TRAF1 gene polymorphism correlates with the titre of Gp210 antibody in patients with primary biliary cirrhosis.

BACKGROUND: Polymorphisms of TRAF1 (Tumor necrosis factor receptor-associated factor 1) are associated with rheumatoid arthritis (RA). Whether TRAF1 polymorphisms confer increased risk for primary biliary cirrhosis (PBC), an autoimmune liver disease which can co-exist with RA, is unknown. AIM OF THE STUDY: To assess the frequency of the RA-conferring susceptibility TRAF1 polymorphisms rs3761847 and rs2900180 in a cohort of PBC patients. The association of TRAF1 polymorphisms with clinical features and autoantibody markers was also analyzed. METHODS: We studied 179 PBC patients and 300 controls. Samples were genotyped for TRAF1 gene polymorphisms by real-time PCR. Autoantibodies were tested by ELISA. RESULTS: The frequency of rs3761847 and rs2900180 polymorphisms did not differ between patients and controls. Laboratory or clinical features were not associated with specific polymorphisms. Gp210 autoantibody titres were conspicuously higher among GG homozygotes of rs3761847 as compared with AA homozygotes (P = 0.02). In contrast, antichromatin titers were higher in AA compared to GG rs3761847 homozygotes (P = 0.04). Rheumatoid factor IgG titres were significantly higher in rs2900180 TT homozygotes than CC homozygotes (P = 0.02). CONCLUSIONS: TRAF1 polymorphisms occur with the similar frequency in PBC patients and in the general population, but their presence is probably involved in the regulation of specific PBC-related autoantibodies.

Fluctuations of antimitochondrial antibodies and anti-gp210 antibody in a patient with primary biliary cholangitis and Sjögren syndrome with subsequent autoimmune hemolytic anemia: A case report.

RATIONALE: Primary biliary cholangitis (PBC) is a rare autoimmune cholestatic liver disease. It is often associated with extrahepatic autoimmune disorders. However, the concurrence of PBC and Sjögren syndrome (SS) with the subsequent onset of autoimmune hemolytic anemia (AIHA) is extremely rare. PATIENT CONCERNS: This study investigated a 60-year-old woman admitted to our hospital with complaints of xerostomia for 5 years, pruritus for 3 years, and abnormal liver function for 3 months. DIAGNOSES: The patient was suffering from typical clinical PBC and SS, and developed decompensated liver cirrhosis after 32 months of ursodeoxycholic acid (UDCA) therapy. In May 2018, she was readmitted to the hospital with a high fever of 39 °C, coughing, and sever fatigue without remission after 3 days of cephalosporin antibiotic therapy. During the clinical course of PBC, her antimitochondrial antibodies (AMA) titers fluctuated from 1:1000 to negative and then to weakly positive, determined by indirect immunofluorescence (IIF), immunoblotting, and enzyme-linked immunosorbent assay (ELISA) based on recombinant mitochondrial antigens; furthermore, her titers of anti-gp210, an antinuclear antibody (ANA), increased sharply. Laboratory tests and imaging were performed to diagnose PBC and SS in September 2015. However, she was subsequently diagnosed with AIHA after 32 months of UDCA therapy based on the identification of pancytopenia, increased reticulocyte (RET) count, and a positive result from the direct Coombs test. INTERVENTIONS: UDCA, hepatic protectant, albumin infusion, chest drainage, rational antibiotic use, diuretics, and methylprednisolone were used to treat the patient. OUTCOMES: Liver cirrhosis was complicated by the development of AIHA, which became severe at 42 months of follow-up. LESSONS: This is the first case report showing a patient with comorbid PBC and SS, as well as the sequential development of AIHA with decreased AMA and increased anti-gp210 titers; this may have been due to immunodeficiency. These findings stress the importance of the serological screening of ANA profile, as well as repeated measurement of ANA and AMA to track PBC progression and prognosis.

