Autoimmune liver diseases (ALD) are characterized by immune-mediated injury of bile ducts or hepatocytes, thus including cholangiopathies such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis, and autoimmune hepatitis. Further, ALD variants manifesting with both hepatocellular and cholangiocellular damage are becoming more common. Serum autoantibodies, together with imaging and histology, are critical to the diagnostic process when ALD is suspected. Because an early diagnosis can influence prognosis, the development of sensitive and specific tests for serum autoantibodies should be a priority for researchers to ensure a more efficient noninvasive workup. Little prognostic value has been observed for any of the ALD serum hallmarks, and a vigorous effort to investigate new and old markers should therefore be undertaken in longitudinal studies as in the recent paradigm of PBC-specific antinuclear antibodies. We review herein the numerous ALD screening tests available in routine and specialized laboratories and comment on their significance in clinical practice.

Interpreting serological tests in diagnosing autoimmune liver diseases.

Increased expression of nuclear envelope gp210 antigen in small bile ducts in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic autoimmune cholestatic liver disease most commonly encountered in postmenopausal women; it is characterized by high-titer serum autoantibodies to mitochondrial antigens, elevated serum IgM, progressive destruction of intrahepatic bile ducts, and ultimately liver cirrhosis and failure. The cytopathic mechanisms leading to the selective destruction of intrahepatic cholangiocytes are still largely unknown. The current theory on the pathogenesis of PBC indicated that environmental factors might trigger autoimmunity in genetically susceptible individuals. In fact, genetic predisposition is critical to disease onset and progression, yet peculiar among autoimmune diseases, as indicated by the lack of a strong association with major histocompatibility complex haplotypes. Further, the recently reported concordance rate among monozygotic twins strenghtens the importance of genetic factors, while also indicating that additional factors, possibly infectious agents or xenobiotics, intervene to trigger the disease. In this review, the available data regarding the genetic factors associated with PBC susceptibility and progression, as well as the available evidence regarding the immunomediated pathogenesis of PBC, will be critically illustrated and discussed.

Genes and (auto)immunity in primary biliary cirrhosis

Antibodies against nuclear components (ANAs) occur in sera of approximately 50% of patients with primary biliary cirrhosis (PBC). By indirect immunofluorescence (IIF) ANA-positive PBC sera generate most frequently, homogeneous, speckled, centromere, and rim-like staining patterns. A perinuclear staining pattern is indicative for the reactivity of the sera with the components of the nuclear envelope. A substantial subset of PBC patients develops antibodies against constituents of the nuclear pore complexes (NPCs). These autoantibodies target two major autoantigens: gp210 glycoprotein and p62 kDa nucleoporin. Originally, a strong reaction of PBC with a 60 kDa protein of NPCs that was affinity purified on wheat-germ agglutinin (WGA)-Sepharose was described. Recently, using human recombinant p62 nucleoporin the identity of the reactivity was confirmed. In this work we compared by immunoprecipitation the reactivity of 20 PBC sera with the two recombinant autoantigens of the NPCs. Two out of 20 (10%) PBC sera precipitated recombinant gp210 glycoprotein and 11 out of 20 (55%) PBC sera reacted with p62 nucleoporin. These results evidence that anti-p62 antibodies occur more frequently than the autoantibodies against gp210 glycoprotein. Considering the recently reported clinical significance of ANAs in PBC, the prognostic value of the anti-NPC antibodies and their correlation with severity and progression of the disease is under evaluation.

Characterization of autoantibodies against components of the nuclear pore complexes: high frequency of anti-p62 nucleoporin antibodies.

Reactivity of sera from patients with primary biliary cirrhosis (PBC) with a 60 kDa component of nuclear pore complexes (NPCs), purified by affinity chromatography on wheat-germ agglutinin (WGA)-Sepharose, was previously detected. Recently, clinical significance of the anti-NPC antibodies in PBC became evident. In the light of recent reports, indicating the correlation of the anti-NPC antibodies with severity and progression of the disease, the characterization of the reactive antigens is becoming essential in the clinical management of patients with PBC. Since accurate autoantibody detection represents one of the fundamental requirements for a reliable testing, we have generated a human recombinant p62 protein and validated an immunoprecipitation assay for the detection of anti-p62. We also demonstrated that the generated human recombinant p62 nucleoporin was modified by N-acetylglucosamine residues. More than 50% of tested PBC sera precipitated 35S-radioactively labeled p62 recombinant nucleoporin and 40% recognized this recombinant antigen by immunoblotting. We compared the reactivity of PBC sera with rat and human nucleoporin. The incidence of anti-p62 nucleoporin positive PBC sera increased by 15% when human recombinant antigen was used. The titer of autoantibodies in p62-positive PBC samples strongly varied. Preadsorption of the PBC sera with p62 recombinant protein completely abolished their reactivity with the antigen. In conclusion, this study unequivocally proves that autoantibodies reacting with the 60 kDa component of NPCs target p62 nucleoporin and, more importantly, provide a better antigen source for future evaluations of the clinical role of anti-p62 in PBC. J. Cell. Biochem. 104: 27–37, 2008. © 2007 Wiley-Liss, Inc.

Characterization of the antibodies to p62 nucleoporin in primary biliary cirrhosis using human recombinant antigen.

544 Prognostic value of autoantibodies against proteins of nuclear pore complexes (anti-NPCS) in early primary biliary cirrhosis (PBC)

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544 Prognostic value of autoantibodies against proteins of nuclear pore complexes (anti-NPCS) in early primary biliary cirrhosis (PBC)