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World J Gastroenterol. 2010 August 7; 16(29): 3616–3629.
Published online 2010 August 7. doi:  10.3748/wjg.v16.i29.3616
PMCID: PMC2915421

Primary biliary cirrhosis: What do autoantibodies tell us?

Abstract

Primary biliary cirrhosis (PBC) is a chronic, progressive, cholestatic, organ-specific autoimmune disease of unknown etiology. It predominantly affects middle-aged women, and is characterized by autoimmune-mediated destruction of small- and medium-size intrahepatic bile ducts, portal inflammation and progressive scarring, which without proper treatment can ultimately lead to fibrosis and hepatic failure. Serum autoantibodies are crucial tools for differential diagnosis of PBC. While it is currently accepted that antimitochondrial antibodies are the most important serological markers of PBC, during the last five decades more than sixty autoantibodies have been explored in these patients, some of which had previously been thought to be specific for other autoimmune diseases.

Keywords: Primary biliary cirrhosis, Autoimmune disease, Autoantibody, Anti-mitochondrial antibody, Anti-gp210 antibody, Anti-sp100 antibody, Anti-centromere antibodies

INTRODUCTION

Primary biliary cirrhosis (PBC) is a progressive autoimmune liver disease characterized by infiltration of lymphocytes in portal tracts, progressive destruction of intrahepatic small bile ducts and the presence of serum antimitochondrial antibodies (AMA)[1,2]. As is the case for the majority of autoimmune diseases, PBC affects predominantly women. Recent investigations have suggested that PBC, sometimes asymptomatic, is not a rare disease. During the last several years advanced biochemical assays, further delineation of specific liver histological findings, more effective serum autoantibody detection methods and improved diagnostic abilities have led to higher prevalence estimates worldwide[3-5]. Currently it is believed that PBC is likely to be triggered by a combination of environmental factors including infection in a genetically susceptible individual. This hypothesis is supported by the high concordance rate of PBC among first-degree relatives and in homozygous twins (approximately 60%)[6,7]. Specific immunologic damage to biliary epithelium and a mechanism of tissue destruction in PBC has been elucidated[8,9]. In addition, epitopes of T cells and B cells targeting mitochondrial autoantigens have been identified[10-12]. Furthermore, a number of autoantibodies previously thought to be specific markers for another autoimmune disease have been detected in patients with PBC.

Disease progression and clinical manifestations in PBC varies. The fact that a variety of autoantibodies have been detected in PBC suggests the disease has a complicated pathogenesis. In this review, the properties of these autoantibodies and their autoantigen characteristics, as well as their pathogenetic and clinical significance were discussed.

AMA

The presence of AMA is pathognomonic for PBC[13], and it is generally accepted that AMA can be detected in serum years before the advent of any clinical manifestation or biochemical abnormality[14-16]. AMA were first described in 1958[17] in sera from patients with chronic liver disorders and then detected by Walker et al[18] in 1965 using an immunofluorescence test. In the past 40 years an enormous number of experimental studies have focused on AMA, and numerous rewarding discoveries have been made. There are nine subtypes of AMA, four of which have been involved in PBC, including anti-M2, anti-M4, anti-M8 and anti-M9. It has been demonstrated that the autoantigens recognized by anti-M2 are located in the inner membranes of mitochondria, whereas those recognized by anti-M4, anti-M8 and anti-M9 are located in the outer mitochondrial membranes. Anti-M9 can be detected in both anti-M2-positive and -negative PBC patients, while anti-M4 is only positive in the presence of anti-M2. All four of these AMA subtypes are relatively specific for the diagnosis of PBC.

Anti-M2

M2 has been found to contain five antigenic determinants, with molecular weights of 70 kDa (a), 56 kDa (b), 51 kDa (c) 45 kDa (d) and 36 kDa (e), all of which were identified subsequently as members of the 2-oxoacid dehydrogenase complex of enzymes within the mitochondrial respiratory chain, including the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the E2 subunit of the branched-chain 2-oxoacid dehydrogenase complex, the E2 subunit of the 2-oxoglutarate dehydrogenase complex, E1t alfa subunits of PDC and E3 binding protein (protein X)[19,20]. The exact molecular weight of the M2 band differs among laboratories according to mitochondria species being used and specifics of techniques for antigen preparation and detection. In patients with PBC, approximately 90%-95% of serum samples react against PDC-E2, making this the most important autoantigen in the disease. Anti-M2 is the most important subtype used in routine diagnostic tests for PBC. Its level in affected sera is high and it also exists in other body fluids such as saliva and bile[21-23]. As AMA is considered to be the hallmark of PBC, a positive test is potentially diagnostic, or at least indicative that the individual is at increased risk for future development of PBC[15].

Anti-M4

The anti-M4 antibody was originally detected in patients with chronic cholestatic liver disease (mixed form) associated with two different types of complement-fixing AMA[24]. M4 is a single antigen with molecular weight of 52 kDa. It can be detected by a complement fixation test but not immunoblotting. Unlike M2, the M4 antigen is trypsin-insensitive and its band at sucrose densities is 1.08 to 1.14. Anti-M4 is found predominantly in patients with histological features of chronic active hepatitis and PBC. Recent studies have identified the major proteins in the M4 fraction which is related to the PDC-E1 subunits and sulphite oxidase[25,26].

Anti-M8

The M8 antigen is also trypsin-sensitive with a band at sucrose densities of 1.16 to 1.24. Anti-M8 has been found only in coexistence with anti-M2, the presence of anti-M8 indicates progressive disease activity. On the other hand, not all anti-M2-positive patients have anti-M8. Like M4, the M8 antigen also locates in the outer mitochondrial membranes[27].

Anti-M9

Anti-M9 antibody was accidentally found when testing anti-M2-positive sera against trypsinized submitochondrial particles from rat liver shown to be devoid of anti-M2[28]. Anti-M9 antibody is detected predominantly in patients with asymptomatic and early PBC, and it also can be positive in anti-M2-negative PBC patients. Unlike anti-M4 and anti-M8, which seem to reflect disease activity, anti-M9 antibody occurs early in PBC. Patients with only anti-M9 have all the typical biochemical features found in classic anti-M2-positive patients, but seem to have slower disease progression and benign outcome, whereas patients having complement-fixing antibodies against anti-M2, anti-M4, and anti-M8 seem to have more active disease and worse outcome[29-31], though this finding wasn’t supported by a blinded study on Dutch PBC patients conducted by Vleggaar et al[32].

