Welcome to the Autoimmunity 2021 Congress Calendar
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ANTI-GLYCOPROTEIN 2 AND PR3-ANCA ARE RISK FACTORS OF SEVERE CLINICAL PHENOTYPE, POOR OUTCOME, AND CHOLANGIOCARCINOMA IN PRIMARY SCLEROSING CHOLANGITIS
Abstract
Background and Aims
Anti-glycoprotein 2(anti-GP2) and PR3-ANCA have been linked with primary sclerosing cholangitis(PSC) in which anti-GP2 IgA was suggested as a marker of disease severity and poor survival related to cholangiocarcinoma(CCA) and PR3-ANCA, as a marker of disease severity. Here we assessed anti-GP2 IgA and PR-3 ANCA as predictive factors of progressive disease course and poor outcome in a large cohort of PSC patients.
Methods
338 patients with PSC [median 32(17-73) years, 65% males, 26% cirrhotic] were prospectively evaluated. Anti-GP2 IgA (isoforms 1/4) detected by ELISAs (GA Generic Assays, Germany) and PR3-ANCA by chemiluminescence immunoassay (CIA; Inova Diagnostics, San Diego; optimized cutoff 10 units). Poor disease outcome was defined as liver transplantation and/or liver-related death during the 14 month median follow-up.
Results
Anti-GP21 IgA occurred in 23%, anti-GP24 IgA in 17%, anti-GP21 and/or GP24 IgA in 30%, and PR3-ANCA in 54.5% of patients. Anti-GP2 IgA and PR3-ANCA associated with poor liver function. Cirrhosis was associated with anti-GP24 IgA(p=0.003). CCA occurred more often in patients with anti-GP21 IgA(p=0.04) and PR3-ANCA (p=0.008). 100% of CCA patients were positive for PR3 and/or GP2 IgA. Significant associations between anti-GP21 IgA(Hazzard Ratio, HR=2.1, p=0.0008), anti-GP24 IgA(HR=2.4, p=0.005), and PR3-ANCA(HR=1.8, p=0.009) and poor outcome were found. Cox proportional-hazards regression indicated anti-GP21 IgA and lower albumin level as independent variables of poor outcome (p<0.0001), whereas anti-GP24 IgA and PR3-ANCA were independent risk factors of CCA (p=0.0019).
Conclusions
Anti-GP2 IgA and PR3-ANCA identify PSC patients at risk of poor outcome, more aggressive course, biliary cancer, and may be of prognostic value in PSC.
RESCUE OF AUTOIMMUNE HEPATITIS BY SOLUBLE MHC-II MOLECULES IN AN IN VITRO AND IN VIVO MURINE EXPERMENTAL MODEL
Abstract
Background and Aims
Soluble MHC class II (sMHC-II) molecules are present in all body fluids of healthy individuals and have been described as molecules maintaining tolerance through the suppression of autoreactive T lymphocytes. Since sMHC-II were successfully shown to alleviate Systemic Lupus Erythematosus symptoms in an experimental mouse model, in the present study it was attempted to administer sMHC-II to a model of experimental, concanavalin A (conA) induced autoimmune hepatitis (AIH).
Methods
This model highly represents the chronic liver inflammation in AIH and is examined by imbalanced interleukin secretion in serum. Experimental tests were performed both in vitro and in vivo.
Results
Following the mitogenic stimulation of spleen cells with conA in vitro, syngeneic sMHC-II, isolated from healthy mouse serum and identified by ELISA and SDS-PAGE, lead to a significant reduction of activated spleen cells, as assessed by tritiated thymidine incorporation assays. The in vivo experimental model was induced by conA injections in male BALB/c mice. The administration of syngeneic sMHC-II in conA-treated mice showed a significant reduction in the levels of IL-2, IL-4 and IL-10, as well as a decrease in the number of the activated splenic T-lymphocytes, as tested by ELISA and immunofluorescence experiments, respectively. In addition, a slower progression in the phenotypical characteristics of the disease was observed, while liver scans showed milder tissue damage in mice who had received sMHCII.
Conclusions
Therefore, the results presented in this study confirm the suppressive ability of the sMHC-II molecules in the model of experimental AIH, possibly highlighting new therapeutic approaches for autoimmune diseases.
SERUM MATRIX METALLOPROTEINASE-3 CONCENTRATION IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS
Abstract
Background and Aims
Matrix metalloproteinase (MMP)-3 plays an important role in connective tissue remodeling, degradation of collagen types II, III, IV, IX, and X, proteoglycans, fibronectin, laminin, and elastin. In addition, MMP-3 can also activate other MMPs such as MMP-1, MMP-7, and MMP-9. Primary biliary cholangitis (PBC) is a cholestatic, autoimmune liver disease, characterized by the progressive destruction of intrahepatic bile ducts, leading to cholestasis, fibrosis, cirrhosis, and liver failure. During fibrosis the balance between production and degradation of the extracellular matrix surrounding hepatocytes is disturbed.
