Antinuclear Antibodies in Primary Biliary Cirrhosis

ABSTRACT

Patients with primary biliary cirrhosis (PBC) generate a variety of autoantibodies, which are primarily directed against mitochondrial antigens (AMA). However, a subgroup of patient sera are also positive for antibodies to nuclear components (ANAs). At indirect immunofluorescence (IIF), PBC sera mostly produce homogeneous, nuclear dot, speckled, centromere, or rim-like patterns. During the last two decades, a number of nuclear structures have been recognized as specific targets of ANA in PBC. These include Sp100 and promyelocytic leukemia proteins, which generate a nuclear dot IIF pattern, and two components of the nuclear pore complex specifically associated with a perinuclear pattern (i.e., gp210 and p62). In recent years, the clinical significance of ANA in PBC has been widely investigated and data indicate that, unlike AMAs, PBC-specific ANAs correlate with disease severity and may therefore be a marker of poor prognosis.

KEYWORDS

Autoimmunity - nuclear antigens - nuclear dots - rim-like - prognosis - anti-p62 nucleoporin antibodies - nuclear pore complexes

REFERENCES

• 1 Talwalkar J A, Lindor K D. Primary biliary cirrhosis.  Lancet. 2003;  362 53-61
• 2 Walker J G, Doniach D, Roitt I M, Sherlock S. Serological tests in diagnosis of primary biliary cirrhosis.  Lancet. 1965;  39 827-831
• 3 Van de Water J, Cooper A, Surh C D et al.. Detection of autoantibodies to recombinant mitochondrial proteins in patients with primary biliary cirrhosis.  N Engl J Med. 1989;  320 1377-1380
• 4 Christensen E, Crowe J, Doniach D et al.. Clinical pattern and course of disease in primary biliary cirrhosis based on an analysis of 236 patients.  Gastroenterology. 1980;  78 236-246
• 5 Invernizzi P, Crosignani A, Battezzati P M et al.. Comparison of the clinical features and clinical course of antimitochondrial antibody-positive and -negative primary biliary cirrhosis.  Hepatology. 1997;  25 1090-1095
• 6 Joshi S, Cauch-Dudek K, Heathcote E J et al.. Antimitochondrial antibody profiles: are they valid prognostic indicators in primary biliary cirrhosis?.  Am J Gastroenterol. 2002;  97 999-1002
• 7 Neuberger J, Bradwell A R. Anti-mitochondrial antibodies in primary biliary cirrhosis.  J Hepatol. 2002;  37 712-716
• 8 Invernizzi P, Podda M, Battezzati P M et al.. Autoantibodies against nuclear pore complexes are associated with more active and severe liver disease in primary biliary cirrhosis.  J Hepatol. 2001;  34 366-372
• 9 Itoh S, Ichida T, Yoshida T et al.. Autoantibodies against a 210 kDa glycoprotein of the nuclear pore complex as a prognostic marker in patients with primary biliary cirrhosis.  J Gastroenterol Hepatol. 1998;  13 257-265
• 10 Miyachi K, Hankins R W, Matsushima H et al.. Profile and clinical significance of anti-nuclear envelope antibodies found in patients with primary biliary cirrhosis: a multicenter study.  J Autoimmun. 2003;  20 247-254
• 11 Muratori P, Muratori L, Ferrari R et al.. Characterization and clinical impact of antinuclear antibodies in primary biliary cirrhosis.  Am J Gastroenterol. 2003;  98 431-437
• 12 Rigopoulou E I, Davies E T, Pares A et al.. Prevalence and clinical significance of isotype specific antinuclear antibodies in primary biliary cirrhosis.  Gut. 2005;  54 528-532
• 13 Invernizzi P, Wesierska-Gadek J, Battezzati P M et al.. Prognostic value of autoantibodies against proteins of nuclear pore complexes (anti-NPCs) in early primary biliary cirrhosis (PBC).  J Hepatol. 2004;  40 159-160 , (abst)
• 14 Nakamura M, Shimizu-Yoshida Y, Takii Y et al.. Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis.  J Hepatol. 2005;  42 386-392
• 15 Newport J W, Forbes D J. The nucleus: structure, function, and dynamics.  Annu Rev Biochem. 1987;  56 535-565
• 16 Dundr M, Misteli T. Functional architecture in the cell nucleus.  Biochem J. 2001;  356 297-310
• 17 de The G, Riviere M, Bernhard W. [Examination by electron microscope of the VX2 tumor of the domestic rabbit derived from the Shope papilloma].  Bull Assoc Fr Etud Cancer. 1960;  47 570-584
