+Model CLINRE-515; No. of Pages 3
ARTICLE IN PRESS
Clinics and Research in Hepatology and Gastroenterology (2013) xxx, xxx—xxx
Available online at
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CLINICAL, BIOLOGICAL AND PHARMACOLOGICAL KEYNOTES
Autoantibodies in primary biliary cirrhosis: Antinuclear envelope autoantibodies Yannick Chantran , Eric Ballot , Catherine Johanet ∗ Unité d’immunologie, CHU Saint-Antoine, AP—HP, 75571 Paris cedex 12, France
Antinuclear envelope autoantibodies (ANEA) are a set of antinuclear antibodies that produce a rim-like pattern using indirect immunofluorescence. ANEA directed against proteins of the nuclear pore complex, such as antigp210 antibodies, are specific to primary biliary cirrhosis (PBC). Detected routinely by commercial enzyme-linked immunosorbent assays (ELISA) or dot blotting, they can therefore be used as diagnostic markers, especially when antimitochondrial antibodies are absent [1,2]. Anti-gp210 antibodies are also considered as prognostic markers of a poor outcome, correlated to a higher risk of hepatic failure. This review is a synthesis of all the data generated thus far concerning ANEA and anti-gp210 antibodies in PBC.
Detection of antinuclear envelope and anti-gp210 autoantibodies Antinuclear envelope autoantibodies (ANEA) were first detected using immunofluorescence (IIF) in a subset of primary biliary cirrhosis (PBC) patients as displaying a thin ring confined to the perinuclear region [3] (Fig. 1). Interestingly, this so-called ‘‘rim-like’’ pattern appeared to be present in PBC regardless of the patient’s antimitochondrial status [4].
∗
Corresponding author. E-mail address: [email protected] (C. Johanet).
The nuclear envelope includes the bilayered nuclear membrane, the nuclear lamina on the luminal side of the inner membrane, and nuclear pores. In PBC, ANEA are directed mainly against proteins in the nuclear pore, which is an aqueous transport channel across the nuclear membrane, thus enabling bidirectional exchanges between the cytosolic compartment and the nucleoplastic microenvironment. Gp210 protein, the principal antigen in the nuclear pore complex, is an integral membrane glycoprotein of 210 kDa that anchors the luminal core of the pore within the nuclear envelope [5]. The lamin B receptor (LBR) [6] is also an integral membrane protein, located outside the nuclear pore complex within the inner layer of the nuclear membrane. Nucleoporin p62 (Nup62), part of the innermost cylindrical layer of the pore complex, has been identified as another specific ANEA in PBC [7], together with other channel nucleoporins of the p62 complex [8]. Other minor ANEA antigens in PBC have been described both within and outside the nuclear pore complex: the Translocated promoter region (Tpr) protein [9], and lamin associated proteins (LAP) [10]. Anti-gp210 autoantibodies are the most important ANEA described in PBC. Initially detected by immunoblotting, the predominant epitopes were then localized within a 15-amino acid linear stretch in the carboxyterminal domain of gp210 protein [11]. Subsequently, a commercial enzyme-linked immunosorbent assay (ELISA) and line immuno-assay (LIA) using a dot blotting technique were designed, and revealed very good correlations with immunoblotting [12,13]. This
2210-7401/$ – see front matter © 2013 Published by Elsevier Masson SAS. http://dx.doi.org/10.1016/j.clinre.2013.10.008
Please cite this article in press as: Chantran Y, et al. Autoantibodies in primary biliary cirrhosis: Antinuclear envelope autoantibodies. Clin Res Hepatol Gastroenterol (2013), http://dx.doi.org/10.1016/j.clinre.2013.10.008
+Model CLINRE-515; No. of Pages 3
ARTICLE IN PRESS
2
Y. Chantran et al.
Figure 1 Immunofluorescence patterns of antinuclear-membrane antibodies on rat liver sections. A. Antinuclear-membrane with AMA2 (× 400). B. Antinuclear-membrane alone (× 400).
test has since enabled the routine detection of anti-gp210 autoantibodies.
