Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis

doi:10.1016/j.jhep.2004.11.016

Journal of Hepatology

Volume 42, Issue 3, March 2005, Pages 386-392

https://doi.org/10.1016/j.jhep.2004.11.016 Get rights and content

Background/Aims

The presence of antibodies to the 210-kDa glycoprotein of the nuclear pore complex (gp210) is highly indicative of primary biliary cirrhosis (PBC). However, the significance of anti-gp210 antibody titers for monitoring PBC remains unresolved.

Methods

We used an ELISA with a gp210 C-terminal peptide as an antigen to assess serum antibody titers in 71 patients with PBC.

Results

Patients were classified into three groups: Group A in whom anti-gp210 titers were sustained at a high level, Group B in whom anti-gp210 status changed from positive to negative under ursodeoxycholic acid (UDCA) therapy, Group C in whom anti-gp210 antibodies were negative at the time of diagnosis. The rate of progression to end-stage hepatic failure was significantly higher in group A (60%) as compared to groups B (0%) and C (4.2%). The sustained antibody response to gp210 was closely associated with the severity of interface hepatitis. The significance of anti-gp210 antibody was confirmed by National Hospital Organization Study Group for Liver Disease in Japan.

Conclusions

The serial quantitation of serum anti-gp210-C-terminal peptide antibodies is useful for monitoring the effect of UDCA and for the early identification of patients at high risk for end-stage hepatic failure.

Introduction

Primary biliary cirrhosis (PBC) is an autoimmune disorder characterized by nonsuppurative inflammatory destruction of small bile ducts that can ultimately lead to biliary cirrhosis [1]. In addition to anti-mitochondrial antibodies (AMAs), a number of nuclear structures have been recognized as targets of the antinuclear antibodies (ANA) in PBC patients [2], [3], [4]. These include several components of the nuclear pore complex, such as the 210-kDa glycoprotein (gp210) and p62 proteins [3], [4], [5]. In this category of ANA, the autoantibody to gp210 is particularly significant as they are specifically detected in approximately 10–30% of PBC patients [6], [7], [8], [9], [10], [11], [12], [13]. In addition, the presence of anti-gp210 antibody has been reported to be associated with the disease activity of PBC, indicating that the anti-gp210 antibody may potentially be useful as a prognostic marker of PBC [14], [15], [16]. However, these studies are largely cross-sectional and the significance of anti-gp210 antibody titers in a clinical setting remains unsettled.

In the present study, in order to elucidate the significance of anti-gp210 antibody titers in a clinical setting, we established an ELISA that quantitates the serum anti-gp210 level using a gp210 C-terminal peptide as an antigen. We then studied the antibody titers of PBC patients in serial serum samples that had been obtained over the course of treatment and stocked in our institution from August 1982 to March 2004. The significance of anti-gp210 antibody titers is discussed in terms of monitoring for the disease activity and the prediction of the long-term outcome of PBC.

Section snippets

Patients and sera

Sera were obtained every 3–12 months from patients with PBC who were treated at our institution during the 22 years between August 1982 and March 2004 and were stored at −20 °C until use. All PBC patients were histologically diagnosed based on internationally accepted criteria [17], [18] and classified by Scheuer's classification [19] using specimens obtained by needle liver biopsy. Of the 73 patients that were definitively diagnosed as PBC, two PBC patients who had episodes of moderate to

Clinical course of PBC patients during the observation period

From August 1982 to March 2004, 71 patients were followed up at our institution for varying periods of 6–216 months (72.8±54.8 months, median 64 months) after the initial definitive diagnosis of PBC using histological criteria. Among the 71 patients, five died of hepatic failure and three patients underwent OLT because of progression to hepatic failure. Three patients, who were negative for anti-gp210 antibodies, developed hepatocellular carcinoma (HCC) and two of them died of HCC. The death of

Discussion

Our results indicated that there are at least three different categories of PBC patients based on the anti-gp210 antibody profile. Group A comprised patients in whom the anti-gp210 antibodies were sustained at a high level under UDCA therapy. Group B consisted of patients in whom anti-gp210 antibody status changed from an initial positive to negative or weakly positive after the initiation of UDCA therapy. Group C contained those patients that were negative for anti-gp210 antibodies at the time

