processed and unprocessed laminin γ2-chain were more pronounced in patients with low interacinar fibrosis. Increases in the protein levels of laminin α1 and α4 chains were observed in patients with low interacinar fibrosis, but not in those with high interacinar fibrosis. Nidogen mRNA and protein levels were similar in SS patients and controls. Interestingly, high levels of nidogen degradation were observed in patients with low interacinar fibrosis. Nidogens were readily detected by immunofluorescence in the basal lamina of the capillaries and stroma in SS patients, but were less apparent in the basal lamina of the acini and ducts.Increases in the amount of mRNA and protein for both the processed and unprocessed laminin γ2-chain were more pronounced in patients with low interacinar fibrosis. Increases in the protein levels of laminin α1 and α4 chains were observed in patients with low interacinar fibrosis, but not in those with high interacinar fibrosis. Nidogen mRNA and protein levels were similar in SS patients and controls. Interestingly, high levels of nidogen degradation were observed in patients with low interacinar fibrosis. Nidogens were readily detected by immunofluorescence in the basal lamina of the capillaries and stroma in SS patients, but were less apparent in the basal lamina of the acini and ducts.ConclusionThese results suggest that the basal lamina of LSGs from patients with SS is undergoing active remodeling, such that alterations are less evident in patients who have advanced morphologic signs of the disease (high interacinar fibrosis). Nidogen proteolysis might account for the disorganization of the basal lamina that is typically observed in LSGs from SS patients, assuming that cleavage impairs their ability to crosslink type IV collagen and laminin networks.These results suggest that the basal lamina of LSGs from patients with SS is undergoing active remodeling, such that alterations are less evident in patients who have advanced morphologic signs of the disease (high interacinar fibrosis). Nidogen proteolysis might account for the disorganization of the basal lamina that is typically observed in LSGs from SS patients, assuming that cleavage impairs their ability to crosslink type IV collagen and laminin networks.
Androgens and Integrins in Salivary Glands in Sjögren’s Syndrome
The Journal of Rheumatology, 2010
Objective.Laminin α1-chain normally induces intercalated duct progenitors to differentiate to acinar cells through integrin (INT) α1ß1 and α2ß1 receptors. Maintenance of acinar cells is impaired in Sjögren’s syndrome (SS), which is also characterized by low levels of serum and salivary androgens. We hypothesized that androgens normally support salivary gland remodeling by upregulating either laminin α1 chain or its cellular α1 or α2 INT subunit-containing receptors.Methods.Intercalated duct and acinar human salivary gland (HSG) cells and labial salivary gland (LSG) biopsies from healthy controls and patients with SS were cultured without or with sex steroids. Laminin α1 chain and INT α1 and α2 subunits were studied using quantitative reverse-transcription real-time polymerase chain reaction and INT α1 and α2 subunits using immunofluorescence staining.Results.INT α1-subunit and α2-subunit messenger RNA (mRNA) levels were increased in intercalated duct and acinar cells by DHEA and tes...
Differential expression of integrins and laminin-5 in normal oral epithelia
APMIS, 1997
p 1 and 04 integrins are receptors on epithelial cells mediating cell-extracellular matrix adhesion. Furthermore, a2pl and a3pl contribute to cell-cell adhesion. Laminin-5 in epithelial basement membranes (BMs) is a ligand for a6p4 and a3pl. Expression of different integrins and laminin-5 was studied in oral epithelium to characterize regional variations in these adhesion molecules. Monoclonal antibodies directed against a2-a6plla6P4 and laminin-5 were examined in cryopreserved biopsies of normal mucosa by immunohistochemistry. Laminin-5 was expressed as a line along the BMs. The junctional epithelium showed a unique phenotype: Laminin-5 was detected in the internal BM at the tooth surface and in the external BM, where excessive laminin-5 was seen in the stroma. a6P4 was expressed in all cells of the junctional epithelium. Integrins a4pl and a5pl were not detected in the epithelia, whereas a201 and a3p 1 showed differential expression. Epithelia with well-developed rete pegs and connective tissue papillae showed polarized a3pl expression along the BM in the rete pegs, in contrast to negative expression at the tips of the connective tissue papillae. A variation in the suprabasal distribution of a2pl and a3pl was observed between epithelia from different regions. a2pl and a3p 1 were detected in basaliparabasal cells in keratinized epithelia, whereas there was increased suprabasal expression in nonkeratinized mucosa. These results indicate inhomogeneity in the basal cell population of oral squamous epithelia and differential expression of integrins, which may reflect differences in the underlying stroma. Laminin-5 deposits in the stroma underneath the junctional epithelium may indicate subclinical gingival inflammation.
