Anti‐p97/VCP Antibodies: An Autoantibody Marker for a Subset of Primary Biliary Cirrhosis Patients with Milder Disease?

Abstract

We previously reported that 12.5% of primary biliary cirrhosis (PBC) sera reacted with a 95 kDa cytosol protein (p95c) that was subsequently identified as a p97/valosin-containing protein (VCP). The clinical features and course of the six anti-p97/VCP-positive PBC patients with Scheuer's stage 1 and 2 liver biopsies were monitored for an average of 15 years. This group was compared with 50 PBC patients that did not have detectable anti-VCP. Autoantibodies to a full-length recombinant p97/VCP were assayed by immunoprecipitation. All six PBC patients with anti-VCP had antibodies to the mitochondrial pyruvate dehydrogenase complex-E2 antigen as measured by an addressable laser bead immunoassay. The first was a male with no evidence of liver failure that died of cerebral infarction at the age of 85. The second was a 73-year-old female with Hashimoto's thyroiditis who has remained clinically stable without ursodeoxycolic acid (UDCA) treatment. Although the third had no HCV antibodies, he developed hepatocellular carcinoma at the age of 76 and died of renal failure at 78. The fourth was a 50-year-old female who remained clinically stable during follow-up and the fifth with Hashimoto's thyroiditis and stable liver function following UCDA treatment. The sixth was a male patient presenting a mild clinical course. The clinical course of these patients was in contrast to the 50 comparison group PBC patients who did not have anti-p97/VCP. As the six PBC patients with anti-p97/VCP antibodies had slowly progressive liver disease and no mortality related to autoimmune liver disease, our observations suggest that this autoantibody might be an indicator of a favourable prognosis.

Autoantibodies to GW bodies and other autoantigens in primary biliary cirrhosis

“…VCP plays a role in nuclear envelope assembly and the post-mitotic formation of the endoplasmic reticulum and Golgi apparatus. This antibody was found in 12% of patients with PBC [52], and was suggested to be associated with a milder course [19]. In general agreement with previous reports, our study found that antibodies to VCP were found in 11% of patients and the average Mayo risk score of the 12 patients positive for anti-VCP was 3·7 compared with 4·1 of the entire cohort.…”

“…The reactivity of the sera with Sm, U1‐RNP, Ro52, SS‐A/Ro60, SS‐B/La, ribosomal P (C22 epitope [17]), Jo‐1 (histidyl‐tRNA synthetase), chromatin and topoisomerase I (Scl‐70) autoantigens was determined by ALBIA (QuantaPlex9; INOVA Diagnostics, Inc., San Diego, CA, USA) on a Luminex 100 flow fluorometer (Luminex Corp., Austin, TX, USA), as described elsewhere [18]. Antibodies to GWB components and other cytoplasmic targets including valosin‐containing protein (VCP) [19], early endosome antigen 1 (EEA1) [20], Ge‐1/Hedls [21], signal recognition particle (SRP) [22], GW182, GW2, GW3 [6], Ribo P2 [23], RNA‐associated protein 55/like Sm antigen (Rap55/LSm14) [24] and cytoplasmic linker protein (CLIP‐170) [25] were also assayed by ALBIA. All proteins were full‐length recombinant human proteins, except GW2 and GW3, which were partial length recombinant proteins.…”

Sorafenib-Mediated Targeting of the AAA+ ATPase p97/VCP Leads to Disruption of the Secretory Pathway, Endoplasmic Reticulum Stress, and Hepatocellular Cancer Cell Death

“…Proteomics studies have suggested that p97/VCP might play some role in the liver regeneration and in fetal liver development (31), and it has also been shown that p97/VCP contributes to the formation of Mallory bodies (32). Moreover, p97/VCP autoantibodies have been found in cases of autoimmune hepatitis (33), primary biliary cirrhosis (34,35), and in HCC (36). Elevated expression of p97/VCP in HCC has also been associated with increased incidence of tumor recurrence (37).…”

Integrative Quantitative Proteomics Unveils Proteostasis Imbalance in Human Hepatocellular Carcinoma Developed on Nonfibrotic Livers

“…They demonstrate that the toxicity of reactive oxygen species produced upon HSP90 inhibition is enhanced by the suppression of glutathione by rapamycin (38). In hepatocellular carcinoma the expression level of VCP is markedly elevated and has been shown to be associated with poor prognosis or has been associated with the presence of auto-antibodies in the serum for liver diseases (39,40), proposing p97/CDC-48 expression levels as a useful marker for the progression of these cancers. Moreover, we found that the alteration of VCP function upon sorafenib treatment impaired protein secretion and led to cell death in HCC cells (41).…”