Our aims in the present study were to determine whether the measurement of serum MMP-3 is clinically useful for assessing ongoing liver fibrolysis in patients with PBC
Methods
Matrix metalloproteinase (MMP)-3 concentration was determined by commercially available ELISA kit (AESKU, Germany) in 70 PBC patients and 30 healthy controls.
Results
The frequencies of PBC patients with higher MMP-3 levels were 60%. PBC patients had greater MMP-3 levels than healthy controls (92.7 ± 118.9 versus 20.8 ±15.7 ng/ml, p< 0.001). Serum MMP-3 levels were significantly elevated in patients with higher bilirubin concentration (120.3 ± 119.2 vs. 66.5 ± 41.8 ng/mL, P< 0.01) and correlated with specific for PBC anti-nuclear autoantibodies.
Conclusions
Our study demonstrated significantly higher MMP-3 levels in PBC patients than in healthy controls and positive correlation with various clinical parameters. Serum MMP-3 was associated with hepatic dysfunction and could play a role in the pathophysiology of hepatic fibrosis in PBC.
GLYCOPROTEIN 2 (GP2) IS PRESENT IN BILE AND MIGHT PLAY A ROLE IN THE PATHOGENESIS OF LITHOGENIC CONDITIONS
Abstract
Background and Aims
Glycoprotein 2 (GP2) IgA has been linked with severity and carcinogenesis in primary sclerosis cholangitis (PSC). The presence of GP2 being a specific marker for mature microfold cells with immunomodulating features has not yet been demonstrated in the biliary tract. Given the putative pathophysiological role of autoimmunity to GP2 in chronic cholestatic conditions, we investigated if GP2 is expressed in the biliary tract and affects bile lithogenicity.
Methods
GP2 was analyzed in serum from healthy individuals and bile samples acquired during living liver donation surgery (N = 10) as well as endoscopic retrograde cholangiopancreatography (ERCP) for recurrent gallstones (N = 12). GP2 was also investigated in gallstones from six patients undergoing cholecystectomy. GP2 concentrations in bile and gallstone extracts were determined employing ELISA and immunoblot. Immunofluorescence was used to confirm the presence of GP2 in stone cryosections.
Results
GP2 was detected in all bile samples from both healthy individuals and patients undergoing ERCP. GP2 concentrations in bile in each group were significantly (P < 0.05) higher than in serum from healthy individuals. Comparison of biliary GP2 showed that its levels in patients undergoing repetitive ERCP were significantly (P < 0.05) higher as compared to liver donors. Analysis of gallbladder stone extracts demonstrated GP2 presence using ELISA and immunoblot, which was confirmed by immunofluorescence.
Conclusions
We demonstrated that GP2 is present in bile and gallstones. Biliary GP2 levels are increased in gallstone disease. The role of GP2 in benign and precancerous hepatobiliary disorders warrants further investigation.
DIAGNOSTIC AND CLINICAL SIGNIFICANCE OF ANTI-KELCH-LIKE 12 AUTOANTIBODIES IN THE PRIMARY BILIARY CHOLANGITIS
Abstract
Background and Aims
Primary biliary cholangitis (PBC) is a slowly progressing cholestatic, autoimmune liver disease, characterized by the presence of anti-mitochondrial (AMA) and antinuclear antibodies (ANA) in the patients sera. The aim of the study was to determine the autoantibodies reactive against novel potential autoantigen in PBC - kelch-like 12 (KLHL12) protein in a well characterized cohort of PBC patients and compare them with other specific autoantibodies and biochemical parameters.
Methods
Study population - 92 PBC patients, 30 pathological controls – 20 primary sclerosing cholangitis (PSC) and 10 autoimmune hepatitis (AIH) patients, 30 healthy blood donors.
AMA, anti-Sp100 and anti-gp210 were detected by commercially available kits (IMTEC-Human, Euroimmun; Germany and Inova Diagnostics; USA). The presence of anti- KLHL12 antibody was determined by an” in-house” ELISA technique using a full-length recombinant human KLHL12 protein.
Results
Anti-KLHL12 antibodies were detected in 35% of the total cohort of PBC patients, including AMA-negative PBC. They were found more frequently in PBC compared with non-PBC disease controls (P < 0.001). Specificity and positive predictive values of this test for PBC were 98% and 96%, respectively. We found anti-KLHL12 antibodies together with anti-Sp100 and/or anti-gp210 in 59 (64%) cases. Presence of anti-KLHL12 was associated with higher concentration of bilirubin and correlate with fibrosis (P<0.05).
Conclusions
Antibodies against KLHL12 protein are highly specific for PBC. The combination of anti-KLHL12 with other markers can increase the diagnostic sensitivity on PBC. Coexistence of different antibodies suggests an autoimmune reaction against multiple nuclear components in some of PBC patients.