Autoantibodies against nuclear pore complexes are associated with more active and severe liver disease in primary biliary cirrhosis

Abstract

Background/Aims: Antibodies against nuclear pore complexes (NPCs) have been detected in primary biliary cirrhosis (PBC), but their clinical relevance is still unsettled.

Methods: We tested sera from 171 consecutive PBC patients and 230 control subjects (149 with autoimmune or viral liver diseases, 28 with systemic lupus erythematosus, and 53 healthy) by immunoblotting for antibodies against purified human NPCs.

Results: Antibodies to NPCs were detected in 27% of the patients with PBC, were highly specific (97%), and were not associated with antimitochondrial antibodies. Their prevalence was higher in symptomatic patients (36 vs. 16%, P<0.01) and was associated (P<0.001) with more severe disease, as assessed by the presence of cirrhosis or its complications (13% prevalence in patients without cirrhosis, 31% in uncomplicated, and 54% in complicated cirrhosis), or by the application of the Mayo prognostic model (12% in the lowest, 21% in the median, 47% in the highest score tertile). Positive patients had higher levels of serum bilirubin (2.2±3.7 vs. 1.0±1.1 mg/dl, P<0.01) and more marked inflammatory infiltrates on liver biopsy (P<0.05).

Conclusions: Autoantibodies to NPCs are more prevalent in PBC patients than in controls and are strongly associated with more active and severe disease.

Introduction

Non-organ-specific autoantibodies are consistently found in primary biliary cirrhosis (PBC), a progressive liver disease characterized by chronic immune-mediated bile duct damage [1]. Besides antimitochondrial antibodies (AMA), the specific marker of PBC detected in at least 90% of the patients [2], [3], antinuclear antibodies (ANA) may also be found in about one-third of the patients by indirect immunofluorescence (IIF) [4]. Over the last decade, a number of nuclear structures have been recognized as targets of ANA in PBC [5], [6]. These include Sp100 [7] and promyelocytic leukemia proteins [8], which generate a nuclear dot pattern at IIF, and several components of the nuclear pore complexes, such as gp210 [9] and p62 [10] proteins, that have been specifically associated with a perinuclear pattern.

It has been surmised that the demonstration of specific antibodies against nuclear proteins conveys clinically relevant information, and the search for such antibodies may assist in the diagnosis of PBC, especially in patients lacking AMA [8], [10], [11], [12], [13]. Some studies have addressed the prognostic value of specific ANA in the disease, but no definite relationship with its course could be demonstrated [8], [11], [12], [14], [15], [16]. However, the conclusions of such studies are affected by a major flaw. Perinuclear ANA have generally been searched for only in ANA-IIF-positive sera [11], [12], [14], but it is now clear that IIF is less sensitive in detecting ANA than immunoblotting and enzymatic immunoassay [17]; systematic underdetection of positive cases can therefore not be excluded. Interestingly, a systematic search of antibodies directed against the major autoantigens of nuclear dots has recently disclosed an association between this family of antibodies and an unfavorable clinical course in a cross-sectional study on a large series of sera from PBC patients [18].

In the present study, we estimated the prevalence and specificity of antibodies against proteins of all of the nuclear pore complexes (anti-NPCs), and appraised their clinical significance in a large population of unselected PBC patients. For purposes of comparison, groups of patients with both hepatic and autoimmune disease, as well as healthy subjects, were investigated.