Clinical usefulness of ANEA in primary biliary cirrhosis Nuclear membrane-staining by IIF is observed in 30% [3,13] to 50% [4,14] of sera from patients with PBC, and in fewer than 1% of control sera. However, the presence of ANEA is not alone specific to PBC. Therefore, the detection of a rimlike pattern is not considered as a diagnostic marker, but is used for screening purposes. Non-specific ANEA such as antilamin antibodies are thus commonly found in patients with systemic lupus erythematosus, antiphospholipid syndrome, thrombocytopenia and autoimmune hepatitis [15]. The prevalence of anti-gp210 antibodies ranges from 10% to 45% [15,16], but is usually estimated at being around 2530% [8,13]. Anti-gp210 antibodies display specificity greater than 99%, although they can occur sporadically, especially in the context of other autoimmune liver conditions [16,17]. There is no evidence for a higher or lower prevalence as a function of antimitochondrial antibody status [18,19]. However, anti-gp210 antibodies are considered to be a very useful diagnostic tool when antimitochondrial antibodies are absent. It is widely admitted that anti-gp210 positivity is also an independent prognostic marker for a poor outcome. It is a significant risk factor for the progression to hepatic failure [20], and accordingly, anti-gp210 negativation under treatment with ursodeoxycholic acid (UDCA) is associated with a better outcome [21]. The monitoring of anti-gp210 antibodies is of no value to the follow-up of transplanted patients: anti-gp210 titres persist with or without any recurrence of the disease [22,23]. Other ANEA (anti-Nup62, anti-LBR, anti-Tpr and antiLAP antibodies) are not detected routinely, and their prevalence, specificity or prognostic value are less well established. Anti-Nup62 antibodies seem to be at least as prevalent as anti-gp210, with a sensitivity ranging from 22% to 55% [7,8,10,24] using conventional detection techniques. Although anti-Nup62 antibodies are considered to be PBCspecific ANEA, it remains a matter of controversy whether this biomarker can attain the same specificity as anti-gp210
antibodies [25]. Anti-LBR antibodies appear to be highly specific to PBC, but their prevalence is lower than 10% [10].
Anti-gp210 autoantibodies and the pathogenesis of primary biliary cirrhosis The pathological significance of ANEA in PBC remains elusive. On the one hand, the presence of ANEA is obviously not a prerequisite for the pathogenesis of this condition. On the other hand, in view of the higher risk of progression to hepatic failure in the event of anti-gp210 positivity, it can be inferred that ANEA are of particular importance to determining the course of the disease. Gp210 protein is thus over-expressed in biliary epithelial cells of the small bile ducts of PBC patients, when compared with other liver diseases. Moreover, the degree of this gp210 expression seems positively correlated to disease activity [26]. Study of the gene polymorphism linked to gp210 has also enabled a clearer understanding of genetic susceptibility to PBC. It has now been established that the HLA-DRB1*0405 allele predisposes patients to anti-gp210 antibody production [27]. Immunoregulatory genes are also involved with humoral autoimmunity: anti-gp210 titres may be dependent on pathways involving pro-inflammatory cytokines such as TNF or IL-6, and/or impaired anti-inflammatory TGF-b signalling [28,29]. The hypothesis has been advanced that ANEA production results from the molecular mimicry of bacterial antigenic determinants, since gp210 was identified as an autoantigen. The recognized epitope sequence of the protein, located in the cytoplasmic carboxyterminal tail, presents high homology with the mutY protein of Escherichia coli and mutB in Salmonella typhimurium [11]. Interestingly, it has also been suggested that anti-gp210 autoimmunity may occur via an endogenous molecular mimicry path, due to cross-reactivity between antimitochondrial and antinuclear antigens, thus allowing immunospreading from antimitochondrial to antinuclear autoimmunity: presentation of the predominant T-cell epitope of mitochondrial protein PDC-E2 can lead to the induction of autoimmune T-cell clones that cross-react with several peptides from gp210 [30].
