Objective. To elucidate the mechanism of the development of T cell infiltrates in the salivary glands of patients with Sjögren's syndrome (SS), we studied T cell-attracting chemokines and their receptors.Methods. The expression of the T cell-attracting chemokines, interferon-␥ (IFN␥)-inducible 10-kd protein (IP-10; also called CXCL10), monokine induced by IFN␥ (Mig; also called CXCL9), and stromal cellderived factor 1 (SDF-1; also called CXCL12), in salivary glands from SS patients was investigated by polymerase chain reaction-enzyme-linked immunosorbent assay (ELISA). Cells that produce chemokines and lymphocytes that express chemokine receptors were identified by immunohistochemistry. The production of IP-10 and Mig proteins by salivary epithelial cells in response to IFN␥ was determined by ELISA.Results. Expression of IP-10 and Mig messenger RNA (mRNA) was significantly up-regulated in SS salivary glands compared with normal salivary glands (both P < 0.01). There was no significant difference in SDF-1 mRNA expression between the SS and normal salivary glands. IP-10 and Mig proteins were predominantly expressed in the ductal epithelium adjacent to lymphoid infiltrates. Most of the CD3؉ infiltrating lymphocytes in dense periductal foci expressed CXCR3, the receptor for IP-10 and Mig. IFN␥ induced the production of high levels of IP-10 and Mig proteins from cultured SS salivary epithelial cells.Conclusion. These findings suggest that IFN␥ stimulates the production of IP-10 and Mig in the SS ductal epithelium, and that IP-10 and Mig are involved in the accumulation of T cell infiltrates in the SS salivary gland. Chemokines or chemokine receptors could be a rational new therapeutic target in SS.
Objective. To assess the role of Fas‐mediated apoptosis in the salivary glands of patients with primary Sjögren's syndrome (SS).
Methods. Expression of Fas, Fas ligand (FasL), and bcl‐2 in salivary gland biopsy material was detected in situ by immunohistochemical staining and reverse transcriptase‐polymerase chain reaction. DNA fragmentation in apoptotic cells was assessed by the enzymatic incorporation of labeled nucleotides (digoxigenin‐dUTP).
Results. The acinar epithelial cells in SS were Fas+ and FasL+, and these cells died by apoptosis. The majority of infiltrating lymphocytes in SS were Fas+ and bcl‐2+, while few lymphocytes expressed FasL. In situ detection of apoptosis showed minimal cell death of lymphocytes, particularly in dense periductal foci. Lymphocytic cell death was significantly lower (P < 0.0001) in these foci compared with that in the interstitium.
Conclusion. Infiltrating lymphocytes in the focal lesions of the salivary glands of patients with SS are blocked in their ability to commit to apoptosis, even though they may express Fas. The presence of bcl‐2 in these cells may explain their inability to undergo apoptosis. The acinar epithelial cells, in contrast, may undergo Fas‐mediated apoptosis. These results suggest that the Fas death pathway may be an important mechanism leading to the glandular destruction found in SS.
Objective-To describe the clinical expression ofprimary Sjogren's syndrome (SS) in men, focusing on extraglandular mm festations (EGM) and serological markers of disease.
Objectives
Macrophage-mannose receptor, CD206, is a marker of alternatively activated macrophages. Activated macrophages play key roles in DM. Interstitial lung disease (ILD) is a leading cause of mortality in patients with DM/clinically amyopathic DM (CADM). In particular, patients with the anti-melanoma differential gene 5 antibody (MDA5) frequently develop fatal rapid progressive ILD. This study aimed to evaluate the clinical implications of alternatively activated macrophages in patients with CADM/DM-ILD with anti-MDA5 antibody (MDA5-CADM/DM-ILD).
Methods
We measured serum concentrations of soluble CD206 (sCD206) in 33 patients with MDA5-CADM/DM-ILD and 36 age- and sex-matched control subjects. Expression levels of CD206 in the lungs from MDA5-CADM/DM-ILD were also examined.
Results
Patients with MDA5-CADM/DM-ILD had higher levels of sCD206 than those in controls (P < 0.0001). Of the 33 patients, 10 MDA5-CADM/DM-ILD patients developed fatal respiratory failure. Concentrations of sCD206 in patients with fatal ILD cases were significantly higher than those in the survivors, and increased sCD206 levels were associated with a higher mortality rate (Log-rank test, P = 0.0009). Age- and gender-adjusted logistic regression analyses showed that sCD206 was an independent prognostic factor for MDA5-CADM/DM-ILD. Importantly, assessment by sCD206 together with PaO2 successfully divided into three groups by their prognosis (P < 0.005, respectively). Pathological analyses showed accumulations of CD206-positive macrophages in lungs from the fatal case rather than those in the non-fatal cases.
Conclusions
Levels of serum sCD206 are increased in MDA5-CADM/DM-ILD and associated with poor prognosis. sCD206 is a potential biomarker to predict the severity of MDA5-CADM/DM-ILD.
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