ROLE OF AMA IN PBC PATHOGENESIS

Although AMA serve as highly sensitive markers for the diagnosis of PBC, autoantibodies against various mitochondrial enzymes can frequently be detected in patients with other diseases, such as primary Sjögren’s syndrome (pSS), scleroderma, autoimmune hepatitis[33,34] and some infectious diseases like tuberculosis and viral hepatitis[35-38]. It is very interesting that the prevalence of AMA in first-degree relatives of PBC probands is as high as 13.1%, whereas in gender, age, race, and residence-matched controls the prevalence is only 1%, suggesting that environmental risks and genetic determinants are likely implicated in the etiology of PBC[7].

As no clinical correlation can be found, and animal models with serum AMA do not consistently have PBC-like liver lesions, the exact role played by AMA in the immunopathology and pathogenesis of PBC remains elusive. However, current data indicate that the destruction of biliary cells is mediated by liver-infiltrating autoreactive T cells specific for the dominant PDC-E2 autoantigen[39]. The dominant epitopes of autoreactive T and B cells have been identified. The CD4+ T cell epitope appears to localize to peptides 163-176, the CD8+ T cell epitope appears to localize to peptides 159-167, while the B cell epitope appears to localize to peptides 167-186[39-43]. Furthermore, the most prominent immune features of autoreactive CD4+ and CD8+ T cells can be detected in peripheral blood from patients with PBC. The disease-related AMA-specific CD8+ T cells are enriched up to about 10-fold and the CD4+ T cells are enriched up to more than 100-fold in liver compared to peripheral blood samples[42,44]. Presently the data suggest that B and T cells in PBC patients respond simultaneously to the same autoantigen, and that both are involved in the pathogenesis of PBC.

Study of stored sera of well-characterized PBC patients followed for 7-28 years indicate that AMA levels are not associated with disease severity and progression. Most studies except the one conducted by Poupon et al[45] did not support that AMA levels could be affected by treatments during the observation period[45-47]. In fact, low levels of AMA persisted for up to 11 years following liver transplantation[47]. AMA are non-organ- and non-species-specific, and contain IgA, IgG and IgM subclasses. Data from PBC patients demonstrate that the presence of AMA IgA in sera or saliva might be associated with disease progression[23] and some studies suggested that greater concentrations of AMA IgA in biliary and mucosal secretions, constant transcytosis, would render the exposed cells more susceptible to apoptosis resulting in subsequent bile duct damage[48], while others proposed the hypothesis that AMA IgA can be transported to the vascular side of the bile duct cell where it can induce apoptosis by reacting with PDC-E2-like molecules located on the luminal surface cell membrane[49]. Many studies have demonstrated that the different AMA IgG subclasses have different clinical significance. PBC patients positive for IgG3 AMA had histologically more advanced disease and were more frequently cirrhotic than those who were negative. Furthermore, there was a positive correlation between AMA IgG3 titers and Mayo risk scores: this subclass is associated with poor prognosis, possibly reflecting the peculiar ability of this isotype to engage mediators of immunological damage[50].

Currently it is believed that a positive AMA titer is virtually pathognomonic of current PBC or risk for future development of the disorder, although the mechanisms leading to the generation of AMA have not been elucidated. Several possible mechanisms have been suggested regarding the generation of AMA, such as oxidative damage, molecular mimicry and changed biliary epithelial cell (BEC) apoptosis[51,52]. The fact that high levels of AMA can be detected in patients with acute liver failure supports the hypothesis that oxidative stress-induced liver damage may lead to induction of AMA[53]. But it is also surprisingly true that the AMA in these patients disappear rapidly, suggesting the pathogenesis of PBC is multifactorial. It has been demonstrated that molecular mimicry between bacterial or viral antigens and mitochondrial antigens can trigger the generation of AMA in PBC[54,55]. Modification of the inner lipoyl domain of E2 with halide or ethyl halide results in increased reactivity of AMA from PBC patients, suggesting that xenobiotics might make cellular components antigenic[56].

There is growing evidence showing that the onset of PBC may be the result of inefficient removal of apoptotic cells. It is of interest to note that a recent report proposed that PDC-E2 in patients with PBC is released without caspase cleavage from apoptotic BEC, supported by the fact that glutathionylation of the lysine lipoic acid moiety on the PDC-E2 is sometimes, though not commonly, decreased by serum AMA via Bcl-2[57]. Other studies show that apoptotic cells are phagocytosed by BECs, a function mediated by anti-CD16, and so consequently act as an exogenous source of autoantigens in cholangiocytes[9,58]. Defects in the elimination of apoptotic cells can lead to secondary necrosis accompanied by subsequent release of intracellular components, which might explain the generation of autoantibodies against intracellular antigens like AMA[59].

Further studies in the field of AMA in PBC have led to speculation about the existence of an AMA-negative PBC subgroup. It is not clear whether there is indeed such a subgroup, having distinct features, or if this is an artifact due to technical limitations of current AMA detection methods leading to false-negative results in some PBC patients[60]. Present data indicate that there is no discernable difference between AMA-positive and -negative PBC in terms of clinical manifestations, liver biochemistry and histopathology findings, disease course, as well as response to treatment[61-63]. As more sensitive and specific serologic tests are applied, many patients initially believed to be AMA-negative are subsequently found to be AMA-positive[64,65]. These findings cast doubt on the existence of a true AMA-negative PBC subgroup.