• 18 Brasch K, Ochs R L. Nuclear bodies (NBs): a newly “rediscovered” organelle.  Exp Cell Res. 1992;  202 211-223
• 19 Spector D L. Nuclear domains.  J Cell Sci. 2001;  114 2891-2893
• 20 Sourvinos G, Everett R D. Visualization of parental HSV-1 genomes and replication compartments in association with ND10 in live infected cells.  EMBO J. 2002;  21 4989-4997
• 21 Eskiw C H, Bazett-Jones D P. The promyelocytic leukemia nuclear body: sites of activity?.  Biochem Cell Biol. 2002;  80 301-310
• 22 Negorev D, Maul G G. Cellular proteins localized at and interacting within ND10/PML nuclear bodies/PODs suggest functions of a nuclear depot.  Oncogene. 2001;  20 7234-7242
• 23 Maul G G, Negorev D, Bell P, Ishov A M. Review: properties and assembly mechanisms of ND10, PML bodies, or PODs.  J Struct Biol. 2000;  129 278-287
• 24 Seeler J S, Dejean A. The PML nuclear bodies: actors or extras?.  Curr Opin Genet Dev. 1999;  9 362-367
• 25 Daniel M T, Koken M, Romagne O et al.. PML protein expression in hematopoietic and acute promyelocytic leukemia cells.  Blood. 1993;  82 1858-1867
• 26 Szostecki C, Krippner H, Penner E, Bautz F A. Autoimmune sera recognize a 100 kD nuclear protein antigen (sp-100).  Clin Exp Immunol. 1987;  68 108-116
• 27 Dent A L, Yewdell J, Puvion-Dutilleul F et al.. LYSP100-associated nuclear domains (LANDs): description of a new class of subnuclear structures and their relationship to PML nuclear bodies.  Blood. 1996;  88 1423-1426
• 28 Pitkanen J, Doucas V, Sternsdorf T et al.. The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein.  J Biol Chem. 2000;  275 16802-16809
• 29 Sternsdorf T, Jensen K, Reich B, Will H. The nuclear dot protein sp100, characterization of domains necessary for dimerization, subcellular localization, and modification by small ubiquitin-like modifiers.  J Biol Chem. 1999;  274 12555-12566
• 30 Guldner H H, Szostecki C, Schroder P et al.. Splice variants of the nuclear dot-associated Sp100 protein contain homologies to HMG-1 and a human nuclear phosphoprotein-box motif.  J Cell Sci. 1999;  112(pt 5) 733-747
• 31 Rogalla P, Kazmierczak B, Flohr A M et al.. Back to the roots of a new exon-the molecular archaeology of a SP100 splice variant.  Genomics. 2000;  63 117-122
• 32 Seeler J S, Marchio A, Sitterlin D et al.. Interaction of SP100 with HP1 proteins: a link between the promyelocytic leukemia-associated nuclear bodies and the chromatin compartment.  Proc Natl Acad Sci USA. 1998;  95 7316-7321
• 33 Guldner H H, Szostecki C, Grotzinger T, Will H. IFN enhance expression of Sp100, an autoantigen in primary biliary cirrhosis.  J Immunol. 1992;  149 4067-4073
• 34 Sternsdorf T, Jensen K, Will H. Evidence for covalent modification of the nuclear dot-associated proteins PML and Sp100 by PIC1/SUMO-1.  J Cell Biol. 1997;  139 1621-1634
• 35 Gerace L, Burke B. Functional organization of the nuclear envelope.  Annu Rev Cell Biol. 1988;  4 335-374
• 36 Ye Q, Worman H J. Primary structure analysis and lamin B and DNA binding of human LBR, an integral protein of the nuclear envelope inner membrane.  J Biol Chem. 1994;  269 11306-11311
• 37 Gerace L, Comeau C, Benson M. Organization and modulation of nuclear lamina structure.  J Cell Sci Suppl. 1984;  1 137-160
• 38 Fisher D Z, Chaudhary N, Blobel G. cDNA sequencing of nuclear lamins A and C reveals primary and secondary structural homology to intermediate filament proteins.  Proc Natl Acad Sci USA. 1986;  83 6450-6454
• 39 McKeon F D, Kirschner M W, Caput D. Homologies in both primary and secondary structure between nuclear envelope and intermediate filament proteins.  Nature. 1986;  319 463-468
• 40 Kaufmann S H. Additional members of the rat liver lamin polypeptide family. Structural and immunological characterization.  J Biol Chem. 1989;  264 13946-13955
• 41 Heald R, McKeon F. Mutations of phosphorylation sites in lamin A that prevent nuclear lamina disassembly in mitosis.  Cell. 1990;  61 579-589
• 42 Nigg E A. Assembly and cell cycle dynamics of the nuclear lamina.  Semin Cell Biol. 1992;  3 245-253