Please cite this article in press as: Chantran Y, et al. Autoantibodies in primary biliary cirrhosis: Antinuclear envelope autoantibodies. Clin Res Hepatol Gastroenterol (2013), http://dx.doi.org/10.1016/j.clinre.2013.10.008
+Model CLINRE-515; No. of Pages 3
ARTICLE IN PRESS
Autoantibodies in primary biliary cirrhosis: Antinuclear envelope autoantibodies
Conclusion Antinuclear envelope antibodies directed against proteins in the nuclear pore complex are specific antinuclear antibodies in PBC. Easily detected using commercial LIA or ELISA tests, anti-gp210 antibodies constitute a useful diagnostic tool in the event of antimitochondrial negativity, as well as a prognostic marker for poor outcome.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
References [1] Heathcote EJ. AASLD practice guidelines: management of primary biliary cirrhosis. Hepatology 2000:1005—13. [2] Beuers U, Boberg KM, Chapman RW, Chazouilleres O, Invernizzi P, Jones DE, et al. EASL clinical practice guidelines: Management of cholestatic liver diseases. J Hepatol 2009;51:237—67. [3] Ruffatti A, Arslan P, Floreani A, De Silvestro G, Calligaro A, Naccarato R, et al. Nuclear membrane-staining antinuclear antibody in patients with primary biliary cirrhosis. J Clin Immunol 1985;5:357—61. [4] Lozano F, Parés A, Borche L, Plana M, Gallart T, Rodés J, et al. Autoantibodies against nuclear envelope-associated proteins in primary biliary cirrhosis. Hepatology 1988;8:930—8. [5] Courvalin JC, Lassoued K, Bartnik E, Blobel G, Wozniak RW. The 210-kD nuclear envelope polypeptide recognized by human autoantibodies in primary biliary cirrhosis is the major glycoprotein of the nuclear pore. J Clin Invest 1990;86:279—85. [6] Courvalin JC, Lassoued K, Worman HJ, Blobel G. Identification and characterization of autoantibodies against the nuclear envelope lamin B receptor from patients with primary biliary cirrhosis. J Exp Med 1990;172:961—7. [7] Wesierska-Gadek J, Hohenauer H, Hitchman E, Penner E. Autoantibodies against nucleoporin p62 constitute a novel marker of primary biliary cirrhosis. Gastroenterology 1996;110:840—7. [8] Miyachi K, Shibata M, Onozuka Y, Kikuchi F, Imai N, Horigome T. Primary biliary cirrhosis sera recognize not only gp210 but also proteins of p62 complex bearing N-acetylglucosamine residues from rat liver nuclear envelope. Mol Biol Rep 1996;23:227—34. [9] Ou Y, Enarson P, Rattner JB, Barr SG, Fritzler MJ. The nuclear pore complex protein Tpr is a common autoantigen in sera that demonstrate nuclear envelope staining by indirect immunofluorescence. Clin Exp Immunol 2004;136:379—87. [10] Miyachi K, Hankins RW, Matsushima H, Kikuchi F, Inomata T, Horigome T, et al. Profile and clinical significance of antinuclear envelope antibodies found in patients with primary biliary cirrhosis: a multicenter study. J Autoimmun 2003;20:247—54. [11] Nickowitz RE, Worman HJ. Autoantibodies from patients with primary biliary cirrhosis recognize a restricted region within the cytoplasmic tail of nuclear pore membrane glycoprotein Gp210. J Exp Med 1993;178:2237—42. [12] Tartakovsky F, Worman HJ. Detection of Gp210 autoantibodies in primary biliary cirrhosis using a recombinant protein containing the predominant autoepitope. Hepatology 1995;21:495—500. [13] Bandin O, Courvalin JC, Poupon R, Dubel L, Homberg JC, Johanet C. Specificity and sensitivity of gp210 autoantibodies detected using an enzyme-linked immunosorbent assay and a synthetic polypeptide in the diagnosis of primary biliary cirrhosis. Hepatology 1996;23:1020—4.