Acknowledgements

The authors thank Drs Eeichi Takezaki, Tatsuji Komatsu, Takehiro Sando, Masaaki Shimada, Akihide Masumoto, Toyokichi Muro, Shigeki Hayashi, Yukio Ohara, Hideharu Harada, Kazuhiro Sugi, Masakazu Kobayashi, Yutaka Mano, Hideo Morimoto, Shin Tanaka, Tetsuo Yamamoto, Yasushi Uchida, Michio Kato, Taizo Hijioka, Hironori Sakai, Hidehiro Nishi in National Hospital Organization Study Group for Liver Disease in Japan NHOSLJ for providing serum samples of PBC patients. This work was supported by

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Autoantibodes to GP210 are a metric for UDCA responses in primary biliary cholangitis
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Antibodies to gp210 and sp100 are specific and unique anti-nuclear autoantibodies (ANAs) associated with primary biliary cholangitis (PBC). Importantly the presence of anti-gp210 and anti-sp100 responses is indicative of poor clinical outcomes. However, the utility of measuring titers of these antibodies remains unclear.
Using the in-house purified gp210 (HSA108-C18) and sp100 (amino acid position 296–386), we quantitatively measured serum autoantibodies to gp210 and sp100 using chemiluminescence immunoassay (CLIA) in a very large cohort of 390 patients with PBC, including 259 cases with no prior ursodesoxycholic acid (UDCA) treatment and 131 cases with UDCA treatment. We also analyzed serial changes in anti-gp210 and anti-sp100 levels in 245 sequential samples from 88 patients.
In our cross-sectional analysis, we detected anti-gp210 immunoglobulin G (IgG) and anti-sp100 IgG autoantibodies in 129 out of 390 (33.1%) and 80 out of 390 (20.5%) PBC patients, respectively. Multivariate analysis revealed that serum IgG (st.β = 0.35, P = 0.003) and gamma-glutamyltransferase (GGT) (st.β = 0.23, P = 0.042) levels at baseline were independently associated with anti-gp210 concentrations. In serial testing, we observed significant fluctuations in anti-gp210 antibody levels. These fluctuations reflected responsiveness to UDCA therapy, particularly in anti-gp210-positive patients with initially lower concentrations in the stages of disease.
Our study reflects that quantitative changes of anti-gp210 antibody are indicative of UDCA responses. There is a great need for newer metrics in PBC and we suggest that a more detailed and longer study of these unique ANAs is warranted.
Primary Biliary Cholangitis: Epidemiology, Diagnosis, and Presentation
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Anti-gp210-positive primary biliary cholangitis: The dilemma of clinical treatment and emerging mechanisms
2023, Annals of Hepatology
Anti-gp210 is the disease-specific anti-nuclear antibody (ANA) of primary biliary cholangitis (PBC). Anti-gp210-positive PBC patients have worse responses to ursodeoxycholic acid (UDCA) as compared with anti-gp210-negative patients. Moreover, anti-gp210-positive patients always present with more severe histopathologic features including lobular inflammation, interfacial hepatitis, and bile duct injury, and have a worse prognosis than their anti-gp210-negative counterparts. Previous studies have identified two antigenic epitopes recognized by anti-gp210. Although the pathogenetic mechanism of anti-gp210 production remains unclear, evidence suggests that the autoimmune response to anti-gp210 production might be due to molecular mimicry induced by bacteria or endogenous peptides. T cells and related cytokines play a critical role in the pathogenesis of PBC, however, the mechanism hasn't been fully understood. Thus, this review focuses on the clinicopathological characteristics of anti-gp210-positive PBC patients, the fundamental research of gp210 antigen, and the possible mechanism of anti-gp210 production to clarify the mechanism of anti-gp210-positive PBC and provide potential molecular targets for disease prevention and treatment in the future.
Autoantibodies in Primary Biliary Cholangitis
2022, Clinics in Liver Disease
The prognostic value of antibodies to gp210 among patients with primary biliary cholangitis in Northeast China
2022, Digestive and Liver Disease