• 43 Pante N, Aebi U. The nuclear pore complex.  J Cell Biol. 1993;  122 977-984
• 44 Greber U F, Senior A, Gerace L. A major glycoprotein of the nuclear pore complex is a membrane-spanning polypeptide with a large lumenal domain and a small cytoplasmic tail.  EMBO J. 1990;  9 1495-1502
• 45 Wozniak R W, Bartnik E, Blobel G. Primary structure analysis of an integral membrane glycoprotein of the nuclear pore.  J Cell Biol. 1989;  108 2083-2092
• 46 Davis L I, Blobel G. Nuclear pore complex contains a family of glycoproteins that includes p62: glycosylation through a previously unidentified cellular pathway.  Proc Natl Acad Sci USA. 1987;  84 7552-7556
• 47 D’Onofrio M, Starr C M, Park M K et al.. Partial cDNA sequence encoding a nuclear pore protein modified by O-linked N-acetylglucosamine.  Proc Natl Acad Sci USA. 1988;  85 9595-9599
• 48 Starr C M, D'Onofrio M, Park M K, Hanover J A. Primary sequence and heterologous expression of nuclear pore glycoprotein p62.  J Cell Biol. 1990;  110 1861-1871
• 49 Carmo-Fonseca M, Kern H, Hurt E C. Human nucleoporin p62 and the essential yeast nuclear pore protein NSP1 show sequence homology and a similar domain organization.  Eur J Cell Biol. 1991;  55 17-30
• 50 Starr C M, Hanover J A. Glycosylation of nuclear pore protein p62. Reticulocyte lysate catalyzes O-linked N-acetylglucosamine addition in vitro.  J Biol Chem. 1990;  265 6868-6873
• 51 Cordes V C, Reidenbach S, Rackwitz H R, Franke W W. Identification of protein p270/Tpr as a constitutive component of the nuclear pore complex-attached intranuclear filaments.  J Cell Biol. 1997;  136 515-529
• 52 Szostecki C, Guldner H H, Netter H J, Will H. Isolation and characterization of cDNA encoding a human nuclear antigen predominantly recognized by autoantibodies from patients with primary biliary cirrhosis.  J Immunol. 1990;  145 4338-4347
• 53 Szostecki C, Will H, Netter H J, Guldner H H. Autoantibodies to the nuclear Sp100 protein in primary biliary cirrhosis and associated diseases: epitope specificity and immunoglobulin class distribution.  Scand J Immunol. 1992;  36 555-564
• 54 Muratori P, Muratori L, Cassani F et al.. Anti-multiple nuclear dots (anti-MND) and anti-SP100 antibodies in hepatic and rheumatological disorders.  Clin Exp Immunol. 2002;  127 172-175
• 55 Wichmann I, Montes-Cano M A, Respaldiza N et al.. Clinical significance of anti-multiple nuclear dots/Sp100 autoantibodies.  Scand J Gastroenterol. 2003;  38 996-999
• 56 Bogdanos D P, Vergani D, Muratori P et al.. Specificity of anti-sp100 antibody for primary biliary cirrhosis.  Scand J Gastroenterol. 2004;  39 405-407
• 57 Rigopoulou E I, Dalekos G N. Anti-sp100 antibodies in primary biliary cirrhosis.  Scand J Gastroenterol. 2004;  39 406-407
• 58 Zuchner D, Sternsdorf T, Szostecki C et al.. Prevalence, kinetics, and therapeutic modulation of autoantibodies against Sp100 and promyelocytic leukemia protein in a large cohort of patients with primary biliary cirrhosis.  Hepatology. 1997;  26 1123-1130
• 59 Sternsdorf T, Guldner H H, Szostecki C et al.. Two nuclear dot-associated proteins, PML and Sp100, are often co-autoimmunogenic in patients with primary biliary cirrhosis.  Scand J Immunol. 1995;  42 257-268
• 60 Janka C, Selmi C, Gershwin M E et al.. Small ubiquitin-related modifiers: a novel and independent class of autoantigens in primary biliary cirrhosis.  Hepatology. 2005;  41 609-616
• 61 Lozano F, Pares A, Borche L et al.. Autoantibodies against nuclear envelope-associated proteins in primary biliary cirrhosis.  Hepatology. 1988;  8 930-938
• 62 Lassoued K, Brenard R, Degos F et al.. Antinuclear antibodies directed to a 200-kilodalton polypeptide of the nuclear envelope in primary biliary cirrhosis. A clinical and immunological study of a series of 150 patients with primary biliary cirrhosis.  Gastroenterology. 1990;  99 181-186
• 63 Courvalin J C, Lassoued K, Bartnik E et al.. 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;  86 279-285
• 64 Nickowitz R E, Worman H J. 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 2237-2242