3
[14] Sfakianaki O, Koulentaki M, Tzardi M, Tsangaridou E, Theodoropoulos PA, Castanas E, et al. Perinuclear antibodies correlate with survival in Greek primary biliary cirrhosis patients. World J Gastroenterol 2010;16:4938—43. [15] Nesher G, Margalit R, Ashkenazi YJ. Antinuclear envelope antibodies: clinical associations. Semin Arthritis Rheum 2001;30:313—20. [16] Bauer A, Habior A. Measurement of gp210 autoantibodies in sera of patients with primary biliary cirrhosis. J Clin Lab Anal 2007;21:227—31. [17] Czaja AJ, Muratori P, Muratori L, Carpentier HA, Bianchi FB. Diagnosic and therapeutic implications of bile duct injury in autoimmune hepatitis. Liver Int 2004;24:322—9. [18] Romero-Gömez M, Wichmann I, Crespo J, Parés A, Rodrigo L, Alvarez A, et al. Serum immunological profile in patients with chronic autoimmune cholestasis. Am J Gastroenterol 2004;99:2150—7. [19] Liu B, Shi XH, Zhang FC, Zhang W, Gao LX. Antimitochondrial antibody-negative primary biliary cirrhosis: a subset of primary biliary cirrhosis. Liver Int 2008;28:333—9. [20] Nakamura M, Kondo H, Mori T, Komori A, Matsuyama M, Ito M, et al. Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis. Hepatology 2007;45:118—27. [21] Nakamura M, Shimizu-Yoshida Y, Takii Y, Komori A, Yokoyama T, Ueki T, et al. Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis. J Hepatol 2005;42:386—92. [22] Dubel L, Farges O, Courvalin JC, Sebagh M, Johanet C. Persistence of gp210 and multiple nuclear dots antibodies does not correlate with recurrence of primary biliary cirrhosis 6 years after liver transplantation. J Hepatol 1998;28: 169—70. [23] Luettig B, Boeker KHW, Schoessler W, Will H, Loges S, Schmidt E, et al. The antinuclear autoantibodies Sp100 and gp210 persist after orthotopic liver transplantation in patients with primary biliary cirrhosis. J Hepatol 1998;28:824—8. [24] Wesierska-Gadek J, Klima A, Komina O, Ranftler C, Invernizzi P, Penner E. Characterization of autoantibodies against components of the nuclear pore complexes. High frequency of anti-p62 nucleoporin antibodies. Ann N Y Acad Sci 2007;1109:519—30. [25] Duarte-Rey C, Bogdanos D, Yang CY, Roberts K, Leung PSC, Anaya JM, et al. Primary biliary cirrhosis and the nuclear pore complex. Autoimmun Rev 2012;11:898—902. [26] Nakamura M, Takii Y, Ito M, Komori A, Yokoyama T, ShimizuYoshida Y. Increased expression of nuclear envelope gp210 antigen in small bile ducts in primary biliary cirrhosis. J Autoimmun 2006;26:138—45. [27] Nakamura M, Yasunami M, Kondo H, Horie H, Aiba Y, Komori A, et al. Analysis of HLA-DRB1 polymorphisms in japanese patients with primary biliary cirrhosis (PBC): the HLA-DRB1 polymorphism determines the relative risk of antinuclear antibodies for disease progression in PBC. Hepatol Res 2010;40: 494—504. [28] Kempinska-podhorodecka A, Shums Z, Wasilewicz M, Wunsch E, Milkiewicz M, Bogdanos DP, et al. TRAF1 gene polymorphism correlates with the titre of gp210 antibody in patients with primary biliary cirrhosis. Clin Dev Immunol 2012;2012:487521, http://dx.doi.org/10.1155/2012/487521. [29] Yang CY, Leung PSC, Yang GX, Kenny TP, Zhang W, Coppel R, et al. Epitope-specific antinuclear antibodies are expressed in a mouse model of primary biliary cirrhosis and are cytokinedependent. Clin Exp Immunol 2012;168:261—7. [30] Shimoda S, Nakamura M, Ishibashi H, Kawano A, Kamihira T, et al. Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis. Gastroenterology 2003;124:1915—25.