ANTINUCLEAR ANTIBODIES IN PBC

Antinuclear dot antibodies (SP100, PML, NDP52 and SP140)

PBC patients often have autoantibodies with nuclear dot (ND) stain patterns in the indirect immunofluorescence (IIF) assay. The major antigens associated with ND are as follows: sp100 proteins, which are transcription-activating proteins autoantigenic primarily in patients with PBC and occasionally in rheumatic disorders[66,67]; promyelocytic leukemia (PML) protein, a transformation and cell-growth suppressing protein aberrantly expressed in PML cells that was discovered in studies of the development of acute PML; NDP52, a protein of the myosin VI binding partners which was previously shown to contribute to innate immunity[68,69]; and sp140 proteins, which are identified as autoantigenic proteins in PBC recently. Sp100 and PML were discovered in the context of leukemic transformation and as autoantigens in PBC[70]. They are reported to be co-autoimmunogenic, often in patients with PBC[71]. The sp100 antigen was described by Szostecki et al[66] as a peptide of 480 amino acids with an aberrant electrophoretic mobility to 100 kDa, and a calculated molecular weight of 53 kDa. It was subsequently characterized by complementary DNA cloning, and the deduced amino acid sequence was found to contain sequence similarities with HIV-1 nef proteins[72]. The prevalence of anti-sp100 antibodies in PBC is about 25%, and it appears to be highly specific for a diagnosis of PBC, but only when other diseases can be excluded and the typical clinical context is present[73,74]. The presence of anti-sp100 antibodies serves as a serologic marker of PBC, which could be useful in clinics to confirm the diagnosis, especially in AMA-negative PBC patients[75,76]. Recent data indicate that as reports of AMA-negative PBC decrease due to development of more sensitive and specific serologic tests for serum AMA, anti-sp100 antibodies appear to be more common in AMA-positive PBC patients than in those who are AMA-negative[77,78]. Also, anti-sp100 antibodies are increasingly found to be present in many clinical conditions, such as systemic lupus erythematosus (SLE) and pSS. It is of interest to note that among female patients with urinary tract infections but no liver disease, 80% of the AMA-positive, but none of the AMA-negative patients were also positive for anti-sp100 antibodies. It is also well established that among PBC patients, about 74% of patients with urinary tract infections were positive for anti-sp100, whereas the positivity was only 4.8% in PBC patients without urinary tract infections[79]. Given the high specificity of anti-sp100 as an immunoserological hallmark of PBC, these findings support the hypothesis that some infections such as Escherichia coli are involved in the induction of PBC-specific autoimmunity.

PML protein was discovered in cells of patients with acute PML as a protein fused with the retinoic acid receptor-a (RAR)[80,81]. PML protein functions as a nuclear hormone receptor transcriptional coactivator[82]. Subsequently it was shown to form ND patterns when tested by immunofluorescence microscopy with serum anti-PML antibodies from PBC patients. Anti-PML antibodies often coexist with anti-sp100 antibodies in individuals with PBC[71], and are present in about 19% of PBC patients[83]. Current study indicates that anti-PML antibodies are highly specific for PBC even when autoantibodies against mitochondrial antigens are not found[84].

Anti-sp140 antibodies were recently identified for the first time in patients with PBC by Granito et al[85]. They are present in about 15% of PBC patients and are highly specific for PBC. Anti-sp140 antibodies coexist with anti-sp100 and anti-PML antibodies. No association was found between anti-sp140 and any particular clinical feature of PBC.

Antinuclear pore antibodies (gp210 and p62)

In addition to AMA, a number of nuclear antigens have been recognized as targets of antinuclear antibodies (ANA) in patients with PBC, including several components of the nuclear pore complex (NPC), such as the gp210 and p62 proteins. These antibodies have a nuclear periphery fluorescence pattern in the IIF assay, as first reported by Ruffatti et al[86] in 1985. Several reports revealed that the frequency of PBC-specific nuclear envelope antibodies ranged from 16% to 30%[76,87], and that the frequency increased greatly when fluorescent-labeled specific antiserum of the IgG subclass was applied[88,89]. In 1990 a study by Lassoued et al[90] showed that autoantibodies from patients with PBC having a punctate fluorescence pattern in IIF react with a protein of molecular mass approximately 200 kDa, which was identified as the NPC membrane protein gp210[91]. Gp210 is an integral glycoprotein of the nuclear pore consisting of three main domains: a large glycosylated luminal domain, a single hydrophobic transmembrane segment and a short cytoplasmic tail. Gp210 is recognized by antibodies in approximately 25% of patients with PBC[92]. The gp210 epitope recognized by most of the autoantibodies is a 15 amino acid stretch in the cytoplasmic, carboxyl-terminal domain of the protein. In the ANA category, these anti-gp210 antibodies are particularly significant since they are highly specific for PBC[93,94]. In addition, several reports link the presence of anti-gp210 antibodies in PBC patients with disease severity and poor prognosis. Since the presence of anti-gp210 antibodies correlates with an unfavorable disease course and more rapid progression, it is useful for monitoring the effect of ursodeoxycholic acid and for the early identification of patients at high risk for end-stage hepatic failure, and so may potentially become an important prognostic marker in PBC patients[95,96]. Findings to date clearly indicate that anti-gp210 antibodies having the best predictive value regarding progression to end-stage hepatic failure. The proposed mechanism for this predictive role is based on the following hypothesis that the breakdown of immunological tolerance to mitochondrial antigens such as PDC-E2 is not enough for the progression to hepatic failure, whereas the breakdown of immunological tolerance to nuclear antigens such as gp210, in which molecular mimicry is involved as well as increased and aberrant expression of gp210 in small bile ducts, may play a crucial role[97].

A few years after the discovery of anti-gp210 antibodies in PBC, reactivity of PBC sera with a 60 kDa component of NPC was reported. Anti-p62 antibodies, which also generate a perinuclear pattern in IIF, were first described in 1987[98-100]. They occur as frequently as the anti-gp210 glycoprotein autoantibodies[101], and with a specificity for PBC of up to 97%. Anti-p62 antibodies reacting with the 60 kDa component localize to the NPC. The frequency of anti-p62 antibodies in PBC is about 30%-55%. Their presence in PBC is not associated with AMA, but is associated with disease progression. Data from a multicenter study indicated that anti-p62 complex antibodies might be related to the progressive or advanced stage of PBC[99,102], that their prevalence is higher in symptomatic patients and that they are associated with more severe disease, defined as the presence of cirrhosis or its complications. In addition, it has been reported that anti-p62-positive patients have higher levels of serum bilirubin and more marked inflammatory infiltrates on liver biopsy[87].

Antinuclear envelope antibodies (Lamin and Lamin B receptor)

The nuclear envelope is a bilayered membranous structure that can be divided into five distinct components: the inner nuclear membrane, having a distinct set of integral membrane proteins; the outer nuclear membrane; a perinuclear space, which is continuous with the lumen of the endoplasmic reticulum; the pore domains, regions where the inner nuclear membrane and outer nuclear membrane come together and fuse; and an underlying nuclear lamina, containing the nuclear lamins[103]. A smooth membrane fluorescence pattern is characteristic of the presence of antibodies to nuclear lamins in IIF using sera from PBC patients. Three subtypes of anti-lamin antibodies have been described: anti-lamin A, B and C[102,104-106]. Anti-lamin antibodies do not seem to be disease-specific as they are found in patients with several different autoimmune disorders, such as SLE, chronic fatigue syndrome, and PBC[107-110]. Anti-lamin A, B and C antibodies are detected with frequencies of 6%-8% in sera from patients with PBC. The usual scenario is to find anti-lamin A and C together, and less frequently either anti-lamin B alone or all three in the same patient[111].