Whether the anti-gp210 antibody can be used as a biomarker in patients with primary biliary cholangitis (PBC) remains controversial.
We aimed to investigate the association between anti-gp210 antibodies and prognosis in ursodeoxycholic acid (UDCA)-treated PBC patients.
We conducted a retrospective cohort study of 180 UDCA-treated PBC patients to assess the prognostic value of anti-gp210 antibodies using the Kaplan–Meier method and Cox proportional hazard regression analysis.
Of the patients included in our analysis, 50 (27.8%) were anti-gp210 positive, and 130 (72.2%) were anti-gp210 negative. The incidence of liver-related death or transplantation was more common in the anti-gp210 + group (22.0 vs. 9.2%, P=0.022). The five-year transplant-free survival rates of anti-gp210-positive patients vs. anti-gp210-negative patients were 77.0% and 90.3%, respectively. We found that the probability of transplant-free survival was significantly lower in the anti-gp210-positive patients than in the anti-gp210-negative patients (log-rank P=0.004). After adjusting for potential confounders using multivariable Cox regression model, positivity for anti-gp210 antibody (hazard ratio: 4.619, 95% confidence interval: 1.895–11.261, P=0.001) was found to be independently associated with an increase in liver-related mortality or transplantation.
In this cohort of UDCA-treated PBC patients, positivity for anti-gp210 antibody was independently associated with a higher risk of liver-related death or transplantation.
Increased sensitivity of gp210 autoantibody detection using a newly designed gp210 antigen
2022, Journal of Immunological Methods
The detection of autoantibody to glycoprotein 210 (gp210 Ab) against a 15 amino-acid peptide epitope by enzyme-linked immunosorbent assay (ELISA) has been widely used in the diagnosis of primary biliary cholangitis (PBC). However, this small peptide antigen presents spatial limitations for antibody access, which reduces the sensitivity of autoantibody detection. A recombinant gp210 antigen was constructed for increased sensitivity in antibody detection is described here.
The gp210 C terminal 18 amino acid coding sequence was ligated to the modified C-terminal 108 amino acid coding sequence of human serum albumin (mHSA108) and produced as a recombinant gp210 antigen mHSA108-gp210-C18. Measurements of gp210 Ab using the gp210 C-terminal 25 amino acid peptide (gp210-C25) and mHSA108-gp210-C18 by in-house ELISA were compared. ELISAs with mHSA108-gp210-C18 and commercial INOVA kit for gp210 Ab detection were also compared in PBC patients and healthy controls. The correlation between the two assays was analyzed and their efficiency in diagnosing was compared.
Of 86 PBC samples, 35 (40.70%) and 44 (52.33%) positive samples were detected for anti-gp210 Ab using gp210-C25 and mHSA108-gp210-C18, respectively. Of 252 samples from PBC, 114 (45.24%) were positive for mHSA108-gp210-C18 ELISA whereas 94 (37.3%) for commercial ELISA (INOVA). All positive samples detected with commercial ELISA kit were also tested positive in mHSA108-gp210-C18 ELISA. Among 374 patients with other autoimmune diseases, anti-gp210 Ab were detected by mHSA108-gp210-C18 ELISA in 0.95% systemic lupus erythematosus (SLE) patients (2/210), 13.04% rheumatoid arthritis (RA) patients (13/97), and 1.47% of Sjögren's Syndrome (SS) patients (1/67).
Compared to the gp210 peptide antigen, the sensitivity of the ELISA system using mHSA108-gp210-C18 antigen was improved. The novel gp210 antigen could be useful for screening patients known to be at increased risk of developing PBC.

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Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis

Background/Aims

Methods

Results

Conclusions

Introduction

Section snippets

Patients and sera

Clinical course of PBC patients during the observation period

Discussion

Acknowledgements

Gastroenterology

Gastroenterology

Hepatology

Hepatology

J Hepatol

Am J Gastroenterol

J Hepatol

Gastroenterology

Hepatology

Gastroenterology

J Hepatol

Hepatol Res

Primary biliary cirrhosis

Am J Pathol

Antimitochondrial antibodies in primary biliary cirrhosis

Semin Liver Dis