Please cite this article in press as: Chantran Y, et al. Autoantibodies in primary biliary cirrhosis: Antinuclear envelope autoantibodies. Clin Res Hepatol Gastroenterol (2013), http://dx.doi.org/10.1016/j.clinre.2013.10.008
ARTICLE IN PRESS
Clinics and Research in Hepatology and Gastroenterology (2013) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
CLINICAL, BIOLOGICAL AND PHARMACOLOGICAL KEYNOTES
Autoantibodies in primary biliary cirrhosis: Antinuclear envelope autoantibodies Yannick Chantran , Eric Ballot , Catherine Johanet ∗ Unité d’immunologie, CHU Saint-Antoine, AP—HP, 75571 Paris cedex 12, France
Antinuclear envelope autoantibodies (ANEA) are a set of antinuclear antibodies that produce a rim-like pattern using indirect immunofluorescence. ANEA directed against proteins of the nuclear pore complex, such as antigp210 antibodies, are specific to primary biliary cirrhosis (PBC). Detected routinely by commercial enzyme-linked immunosorbent assays (ELISA) or dot blotting, they can therefore be used as diagnostic markers, especially when antimitochondrial antibodies are absent [1,2]. Anti-gp210 antibodies are also considered as prognostic markers of a poor outcome, correlated to a higher risk of hepatic failure. This review is a synthesis of all the data generated thus far concerning ANEA and anti-gp210 antibodies in PBC.
Detection of antinuclear envelope and anti-gp210 autoantibodies Antinuclear envelope autoantibodies (ANEA) were first detected using immunofluorescence (IIF) in a subset of primary biliary cirrhosis (PBC) patients as displaying a thin ring confined to the perinuclear region [3] (Fig. 1). Interestingly, this so-called ‘‘rim-like’’ pattern appeared to be present in PBC regardless of the patient’s antimitochondrial status [4].
∗
Corresponding author. E-mail address: [email protected] (C. Johanet).
The nuclear envelope includes the bilayered nuclear membrane, the nuclear lamina on the luminal side of the inner membrane, and nuclear pores. In PBC, ANEA are directed mainly against proteins in the nuclear pore, which is an aqueous transport channel across the nuclear membrane, thus enabling bidirectional exchanges between the cytosolic compartment and the nucleoplastic microenvironment. Gp210 protein, the principal antigen in the nuclear pore complex, is an integral membrane glycoprotein of 210 kDa that anchors the luminal core of the pore within the nuclear envelope [5]. The lamin B receptor (LBR) [6] is also an integral membrane protein, located outside the nuclear pore complex within the inner layer of the nuclear membrane. Nucleoporin p62 (Nup62), part of the innermost cylindrical layer of the pore complex, has been identified as another specific ANEA in PBC [7], together with other channel nucleoporins of the p62 complex [8]. Other minor ANEA antigens in PBC have been described both within and outside the nuclear pore complex: the Translocated promoter region (Tpr) protein [9], and lamin associated proteins (LAP) [10]. Anti-gp210 autoantibodies are the most important ANEA described in PBC. Initially detected by immunoblotting, the predominant epitopes were then localized within a 15-amino acid linear stretch in the carboxyterminal domain of gp210 protein [11]. Subsequently, a commercial enzyme-linked immunosorbent assay (ELISA) and line immuno-assay (LIA) using a dot blotting technique were designed, and revealed very good correlations with immunoblotting [12,13]. This
2210-7401/$ – see front matter © 2013 Published by Elsevier Masson SAS. http://dx.doi.org/10.1016/j.clinre.2013.10.008
Please cite this article in press as: Chantran Y, et al. Autoantibodies in primary biliary cirrhosis: Antinuclear envelope autoantibodies. Clin Res Hepatol Gastroenterol (2013), http://dx.doi.org/10.1016/j.clinre.2013.10.008
+Model CLINRE-515; No. of Pages 3
ARTICLE IN PRESS
2
Y. Chantran et al.
Figure 1 Immunofluorescence patterns of antinuclear-membrane antibodies on rat liver sections. A. Antinuclear-membrane with AMA2 (× 400). B. Antinuclear-membrane alone (× 400).
test has since enabled the routine detection of anti-gp210 autoantibodies.