Early Prognostic Utility of Gp210 Antibody-Positive Rate in Primary Biliary Cholangitis: A Meta-Analysis.

BACKGROUND: The prevalence of primary biliary cholangitis (PBC), which is an autoimmune liver disease, has increased over time. PBC often leads to severe consequences, such as liver failure and death. Stratification tools using biochemical liver tests are needed to assess and predict the progression of this disease at the time of PBC diagnosis. METHODS: We searched PubMed, Cochrane Library, Web of Science, and Embase for studies focused on the relationship between positive rates of Gp210 antibodies and poor prognosis of PBC. The primary end point was the number of PBC patients with poor outcome in the Gp210 antibody (+) and Gp210 antibody (-) groups. The secondary end point was the basic serum level of alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TBIL), and IgM in the two groups. The age and number of female patients were also measured. RESULTS: A total of 5 studies, comprising 737 patients, were included in this analysis. A positive rate of Gp210 antibodies was positively correlated with poor outcomes and with many types of progression in PBC, especially liver failure. Mortality was also higher in the Gp210 antibody (+) group. Furthermore, the serum levels of ALP and IgM were associated with the positive rate of Gp210 antibodies, while the serum levels of ALT and TBIL were not. The age and number of female patients were also not associated with the positive rate of Gp210 antibodies. CONCLUSION: PBC-specific Gp120 antibodies are optimal predictors of PBC prognosis at the time of diagnosis. Some other liver function indicators, such as ALP and IgM, can be used as predictors to complement Gp210 antibodies to establish a stratification tool to predict the prognosis of PBC at the time of diagnosis.

Autoantibody Response to ZRF1 and KRR1 SEREX Antigens in Patients with Breast Tumors of Different Histological Types and Grades.

Purpose. To investigate a frequency of antibody response to SEREX-identified medullary breast carcinoma autoantigens ZRF1 and KRR1 in sera of breast cancer patients taking into account clinical and molecular characteristics of tumors for opening of new perspectives in creation of minimally invasive immunological tests for cancer diagnostics. Methods. Enzyme-linked immunosorbent assay and bioinformatics analysis. Results. Increased frequency of antibody response was found in sera of breast cancer patients to ZRF and KRR1 antigens. The antibody response to these antigens was higher in sera of patients with invasive ductal carcinoma than in sera of patients with other histological types of breast tumors. Moreover, more frequent antibody response to ZRF antigen was found in sera of patients with less aggressive tumors. The sequence analysis of ZRF1 antigen SEREX clones obtained from cDNA libraries of different tumors demonstrates that they encode different protein isoforms. Conclusion. Tumor-associated antigens KRR1 and ZRF1 and their cognate autoantibodies could be considered as potential molecular markers of breast cancer which need to be further investigated.

Allgrove syndrome.

Allgrove syndrome is a rare autosomal recessive disorder. It is also known as the 3A syndrome and characterised by the triad of achalasia, alacrima and adrenal insufficiency. The AAAS gene is encoded on chromosome 12q13. We report the case of a 23-year-old woman who presented at the hospital with adrenal crisis that was triggered by infection of the urinary system and gastrointestinal bleeding. She had a known diagnosis of achalasia for eight years, and ophthalmologic examination revealed alacrima. Based on our findings, the patient was diagnosed with Allgrove syndrome.

Increased serum level of Nup88 protein is associated with the development of colorectal cancer.