Lamin B receptor (LBR) is a protein integral to the inner nuclear membrane with a nucleoplasmic, amino-terminal domain of 208 amino acids, followed by a carboxyl-terminal domain with eight putative transmembrane segments. Anti-LBR antibodies from PBC patients recognize the nucleoplasmic, amino-terminal domain but not the carboxyl-terminal domain. Anti-LBR antibodies appear to be highly specific for PBC, but their clinical significance is unclear. The prevalence of anti-LBR antibodies in PBC is approximately 2%-6%[76,102,112,113].

Anti-centromere antibodies

Anti-centromere antibodies (ACA) are important diagnostic markers of systemic sclerosis (SSc), found in about 25% of these patients[114]. In patients with CREST syndrome or limited cutaneous SSc, the positivity rises to 50%-90%. ACA in SSc are usually associated with a good prognosis, though they are not specific for SSc. ACA can be detected in patients with other rheumatic diseases including pSS, SLE and PBC (about 30%)[115-120]. It is of interest to note that several subtypes of ACA have been identified, including anti-CENP-A, anti-CENP-B, anti-CENP-C and anti-CENP-O antibodies[121]. Research during the past several years has found that prevalence of the ACA subtypes differs among various autoimmune diseases[122]. Recent studies have demonstrated that ACA positivity in patients with PBC is of significant predictive value for progression to portal hypertension[123,124].

OTHER AUTOANTIBODIES DETECTED IN PBC

Although extensive research has focused on AMA, it is of interest to note that, to date, more than sixty different autoantibodies have been found in PBC patients. Some target at nuclear or cytoplasmic molecules and cell membranes, while others react with lipid components. Some, like AMA, occur frequently and almost universally in PBC, while others, like anti-lamin and anti-LBR, are present in only a few patients. It should be noted that among these autoantibodies, some are not specific for any disease, and some are thought to be more closely related to other autoimmune diseases, such as anti-CCP which is relatively specific for rheumatoid arthritis[125,126]. Prevalence and properties of these autoantibodies in PBC are summarized in Table Table11.

Table 1
Autoantibodies in primary biliary cirrhosis that are closely related to other autoimmune diseases

CONCLUSION

The presence of serum autoantibodies is characteristic of PBC, and is useful in the clinical diagnostic process in combination with histology and imaging studies. Numerous autoantibodies are found in sera from patients with PBC. This suggests that the development of PBC is a multi-factorial process. With growing numbers of clinical studies of autoimmune diseases and extensive application of more sensitive testing methods for antibodies, it has gradually been realized that the association between an individual autoantibody and autoimmune disease is not as specific as previously thought. AMA is very sensitive and anti-gp210 and anti-sp100 are highly specific for PBC. Other antibodies found in PBC, such as ACA, ASCA, ANCA and anti-sm, could also be found in other autoimmune diseases[131,161,162,168]. Although some autoantibodies are believed to be associated with the pathogenesis of PBC, these associations are likely to be extremely complicated and surely exert complex effects in many different ways. It is hard to understand these delicate associations based on our current knowledge of PBC, and further advanced studies are required to elucidate the pathogenesis of this autoimmune disease.

Footnotes

Peer reviewers: Christopher O’Brien, MD, Professor of Clinical Medicine, Chief of Clinical Hepatology, Center for Liver Diseases, Division of Liver and GI Transplantation, University of Miami School of Medicine, 1500 Northwest 12th Ave., Suite #1101, Miami, FL 33136, United States; Dr. Ulrich Beuers, Professor, Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, PO Box 22700, NL-1100 Amsterdam, The Netherlands; Atsushi Tanaka, MD, PhD, Associate Professor, Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8605, Japan