Clinical usefulness of ANEA in primary biliary cirrhosis Nuclear membrane-staining by IIF is observed in 30% [3,13] to 50% [4,14] of sera from patients with PBC, and in fewer than 1% of control sera. However, the presence of ANEA is not alone specific to PBC. Therefore, the detection of a rimlike pattern is not considered as a diagnostic marker, but is used for screening purposes. Non-specific ANEA such as antilamin antibodies are thus commonly found in patients with systemic lupus erythematosus, antiphospholipid syndrome, thrombocytopenia and autoimmune hepatitis [15]. The prevalence of anti-gp210 antibodies ranges from 10% to 45% [15,16], but is usually estimated at being around 2530% [8,13]. Anti-gp210 antibodies display specificity greater than 99%, although they can occur sporadically, especially in the context of other autoimmune liver conditions [16,17]. There is no evidence for a higher or lower prevalence as a function of antimitochondrial antibody status [18,19]. However, anti-gp210 antibodies are considered to be a very useful diagnostic tool when antimitochondrial antibodies are absent. It is widely admitted that anti-gp210 positivity is also an independent prognostic marker for a poor outcome. It is a significant risk factor for the progression to hepatic failure [20], and accordingly, anti-gp210 negativation under treatment with ursodeoxycholic acid (UDCA) is associated with a better outcome [21]. The monitoring of anti-gp210 antibodies is of no value to the follow-up of transplanted patients: anti-gp210 titres persist with or without any recurrence of the disease [22,23]. Other ANEA (anti-Nup62, anti-LBR, anti-Tpr and antiLAP antibodies) are not detected routinely, and their prevalence, specificity or prognostic value are less well established. Anti-Nup62 antibodies seem to be at least as prevalent as anti-gp210, with a sensitivity ranging from 22% to 55% [7,8,10,24] using conventional detection techniques. Although anti-Nup62 antibodies are considered to be PBCspecific ANEA, it remains a matter of controversy whether this biomarker can attain the same specificity as anti-gp210
antibodies [25]. Anti-LBR antibodies appear to be highly specific to PBC, but their prevalence is lower than 10% [10].
Anti-gp210 autoantibodies and the pathogenesis of primary biliary cirrhosis The pathological significance of ANEA in PBC remains elusive. On the one hand, the presence of ANEA is obviously not a prerequisite for the pathogenesis of this condition. On the other hand, in view of the higher risk of progression to hepatic failure in the event of anti-gp210 positivity, it can be inferred that ANEA are of particular importance to determining the course of the disease. Gp210 protein is thus over-expressed in biliary epithelial cells of the small bile ducts of PBC patients, when compared with other liver diseases. Moreover, the degree of this gp210 expression seems positively correlated to disease activity [26]. Study of the gene polymorphism linked to gp210 has also enabled a clearer understanding of genetic susceptibility to PBC. It has now been established that the HLA-DRB1*0405 allele predisposes patients to anti-gp210 antibody production [27]. Immunoregulatory genes are also involved with humoral autoimmunity: anti-gp210 titres may be dependent on pathways involving pro-inflammatory cytokines such as TNF or IL-6, and/or impaired anti-inflammatory TGF-b signalling [28,29]. The hypothesis has been advanced that ANEA production results from the molecular mimicry of bacterial antigenic determinants, since gp210 was identified as an autoantigen. The recognized epitope sequence of the protein, located in the cytoplasmic carboxyterminal tail, presents high homology with the mutY protein of Escherichia coli and mutB in Salmonella typhimurium [11]. Interestingly, it has also been suggested that anti-gp210 autoimmunity may occur via an endogenous molecular mimicry path, due to cross-reactivity between antimitochondrial and antinuclear antigens, thus allowing immunospreading from antimitochondrial to antinuclear autoimmunity: presentation of the predominant T-cell epitope of mitochondrial protein PDC-E2 can lead to the induction of autoimmune T-cell clones that cross-react with several peptides from gp210 [30].