Nucleoporin88 (Nup88) has been shown to be overexpressed in a wide variety of malignancies including colorectal cancer (CRC). However, no study about serum Nup88 in human CRC was reported. Therefore, in this study, we investigated the level of serum Nup88 protein and its relationships with clinicopathological variables in CRC. The serum concentration of Nup88 protein was determined by a quantitative sandwich enzyme-linked immunosorbent assay (ELISA) in 118 pre-operative serum samples, 66 post-operative and 96 healthy controls. Among the patients, the levels of CEA (n = 91) and CA19-9 (n = 87) in the pre-operative serum were measured, and DNA sequencing was performed in 12 CRCs and 2 samples from non-cancerous colon tissue. In the same patients, the level of pre-operative serum Nup88 was significantly higher than that of post-operative Nup88 (P = 0.021). Furthermore, the level of pre-operative Nup88 was positively related to the depth of tumor invasion (P = 0.002) and advanced stage (P = 0.001). The level of pre-operative Nup88 in the left colon tended to be higher than that in the right colon and the rectum (P = 0.063). DNA sequencing results showed that there were two single nucleotide polymorphisms, distributed in exon 6 (NM_002532.3:c.1044G>A (ACG-ACA, Thr → Thr) and exon 10 (NM_002532.3:c.1389A>T, CCA-CCT, Pro → Pro). Serum Nup88 might be a candidate for a new biomarker implicated in the development and aggressiveness of CRCs.

Is prevalence of PBC underestimated in patients with systemic sclerosis?

BACKGROUND: Clinically significant primary biliary cirrhosis occurs in 2.5% of patients with systemic sclerosis. Primary biliary cirrhosis-specific autoantibodies include anti-mitochondrial, anti-glycoprotein 210, and anti-sp100 antibodies. The majority of asymptomatic anti-mitochondrial-positive subjects express histological features of primary biliary cirrhosis. Early detection of primary biliary cirrhosis is important, as timely introduction of ursodeoxycholic acid may improve prognosis. The aim was to assess the prevalence of MIT3 IgG-anti-mitochondrial, gp210, sp100 and other autoantibodies in patients with systemic sclerosis and compare the clinical and biochemical parameters in those who are primary biliary cirrhosis-specific autoantibodies positive and negative. MATERIALS/METHODS: Fifty-two consecutive patients with systemic sclerosis were included. Thirty-three suffered from limited skin SS and 19 from diffuse SS. RESULTS: Eight (15%) patients with systemic sclerosis tested positive for primary biliary cirrhosis-specific autoantibodies. No significant differences were observed between primary biliary cirrhosis-specific autoantibodies positive and negative subjects in terms of various demographic, clinical or biochemical features. A trend towards increased prevalence of chronic fatigue in primary biliary cirrhosis-specific autoantibodies positive patients was observed. CONCLUSIONS: Primary biliary cirrhosis-specific autoantibodies were detected in 15% of the systemic sclerosis patients. Since patients with primary biliary cirrhosis-specific antibodies are at high-risk or do suffer from primary biliary cirrhosis, screening for primary biliary cirrhosis-specific autoantibodies may be considered during routine assessment of systemic sclerosis.

Measurement of gp210 autoantibodies in sera of patients with primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune liver disease with unknown etiology. Patients with PBC have antimitochondrial autoantibodies (AMA) and additionally 50% of them have antinuclear antibodies (ANA). A 15-amino acid fragment (DRKASPPSGLWSPAY) from the C-terminal part of the nuclear envelope glycoprotein gp210 has been proposed as one of the antigenic targets for ANA. The aim of this work was to develop an immunoenzymatic assay for determination of gp210 autoantibodies using for its binding a synthetic pentadecapeptide derived from the gp210 amino acid sequence and to determine level of these autoantibodies in sera of patients with PBC and other autoimmune liver diseases from Poland. Polystyrene microtitration plates coated with the synthetic peptide were consecutively incubated with diluted sera, anti-human immunoglobulin G (IgG) antibodies conjugated with horseradish peroxidase, and with tetramethylobenzidine. Optical density (OD) was read at 450 nm. The mean values of the intra- and interassay of variation coefficients of the test were 4.1 and 10.2%, respectively. Anti-gp210 was detected in 44% of PBC patients and in 6% of patients with PSC. The results were negative for healthy blood donors and other controls. The specificity of the test was 99%, so the anti-gp-210 autoantibodies estimated on DRKASPPSGLWSPAY can be a reliable marker of PBC.