S- Editor Tian L L- Editor O’Neill M E- Editor Zheng XM

References

1. Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353:1261–1273. [PubMed]
2. Prince M, Chetwynd A, Newman W, Metcalf JV, James OF. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology. 2002;123:1044–1051. [PubMed]
3. Kim WR, Lindor KD, Locke GR 3rd, Therneau TM, Homburger HA, Batts KP, Yawn BP, Petz JL, Melton LJ 3rd, Dickson ER. Epidemiology and natural history of primary biliary cirrhosis in a US community. Gastroenterology. 2000;119:1631–1636. [PubMed]
4. Selmi C, Invernizzi P, Zuin M, Podda M, Gershwin ME. Genetics and geoepidemiology of primary biliary cirrhosis: following the footprints to disease etiology. Semin Liver Dis. 2005;25:265–280. [PubMed]
5. Prince MI, James OF. The epidemiology of primary biliary cirrhosis. Clin Liver Dis. 2003;7:795–819. [PubMed]
6. Selmi C, Mayo MJ, Bach N, Ishibashi H, Invernizzi P, Gish RG, Gordon SC, Wright HI, Zweiban B, Podda M, et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology. 2004;127:485–492. [PubMed]
7. Lazaridis KN, Juran BD, Boe GM, Slusser JP, de Andrade M, Homburger HA, Ghosh K, Dickson ER, Lindor KD, Petersen GM. Increased prevalence of antimitochondrial antibodies in first-degree relatives of patients with primary biliary cirrhosis. Hepatology. 2007;46:785–792. [PubMed]
8. Allina J, Hu B, Sullivan DM, Fiel MI, Thung SN, Bronk SF, Huebert RC, van de Water J, LaRusso NF, Gershwin ME, et al. T cell targeting and phagocytosis of apoptotic biliary epithelial cells in primary biliary cirrhosis. J Autoimmun. 2006;27:232–241. [PubMed]
9. He XS, Ansari AA, Ridgway WM, Coppel RL, Gershwin ME. New insights to the immunopathology and autoimmune responses in primary biliary cirrhosis. Cell Immunol. 2006;239:1–13. [PubMed]
10. Kita H. Autoreactive CD8-specific T-cell response in primary biliary cirrhosis. Hepatol Res. 2007;37 Suppl 3:S402–S405. [PubMed]
11. Ichiki Y, Shimoda S, Hara H, Shigematsu H, Nakamura M, Hayashida K, Ishibashi H, Niho Y. Analysis of T-cell receptor beta of the T-cell clones reactive to the human PDC-E2 163-176 peptide in the context of HLA-DR53 in patients with primary biliary cirrhosis. Hepatology. 1997;26:728–733. [PubMed]
12. Moteki S, Leung PS, Dickson ER, Van Thiel DH, Galperin C, Buch T, Alarcon-Segovia D, Kershenobich D, Kawano K, Coppel RL. Epitope mapping and reactivity of autoantibodies to the E2 component of 2-oxoglutarate dehydrogenase complex in primary biliary cirrhosis using recombinant 2-oxoglutarate dehydrogenase complex. Hepatology. 1996;23:436–444. [PubMed]
13. Meda F, Zuin M, Invernizzi P, Vergani D, Selmi C. Serum autoantibodies: a road map for the clinical hepatologist. Autoimmunity. 2008;41:27–34. [PubMed]
14. Abe M, Onji M. Natural history of primary biliary cirrhosis. Hepatol Res. 2008;38:639–645. [PubMed]
15. Oertelt S, Rieger R, Selmi C, Invernizzi P, Ansari AA, Coppel RL, Podda M, Leung PS, Gershwin ME. A sensitive bead assay for antimitochondrial antibodies: Chipping away at AMA-negative primary biliary cirrhosis. Hepatology. 2007;45:659–665. [PubMed]
16. Neuberger J, Thomson R. PBC and AMA--what is the connection? Hepatology. 1999;29:271–276. [PubMed]
17. Gajdusek DC. An autoimmune reaction against human tissue antigens in certain acute and chronic diseases. I. Serological investigations. AMA Arch Intern Med. 1958;101:9–29. [PubMed]
18. Walker JG, Doniach D, Roitt IM, Sherlock S. Serological tests in diagnosis of primary biliary cirrhosis. Lancet. 1965;1:827–831. [PubMed]
19. Lindenborn-Fotinos J, Baum H, Berg PA. Mitochondrial antibodies in primary biliary cirrhosis: species and nonspecies specific determinants of M2 antigen. Hepatology. 1985;5:763–769. [PubMed]
20. Gershwin ME, Mackay IR, Sturgess A, Coppel RL. Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol. 1987;138:3525–3531. [PubMed]
21. Reynoso-Paz S, Leung PS, Van De Water J, Tanaka A, Munoz S, Bass N, Lindor K, Donald PJ, Coppel RL, Ansari AA, et al. Evidence for a locally driven mucosal response and the presence of mitochondrial antigens in saliva in primary biliary cirrhosis. Hepatology. 2000;31:24–29. [PubMed]
22. Nishio A, Van de Water J, Leung PS, Joplin R, Neuberger JM, Lake J, Björkland A, Tötterman TH, Peters M, Worman HJ, et al. Comparative studies of antimitochondrial autoantibodies in sera and bile in primary biliary cirrhosis. Hepatology. 1997;25:1085–1089. [PubMed]
23. Tanaka A, Nezu S, Uegaki S, Mikami M, Okuyama S, Kawamura N, Aiso M, Gershwin ME, Takahashi S, Selmi C, et al. The clinical significance of IgA antimitochondrial antibodies in sera and saliva in primary biliary cirrhosis. Ann N Y Acad Sci. 2007;1107:259–270. [PubMed]
24. Berg PA, Wiedmann KH, Sayers T, Klöppel G, Lindner H. Serological classification of chronic cholestatic liver disease by the use of two different types of antimitochondrial antibodies. Lancet. 1980;2:1329–1332. [PubMed]
25. Berg CP, Stein GM, Klein R, Pascu M, Berg T, Kammer W, Priemer M, Nordheim A, Schulze-Osthoff K, Gregor M, et al. Demonstration of PDC-E1 subunits as major antigens in the complement-fixing fraction M4 and re-evaluation of PDC-E1-specific antibodies in PBC patients. Liver Int. 2006;26:846–855. [PubMed]
26. Preuss B, Berg C, Altenberend F, Gregor M, Stevanovic S, Klein R. Demonstration of autoantibodies to recombinant human sulphite oxidase in patients with chronic liver disorders and analysis of their clinical relevance. Clin Exp Immunol. 2007;150:312–321. [PubMed]
27. Weber P, Brenner J, Stechemesser E, Klein R, Weckenmann U, Klöppel G, Kirchhof M, Fintelmann V, Berg PA. Characterization and clinical relevance of a new complement-fixing antibody--anti-M8--in patients with primary biliary cirrhosis. Hepatology. 1986;6:553–559. [PubMed]