Please cite this article in press as: Chantran Y, et al. Autoantibodies in primary biliary cirrhosis: Antinuclear envelope autoantibodies. Clin Res Hepatol Gastroenterol (2013), http://dx.doi.org/10.1016/j.clinre.2013.10.008
+Model CLINRE-515; No. of Pages 3
ARTICLE IN PRESS
Autoantibodies in primary biliary cirrhosis: Antinuclear envelope autoantibodies
Conclusion Antinuclear envelope antibodies directed against proteins in the nuclear pore complex are specific antinuclear antibodies in PBC. Easily detected using commercial LIA or ELISA tests, anti-gp210 antibodies constitute a useful diagnostic tool in the event of antimitochondrial negativity, as well as a prognostic marker for poor outcome.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
References [1] Heathcote EJ. AASLD practice guidelines: management of primary biliary cirrhosis. Hepatology 2000:1005—13. [2] Beuers U, Boberg KM, Chapman RW, Chazouilleres O, Invernizzi P, Jones DE, et al. EASL clinical practice guidelines: Management of cholestatic liver diseases. J Hepatol 2009;51:237—67. [3] Ruffatti A, Arslan P, Floreani A, De Silvestro G, Calligaro A, Naccarato R, et al. Nuclear membrane-staining antinuclear antibody in patients with primary biliary cirrhosis. J Clin Immunol 1985;5:357—61. [4] Lozano F, Parés A, Borche L, Plana M, Gallart T, Rodés J, et al. Autoantibodies against nuclear envelope-associated proteins in primary biliary cirrhosis. Hepatology 1988;8:930—8. [5] Courvalin JC, Lassoued K, Bartnik E, Blobel G, Wozniak RW. The 210-kD nuclear envelope polypeptide recognized by human autoantibodies in primary biliary cirrhosis is the major glycoprotein of the nuclear pore. J Clin Invest 1990;86:279—85. [6] Courvalin JC, Lassoued K, Worman HJ, Blobel G. Identification and characterization of autoantibodies against the nuclear envelope lamin B receptor from patients with primary biliary cirrhosis. J Exp Med 1990;172:961—7. [7] Wesierska-Gadek J, Hohenauer H, Hitchman E, Penner E. Autoantibodies against nucleoporin p62 constitute a novel marker of primary biliary cirrhosis. Gastroenterology 1996;110:840—7. [8] Miyachi K, Shibata M, Onozuka Y, Kikuchi F, Imai N, Horigome T. Primary biliary cirrhosis sera recognize not only gp210 but also proteins of p62 complex bearing N-acetylglucosamine residues from rat liver nuclear envelope. Mol Biol Rep 1996;23:227—34. [9] Ou Y, Enarson P, Rattner JB, Barr SG, Fritzler MJ. The nuclear pore complex protein Tpr is a common autoantigen in sera that demonstrate nuclear envelope staining by indirect immunofluorescence. Clin Exp Immunol 2004;136:379—87. [10] Miyachi K, Hankins RW, Matsushima H, Kikuchi F, Inomata T, Horigome T, et al. Profile and clinical significance of antinuclear envelope antibodies found in patients with primary biliary cirrhosis: a multicenter study. J Autoimmun 2003;20:247—54. [11] Nickowitz RE, Worman HJ. Autoantibodies from patients with primary biliary cirrhosis recognize a restricted region within the cytoplasmic tail of nuclear pore membrane glycoprotein Gp210. J Exp Med 1993;178:2237—42. [12] Tartakovsky F, Worman HJ. Detection of Gp210 autoantibodies in primary biliary cirrhosis using a recombinant protein containing the predominant autoepitope. Hepatology 1995;21:495—500. [13] Bandin O, Courvalin JC, Poupon R, Dubel L, Homberg JC, Johanet C. Specificity and sensitivity of gp210 autoantibodies detected using an enzyme-linked immunosorbent assay and a synthetic polypeptide in the diagnosis of primary biliary cirrhosis. Hepatology 1996;23:1020—4.