Journal of Autoimmunity, 1997
Previous studies have demonstrated increased expression of a laminin-like protein in labial salivary glands from Sjögren's syndrome (SS) patients. The objective of the present study was to verify the identity of this protein and to compare lymphocytic infiltration and laminin expression in minor salivary gland ductal epithelium. This was carried out by comparing laminin protein and laminin mRNA expression in 13 SS patients, 11 normal controls, and 12 patients with non-specific sialoadenitis. Laminin protein and laminin mRNA expression was determined using immunoperoxidase (IP) and in situ hybridization (ISH) techniques, respectively. In addition, the relationship between lymphocytic infiltration and laminin expression was evaluated on adjacent serial salivary gland sections from SS patients, using routine histological methods and IP immunohistochemistry. Biopsies from SS patients showed significant increases in staining for both laminin protein and laminin mRNA compared to normal controls. On seven of the eight SS samples that showed significant laminin protein staining, the ductal epithelial staining occurred in the absence of periductal lymphocytic foci. Results of the ISH assay strongly suggest that the increased expression of the laminin-like protein is laminin, since the cDNA probe was specific for the B1 chain of laminin. In addition, this increased expression in ductal epithelial cells occurs without significant lymphocytic infiltration. These studies provide further evidence that altered laminin expression is an early event associated with salivary gland pathology in SS, since these data demonstrate a potential pathologic event prior to the arrival of lymphocytes. Further studies are underway to examine the relationship between laminin and lymphocytic infiltration in salivary gland pathology.
Arthritis and Rheumatism, 2003
ObjectiveTo determine the effect of matrix metalloproteinase (MMP) activity from the labial salivary glands (LSGs) of Sjögren's syndrome (SS) patients on proteins of the extracellular matrix (ECM) that form the basal lamina and stroma, and to compare this effect with the structural integrity of acini and ducts as well as the functionality of the LSGs.To determine the effect of matrix metalloproteinase (MMP) activity from the labial salivary glands (LSGs) of Sjögren's syndrome (SS) patients on proteins of the extracellular matrix (ECM) that form the basal lamina and stroma, and to compare this effect with the structural integrity of acini and ducts as well as the functionality of the LSGs.MethodsGelatinase activity was determined by zymography. The digestion pattern of extracellular matrix (ECM) macromolecules was detected by gel electrophoresis and quantified by densitometry. The structural integrity of acini and ducts was evaluated by light and electron microscopy. Secretory function was evaluated by measuring unstimulated salivary flow and by scintigraphy.Gelatinase activity was determined by zymography. The digestion pattern of extracellular matrix (ECM) macromolecules was detected by gel electrophoresis and quantified by densitometry. The structural integrity of acini and ducts was evaluated by light and electron microscopy. Secretory function was evaluated by measuring unstimulated salivary flow and by scintigraphy.ResultsLSG extracts showed increased levels of proteolytic activity toward purified proteins of the basal lamina (laminin and type IV collagen) and stroma (types I and III collagen and fibronectin). Enhanced degradation was most evident for fibronectin, laminin, and type IV collagen. Analysis of the ultrastructure of the acinar and ductal basal lamina revealed abnormalities ranging from disorganization to disappearance of this ECM structure. These changes were paralleled by an important loss of microvilli on the apical surface, as well as decreased unstimulated salivary flow. Interestingly, the results were similar in LSGs from all SS patients, regardless of the proximity of infiltrating mononuclear cell foci.LSG extracts showed increased levels of proteolytic activity toward purified proteins of the basal lamina (laminin and type IV collagen) and stroma (types I and III collagen and fibronectin). Enhanced degradation was most evident for fibronectin, laminin, and type IV collagen. Analysis of the ultrastructure of the acinar and ductal basal lamina revealed abnormalities ranging from disorganization to disappearance of this ECM structure. These changes were paralleled by an important loss of microvilli on the apical surface, as well as decreased unstimulated salivary flow. Interestingly, the results were similar in LSGs from all SS patients, regardless of the proximity of infiltrating mononuclear cell foci.ConclusionOur observation that the proteolytic action of MMPs toward ECM macromolecules is increased in SS patients provides a rationale for understanding the dramatic changes in the structural organization observed in the basal lamina and apical surface of acini in these patients. The results provide new evidence that acinar and ductal cells from the LSGs of SS patients display a molecular potential, with increased capacity to markedly disorganize their ECM environment and, thus, damage their architecture and functionality.Our observation that the proteolytic action of MMPs toward ECM macromolecules is increased in SS patients provides a rationale for understanding the dramatic changes in the structural organization observed in the basal lamina and apical surface of acini in these patients. The results provide new evidence that acinar and ductal cells from the LSGs of SS patients display a molecular potential, with increased capacity to markedly disorganize their ECM environment and, thus, damage their architecture and functionality.
Arthritis & Rheumatism, 2003
Objective. To determine the effect of matrix metalloproteinase (MMP) activity from the labial salivary glands (LSGs) of Sjögren's syndrome (SS) patients on proteins of the extracellular matrix (ECM) that form the basal lamina and stroma, and to compare this effect with the structural integrity of acini and ducts as well as the functionality of the LSGs. Methods. Gelatinase activity was determined by zymography. The digestion pattern of extracellular matrix (ECM) macromolecules was detected by gel electrophoresis and quantified by densitometry. The structural integrity of acini and ducts was evaluated by light and electron microscopy. Secretory function was evaluated by measuring unstimulated salivary flow and by scintigraphy. Results. LSG extracts showed increased levels of proteolytic activity toward purified proteins of the basal lamina (laminin and type IV collagen) and stroma (types I and III collagen and fibronectin). Enhanced degradation was most evident for fibronectin, laminin, and type IV collagen. Analysis of the ultrastructure of Dr.