28. Klein R, Berg PA. Characterization of a new mitochondrial antigen-antibody system (M9/anti-M9) in patients with anti-M2 positive and anti-M2 negative primary biliary cirrhosis. Clin Exp Immunol. 1988;74:68–74. [PubMed]
29. Berg PA, Klein R. Mitochondrial antigen/antibody systems in primary biliary cirrhosis: revisited. Liver. 1995;15:281–292. [PubMed]
30. Klein R, Pointner H, Zilly W, Glässner-Bittner B, Breuer N, Garbe W, Fintelmann V, Kalk JF, Müting D, Fischer R, et al. Antimitochondrial antibody profiles in primary biliary cirrhosis distinguish at early stages between a benign and a progressive course: a prospective study on 200 patients followed for 10 years. Liver. 1997;17:119–128. [PubMed]
31. Klein R, Klöppel G, Garbe W, Fintelmann V, Berg PA. Antimitochondrial antibody profiles determined at early stages of primary biliary cirrhosis differentiate between a benign and a progressive course of the disease. A retrospective analysis of 76 patients over 6-18 years. J Hepatol. 1991;12:21–27. [PubMed]
32. Vleggaar FP, van Buuren HR. No prognostic significance of antimitochondrial antibody profile testing in primary biliary cirrhosis. Hepatogastroenterology. 2004;51:937–940. [PubMed]
33. Chung L, Utz PJ. Antibodies in scleroderma: direct pathogenicity and phenotypic associations. Curr Rheumatol Rep. 2004;6:156–163. [PubMed]
34. O'Brien C, Joshi S, Feld JJ, Guindi M, Dienes HP, Heathcote EJ. Long-term follow-up of antimitochondrial antibody-positive autoimmune hepatitis. Hepatology. 2008;48:550–556. [PubMed]
35. Nardi N, Brito-Zerón P, Ramos-Casals M, Aguiló S, Cervera R, Ingelmo M, Font J. Circulating auto-antibodies against nuclear and non-nuclear antigens in primary Sjögren's syndrome: prevalence and clinical significance in 335 patients. Clin Rheumatol. 2006;25:341–346. [PubMed]
36. Ramos-Casals M, Pares A, Jara LJ, Solans R, Viñas O, Vázquez P, Sánchez-Tapias JM, Rodés J, Font J. Antimitochondrial antibodies in patients with chronic hepatitis C virus infection: description of 18 cases and review of the literature. J Viral Hepat. 2005;12:648–654. [PubMed]
37. Montano-Loza AJ, Carpenter HA, Czaja AJ. Frequency, behavior, and prognostic implications of antimitochondrial antibodies in type 1 autoimmune hepatitis. J Clin Gastroenterol. 2008;42:1047–1053. [PubMed]
38. Klein R, Wiebel M, Engelhart S, Berg PA. Sera from patients with tuberculosis recognize the M2a-epitope (E2-subunit of pyruvate dehydrogenase) specific for primary biliary cirrhosis. Clin Exp Immunol. 1993;92:308–316. [PubMed]
39. Shimoda S, Van de Water J, Ansari A, Nakamura M, Ishibashi H, Coppel RL, Lake J, Keeffe EB, Roche TE, Gershwin ME. Identification and precursor frequency analysis of a common T cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis. J Clin Invest. 1998;102:1831–1840. [PMC free article] [PubMed]
40. Kamihira T, Shimoda S, Harada K, Kawano A, Handa M, Baba E, Tsuneyama K, Nakamura M, Ishibashi H, Nakanuma Y, et al. Distinct costimulation dependent and independent autoreactive T-cell clones in primary biliary cirrhosis. Gastroenterology. 2003;125:1379–1387. [PubMed]
41. Kita H, Ansari AA, He XS, Lian ZX, Van de Water J, Coppel RL, Luketic V, Kaplan M, Inamori H, Isoda N, et al. Proteasome is required for class I-restricted presentation by Fcgamma receptor-mediated endocytosis in primary biliary cirrhosis. J Autoimmun. 2003;21:175–182. [PubMed]
42. Kita H, Matsumura S, He XS, Ansari AA, Lian ZX, Van de Water J, Coppel RL, Kaplan MM, Gershwin ME. Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis. J Clin Invest. 2002;109:1231–1240. [PMC free article] [PubMed]
43. Tanimoto H, Shimoda S, Nakamura M, Ishibashi H, Kawano A, Kamihira T, Matsushita S, Gershwin ME, Harada M. Promiscuous T cells selected by Escherichia coli: OGDC-E2 in primary biliary cirrhosis. J Autoimmun. 2003;20:255–263. [PubMed]
44. Kita H, Lian ZX, Van de Water J, He XS, Matsumura S, Kaplan M, Luketic V, Coppel RL, Ansari AA, Gershwin ME. Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells. J Exp Med. 2002;195:113–123. [PMC free article] [PubMed]
45. Poupon RE, Balkau B, Eschwège E, Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med. 1991;324:1548–1554. [PubMed]
46. Benson GD, Kikuchi K, Miyakawa H, Tanaka A, Watnik MR, Gershwin ME. Serial analysis of antimitochondrial antibody in patients with primary biliary cirrhosis. Clin Dev Immunol. 2004;11:129–133. [PMC free article] [PubMed]
47. Luettig B, Boeker KH, Schoessler W, Will H, Loges S, Schmidt E, Worman HJ, Gershwin ME, Manns MP. The antinuclear autoantibodies Sp100 and gp210 persist after orthotopic liver transplantation in patients with primary biliary cirrhosis. J Hepatol. 1998;28:824–828. [PubMed]
48. Matsumura S, Van De Water J, Leung P, Odin JA, Yamamoto K, Gores GJ, Mostov K, Ansari AA, Coppel RL, Shiratori Y, et al. Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis. Hepatology. 2004;39:1415–1422. [PubMed]
49. Selmi C, Zuin M, Gershwin ME. The unfinished business of primary biliary cirrhosis. J Hepatol. 2008;49:451–460. [PMC free article] [PubMed]
50. Rigopoulou EI, Davies ET, Bogdanos DP, Liaskos C, Mytilinaiou M, Koukoulis GK, Dalekos GN, Vergani D. Antimitochondrial antibodies of immunoglobulin G3 subclass are associated with a more severe disease course in primary biliary cirrhosis. Liver Int. 2007;27:1226–1231. [PubMed]
51. Lleo A, Selmi C, Invernizzi P, Podda M, Gershwin ME. The consequences of apoptosis in autoimmunity. J Autoimmun. 2008;31:257–262. [PMC free article] [PubMed]
52. Lleo A, Invernizzi P, Selmi C, Coppel RL, Alpini G, Podda M, Mackay IR, Gershwin ME. Autophagy: highlighting a novel player in the autoimmunity scenario. J Autoimmun. 2007;29:61–68. [PMC free article] [PubMed]