3
[14] Sfakianaki O, Koulentaki M, Tzardi M, Tsangaridou E, Theodoropoulos PA, Castanas E, et al. Perinuclear antibodies correlate with survival in Greek primary biliary cirrhosis patients. World J Gastroenterol 2010;16:4938—43. [15] Nesher G, Margalit R, Ashkenazi YJ. Antinuclear envelope antibodies: clinical associations. Semin Arthritis Rheum 2001;30:313—20. [16] Bauer A, Habior A. Measurement of gp210 autoantibodies in sera of patients with primary biliary cirrhosis. J Clin Lab Anal 2007;21:227—31. [17] Czaja AJ, Muratori P, Muratori L, Carpentier HA, Bianchi FB. Diagnosic and therapeutic implications of bile duct injury in autoimmune hepatitis. Liver Int 2004;24:322—9. [18] Romero-Gömez M, Wichmann I, Crespo J, Parés A, Rodrigo L, Alvarez A, et al. Serum immunological profile in patients with chronic autoimmune cholestasis. Am J Gastroenterol 2004;99:2150—7. [19] Liu B, Shi XH, Zhang FC, Zhang W, Gao LX. Antimitochondrial antibody-negative primary biliary cirrhosis: a subset of primary biliary cirrhosis. Liver Int 2008;28:333—9. [20] Nakamura M, Kondo H, Mori T, Komori A, Matsuyama M, Ito M, et al. Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis. Hepatology 2007;45:118—27. [21] Nakamura M, Shimizu-Yoshida Y, Takii Y, Komori A, Yokoyama T, Ueki T, et al. Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis. J Hepatol 2005;42:386—92. [22] Dubel L, Farges O, Courvalin JC, Sebagh M, Johanet C. Persistence of gp210 and multiple nuclear dots antibodies does not correlate with recurrence of primary biliary cirrhosis 6 years after liver transplantation. J Hepatol 1998;28: 169—70. [23] Luettig B, Boeker KHW, Schoessler W, Will H, Loges S, Schmidt E, et al. The antinuclear autoantibodies Sp100 and gp210 persist after orthotopic liver transplantation in patients with primary biliary cirrhosis. J Hepatol 1998;28:824—8. [24] Wesierska-Gadek J, Klima A, Komina O, Ranftler C, Invernizzi P, Penner E. Characterization of autoantibodies against components of the nuclear pore complexes. High frequency of anti-p62 nucleoporin antibodies. Ann N Y Acad Sci 2007;1109:519—30. [25] Duarte-Rey C, Bogdanos D, Yang CY, Roberts K, Leung PSC, Anaya JM, et al. Primary biliary cirrhosis and the nuclear pore complex. Autoimmun Rev 2012;11:898—902. [26] Nakamura M, Takii Y, Ito M, Komori A, Yokoyama T, ShimizuYoshida Y. Increased expression of nuclear envelope gp210 antigen in small bile ducts in primary biliary cirrhosis. J Autoimmun 2006;26:138—45. [27] Nakamura M, Yasunami M, Kondo H, Horie H, Aiba Y, Komori A, et al. Analysis of HLA-DRB1 polymorphisms in japanese patients with primary biliary cirrhosis (PBC): the HLA-DRB1 polymorphism determines the relative risk of antinuclear antibodies for disease progression in PBC. Hepatol Res 2010;40: 494—504. [28] Kempinska-podhorodecka A, Shums Z, Wasilewicz M, Wunsch E, Milkiewicz M, Bogdanos DP, et al. TRAF1 gene polymorphism correlates with the titre of gp210 antibody in patients with primary biliary cirrhosis. Clin Dev Immunol 2012;2012:487521, http://dx.doi.org/10.1155/2012/487521. [29] Yang CY, Leung PSC, Yang GX, Kenny TP, Zhang W, Coppel R, et al. Epitope-specific antinuclear antibodies are expressed in a mouse model of primary biliary cirrhosis and are cytokinedependent. Clin Exp Immunol 2012;168:261—7. [30] Shimoda S, Nakamura M, Ishibashi H, Kawano A, Kamihira T, et al. Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis. Gastroenterology 2003;124:1915—25.
Please cite this article in press as: Chantran Y, et al. Autoantibodies in primary biliary cirrhosis: Antinuclear envelope autoantibodies. Clin Res Hepatol Gastroenterol (2013), http://dx.doi.org/10.1016/j.clinre.2013.10.008