• 65 Wesierska-Gadek J, Hohenauer H, Hitchman E, Penner E. Autoantibodies from patients with primary biliary cirrhosis preferentially react with the amino-terminal domain of nuclear pore complex glycoprotein gp210.  J Exp Med. 1995;  182 1159-1162
• 66 Wesierska-Gadek J, Hohenauer H, Hitchman E, Penner E. Autoantibodies against constituents of nuclear pore complexes in patients with primary biliary cirrhosis and autoimmune hepatitis.  Acta Biochim Pol. 1995;  42 197-200
• 67 Wesierska-Gadek J, Hohenauer H, Hitchman E, Penner E. Anti-gp210 antibodies in sera of patients with primary biliary cirrhosis. Identification of a 64 kD fragment of gp210 as a major epitope.  Hum Antibodies Hybridomas. 1996;  7 167-174
• 68 Wesierska-Gadek J, Hohenuer H, Hitchman E, Penner E. Autoantibodies against nucleoporin p62 constitute a novel marker of primary biliary cirrhosis.  Gastroenterology. 1996;  110 840-847
• 69 Miyachi K, Shibata M, Onozuka Y et al.. Primary biliary cirrhosis sera recognize not only gp210 but also proteins of the p62 complex bearing N-acetylglucosamine residues from rat liver nuclear envelope. Anti-p62 complex antibody in PBC.  Mol Biol Rep. 1996;  23 227-234
• 70 Kraemer D M, Kraus M R, Kneitz C, Tony H P. Nucleoporin p62 antibodies in a case of mixed connective tissue disease.  Clin Diagn Lab Immunol. 2003;  10 329-331
• 71 Cordes V, Waizenegger I, Krohne G. Nuclear pore complex glycoprotein p62 of Xenopus laevis and mouse: cDNA cloning and identification of its glycosylated region.  Eur J Cell Biol. 1991;  55 31-47
• 72 Buss F, Kent H, Stewart M et al.. Role of different domains in the self-association of rat nucleoporin p62.  J Cell Sci. 1994;  107(pt 2) 631-638
• 73 Wesierska-Gadek J, Penner E, Hitchman E, Sauermann G. Antibodies to nuclear lamins in autoimmune liver disease.  Clin Immunol Immunopathol. 1988;  49 107-115
• 74 Bandin O, Courvalin J C, Poupon R et al.. 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 1020-1024
• 75 Ou Y, Enarson P, Rattner J B et al.. The nuclear pore complex protein Tpr is a common autoantigen in sera that demonstrate nuclear envelope staining by indirect immunofluorescence.  Clin Exp Immunol. 2004;  136 379-387
• 76 Courvalin J C, Lassoued K, Worman H J, Blobel G. Identification and characterization of autoantibodies against the nuclear envelope lamin B receptor from patients with primary biliary cirrhosis.  J Exp Med. 1990;  172 961-967
• 77 Lin F, Noyer C M, Ye Q et al.. Autoantibodies from patients with primary biliary cirrhosis recognize a region within the nucleoplasmic domain of inner nuclear membrane protein LBR.  Hepatology. 1996;  23 57-61
• 78 Fida S, Myers M A, Whittingham S et al.. Autoantibodies to the transcriptional factor SOX13 in primary biliary cirrhosis compared with other diseases.  J Autoimmun. 2002;  19 251-257
• 79 Kasimiotis H, Myers M A, Argentaro A et al.. Sex-determining region Y-related protein SOX13 is a diabetes autoantigen expressed in pancreatic islets.  Diabetes. 2000;  49 555-561
• 80 Fida S, Myers M, Mackay I R et al.. Antibodies to diabetes-associated autoantigens in Indian patients with Type 1 diabetes: prevalence of anti-ICA512/IA2 and anti-SOX13.  Diabetes Res Clin Pract. 2001;  52 205-211
• 81 Dickson E R, Grambsch P M, Fleming T R et al.. Prognosis in primary biliary cirrhosis: model for decision making.  Hepatology. 1989;  10 1-7
• 82 Nickowitz R E, Wozniak R W, Schaffner F, Worman H J. Autoantibodies against integral membrane proteins of the nuclear envelope in patients with primary biliary cirrhosis.  Gastroenterology. 1994;  106 193-199
• 83 Yang W H, Yu J H, Nakajima A et al.. Do antinuclear antibodies in primary biliary cirrhosis patients identify increased risk for liver failure?.  Clin Gastroenterol Hepatol. 2004;  2 1116-1122
• 84 Miyakawa H, Tanaka A, Kikuchi K et al.. Detection of antimitochondrial autoantibodies in immunofluorescent AMA-negative patients with primary biliary cirrhosis using recombinant autoantigens.  Hepatology. 2001;  34 243-248