53. Leung PS, Rossaro L, Davis PA, Park O, Tanaka A, Kikuchi K, Miyakawa H, Norman GL, Lee W, Gershwin ME. Antimitochondrial antibodies in acute liver failure: implications for primary biliary cirrhosis. Hepatology. 2007;46:1436–1442. [PubMed]
54. Bogdanos DP, Choudhuri K, Vergani D. Molecular mimicry and autoimmune liver disease: virtuous intentions, malign consequences. Liver. 2001;21:225–232. [PubMed]
55. Sutton I, Neuberger J. Primary biliary cirrhosis: seeking the silent partner of autoimmunity. Gut. 2002;50:743–746. [PMC free article] [PubMed]
56. Long SA, Quan C, Van de Water J, Nantz MH, Kurth MJ, Barsky D, Colvin ME, Lam KS, Coppel RL, Ansari A, et al. Immunoreactivity of organic mimeotopes of the E2 component of pyruvate dehydrogenase: connecting xenobiotics with primary biliary cirrhosis. J Immunol. 2001;167:2956–2963. [PubMed]
57. Odin JA, Huebert RC, Casciola-Rosen L, LaRusso NF, Rosen A. Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis. J Clin Invest. 2001;108:223–232. [PMC free article] [PubMed]
58. Allina J, Stanca CM, Garber J, Hu B, Sautes-Fridman C, Bach N, Odin JA. Anti-CD16 autoantibodies and delayed phagocytosis of apoptotic cells in primary biliary cirrhosis. J Autoimmun. 2008;30:238–245. [PubMed]
59. Berg CP, Stein GM, Keppeler H, Gregor M, Wesselborg S, Lauber K. Apoptosis-associated antigens recognized by autoantibodies in patients with the autoimmune liver disease primary biliary cirrhosis. Apoptosis. 2008;13:63–75. [PubMed]
60. Muratori P, Muratori L, Gershwin ME, Czaja AJ, Pappas G, MacCariello S, Granito A, Cassani F, Loria P, Lenzi M, et al. 'True' antimitochondrial antibody-negative primary biliary cirrhosis, low sensitivity of the routine assays, or both? Clin Exp Immunol. 2004;135:154–158. [PubMed]
61. Hirschfield GM, Heathcote EJ. Antimitochondrial antibody-negative primary biliary cirrhosis. Clin Liver Dis. 2008;12:323–331; viii-ix. [PubMed]
62. 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;28:233–239. [PubMed]
63. Zhang FK, Jia JD, Wang BE. Clinical evaluation of serum antimitochondrial antibody-negative primary biliary cirrhosis. Hepatobiliary Pancreat Dis Int. 2004;3:288–291. [PubMed]
64. Dähnrich C, Pares A, Caballeria L, Rosemann A, Schlumberger W, Probst C, Mytilinaiou M, Bogdanos D, Vergani D, Stöcker W, et al. New ELISA for detecting primary biliary cirrhosis-specific antimitochondrial antibodies. Clin Chem. 2009;55:978–985. [PubMed]
65. Mendes F, Lindor KD. Antimitochondrial antibody-negative primary biliary cirrhosis. Gastroenterol Clin North Am. 2008;37:479–484, viii. [PubMed]
66. Szostecki C, Krippner H, Penner E, Bautz FA. Autoimmune sera recognize a 100 kD nuclear protein antigen (sp-100) Clin Exp Immunol. 1987;68:108–116. [PubMed]
67. Fusconi M, Cassani F, Govoni M, Caselli A, Farabegoli F, Lenzi M, Ballardini G, Zauli D, Bianchi FB. Anti-nuclear antibodies of primary biliary cirrhosis recognize 78-92-kD and 96-100-kD proteins of nuclear bodies. Clin Exp Immunol. 1991;83:291–297. [PubMed]
68. Morriswood B, Ryzhakov G, Puri C, Arden SD, Roberts R, Dendrou C, Kendrick-Jones J, Buss F. T6BP and NDP52 are myosin VI binding partners with potential roles in cytokine signalling and cell adhesion. J Cell Sci. 2007;120:2574–2585. [PMC free article] [PubMed]
69. Thurston TL, Ryzhakov G, Bloor S, von Muhlinen N, Randow F. The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat Immunol. 2009;10:1215–1221. [PubMed]
70. Bernstein RM, Neuberger JM, Bunn CC, Callender ME, Hughes GR, Williams R. Diversity of autoantibodies in primary biliary cirrhosis and chronic active hepatitis. Clin Exp Immunol. 1984;55:553–560. [PubMed]
71. Sternsdorf T, Guldner HH, Szostecki C, Grötzinger T, Will H. 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. [PubMed]
72. Szostecki C, Will H, Netter HJ, Guldner HH. 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. [PubMed]
73. Pawlotsky JM, Andre C, Metreau JM, Beaugrand M, Zafrani ES, Dhumeaux D. Multiple nuclear dots antinuclear antibodies are not specific for primary biliary cirrhosis. Hepatology. 1992;16:127–131. [PubMed]
74. Wichmann I, Montes-Cano MA, Respaldiza N, Alvarez A, Walter K, Franco E, Sanchez-Roman J, Núñez-Roldán A. Clinical significance of anti-multiple nuclear dots/Sp100 autoantibodies. Scand J Gastroenterol. 2003;38:996–999. [PubMed]
75. Worman HJ, Courvalin JC. Antinuclear antibodies specific for primary biliary cirrhosis. Autoimmun Rev. 2003;2:211–217. [PubMed]
76. Muratori P, Muratori L, Ferrari R, Cassani F, Bianchi G, Lenzi M, Rodrigo L, Linares A, Fuentes D, Bianchi FB. Characterization and clinical impact of antinuclear antibodies in primary biliary cirrhosis. Am J Gastroenterol. 2003;98:431–437. [PubMed]
77. Manuel Lucena J, Montes Cano M, Luis Caro J, Respaldiza N, Alvarez A, Sánchez-Román J, Núñez-Roldán A, Wichmann I. Comparison of two ELISA assays for anti-Sp100 determination. Ann N Y Acad Sci. 2007;1109:203–211. [PubMed]
78. Milkiewicz P, Buwaneswaran H, Coltescu C, Shums Z, Norman GL, Heathcote EJ. Value of autoantibody analysis in the differential diagnosis of chronic cholestatic liver disease. Clin Gastroenterol Hepatol. 2009;7:1355–1360. [PubMed]
79. Bogdanos DP, Baum H, Butler P, Rigopoulou EI, Davies ET, Ma Y, Burroughs AK, Vergani D. Association between the primary biliary cirrhosis specific anti-sp100 antibodies and recurrent urinary tract infection. Dig Liver Dis. 2003;35:801–805. [PubMed]
80. Kakizuka A, Miller WH Jr, Umesono K, Warrell RP Jr, Frankel SR, Murty VV, Dmitrovsky E, Evans RM. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell. 1991;66:663–674. [PubMed]
81. Borden KL. Pondering the promyelocytic leukemia protein (PML) puzzle: possible functions for PML nuclear bodies. Mol Cell Biol. 2002;22:5259–5269. [PMC free article] [PubMed]
82. Bloch DB, Nakajima A, Gulick T, Chiche JD, Orth D, de La Monte SM, Bloch KD. Sp110 localizes to the PML-Sp100 nuclear body and may function as a nuclear hormone receptor transcriptional coactivator. Mol Cell Biol. 2000;20:6138–6146. [PMC free article] [PubMed]
83. Züchner D, Sternsdorf T, Szostecki C, Heathcote EJ, Cauch-Dudek K, Will H. 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. [PubMed]
84. Szostecki C, Guldner HH, Will H. Autoantibodies against "nuclear dots" in primary biliary cirrhosis. Semin Liver Dis. 1997;17:71–78. [PubMed]
85. Granito A, Yang WH, Muratori L, Lim MJ, Nakajima A, Ferri S, Pappas G, Quarneti C, Bianchi FB, Bloch DB, et al. PML nuclear body component Sp140 is a novel autoantigen in primary biliary cirrhosis. Am J Gastroenterol. 2010;105:125–131. [PubMed]
86. Ruffatti A, Arslan P, Floreani A, De Silvestro G, Calligaro A, Naccarato R, Todesco S. Nuclear membrane-staining antinuclear antibody in patients with primary biliary cirrhosis. J Clin Immunol. 1985;5:357–361. [PubMed]
87. Invernizzi P, Podda M, Battezzati PM, Crosignani A, Zuin M, Hitchman E, Maggioni M, Meroni PL, Penner E, Wesierska-Gadek J. Autoantibodies against nuclear pore complexes are associated with more active and severe liver disease in primary biliary cirrhosis. J Hepatol. 2001;34:366–372. [PubMed]
88. Rigopoulou EI, Davies ET, Pares A, Zachou K, Liaskos C, Bogdanos DP, Rodes J, Dalekos GN, Vergani D. Prevalence and clinical significance of isotype specific antinuclear antibodies in primary biliary cirrhosis. Gut. 2005;54:528–532. [PMC free article] [PubMed]
89. Muratori P, Granito A, Ferri S, Pappas G, Volta U, Menichella R, Bianchi FB, Lenzi M, Muratori L. Multiple nuclear dots and rim-like/membranous IgG isotypes in primary biliary cirrhosis. Autoimmunity. 2009;42:224–227. [PubMed]
90. Lassoued K, Brenard R, Degos F, Courvalin JC, Andre C, Danon F, Brouet JC, Zine-el-Abidine Y, Degott C, Zafrani S. 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. [PubMed]
91. 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;86:279–285. [PMC free article] [PubMed]
92. Worman HJ. Nuclear envelope protein autoantigens in primary biliary cirrhosis. Hepatol Res. 2007;37 Suppl 3:S406–S411. [PubMed]
93. Gao L, Tian X, Liu B, Zhang F. The value of antinuclear antibodies in primary biliary cirrhosis. Clin Exp Med. 2008;8:9–15. [PubMed]
94. Bauer A, Habior A. Measurement of gp210 autoantibodies in sera of patients with primary biliary cirrhosis. J Clin Lab Anal. 2007;21:227–231. [PubMed]
95. Nakamura M, Shimizu-Yoshida Y, Takii Y, Komori A, Yokoyama T, Ueki T, Daikoku M, Yano K, Matsumoto T, Migita K, et al. Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis. J Hepatol. 2005;42:386–392. [PubMed]
96. Nakamura M, Komori A, Ito M, Kondo H, Aiba Y, Migita K, Nagaoka S, Ohata K, Yano K, Abiru S, et al. Predictive role of anti-gp210 and anticentromere antibodies in long-term outcome of primary biliary cirrhosis. Hepatol Res. 2007;37 Suppl 3:S412–S419. [PubMed]
97. Nakamura M, Takii Y, Ito M, Komori A, Yokoyama T, Shimizu-Yoshida Y, Koyabu M, Matsuyama M, Mori T, Kamihira T, et al. Increased expression of nuclear envelope gp210 antigen in small bile ducts in primary biliary cirrhosis. J Autoimmun. 2006;26:138–145. [PubMed]
98. Davis LI, 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. [PubMed]
99. 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. [PubMed]
100. Invernizzi P, Selmi C, Ranftler C, Podda M, Wesierska-Gadek J. Antinuclear antibodies in primary biliary cirrhosis. Semin Liver Dis. 2005;25:298–310. [PubMed]
101. 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;1109:519–530. [PubMed]
102. Miyachi K, Hankins RW, Matsushima H, Kikuchi F, Inomata T, Horigome T, Shibata M, Onozuka Y, Ueno Y, Hashimoto E, 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. [PubMed]
103. Salina D, Bodoor K, Enarson P, Raharjo WH, Burke B. Nuclear envelope dynamics. Biochem Cell Biol. 2001;79:533–542. [PubMed]
104. Fisher DZ, 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. [PubMed]
105. Krohne G, Wolin SL, McKeon FD, Franke WW, Kirschner MW. Nuclear lamin LI of Xenopus laevis: cDNA cloning, amino acid sequence and binding specificity of a member of the lamin B subfamily. EMBO J. 1987;6:3801–3808. [PubMed]
106. Wesierska-Gadek J, Penner E, Hitchman E, Sauermann G. Antibodies to nuclear lamins in autoimmune liver disease. Clin Immunol Immunopathol. 1988;49:107–115. [PubMed]
107. Senécal JL, Ichiki S, Girard D, Raymond Y. Autoantibodies to nuclear lamins and to intermediate filament proteins: natural, pathologic or pathogenic? J Rheumatol. 1993;20:211–219. [PubMed]
108. Konstantinov K, von Mikecz A, Buchwald D, Jones J, Gerace L, Tan EM. Autoantibodies to nuclear envelope antigens in chronic fatigue syndrome. J Clin Invest. 1996;98:1888–1896. [PMC free article] [PubMed]
109. Dieudé M, Senécal JL, Rauch J, Hanly JG, Fortin P, Brassard N, Raymond Y. Association of autoantibodies to nuclear lamin B1 with thromboprotection in systemic lupus erythematosus: lack of evidence for a direct role of lamin B1 in apoptotic blebs. Arthritis Rheum. 2002;46:2695–2707. [PubMed]
110. Coppo P, Clauvel JP, Bengoufa D, Fuentes V, Gouilleux-Gruart V, Courvalin JC, Lassoued K. Autoimmune cytopenias associated with autoantibodies to nuclear envelope polypeptides. Am J Hematol. 2004;77:241–249. [PubMed]
111. Nesher G, Margalit R, Ashkenazi YJ. Anti-nuclear envelope antibodies: Clinical associations. Semin Arthritis Rheum. 2001;30:313–320. [PubMed]
112. Lin F, Noyer CM, Ye Q, Courvalin JC, Worman HJ. 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. [PubMed]
113. 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;172:961–967. [PMC free article] [PubMed]
114. Vázquez-Abad D, Rothfield NF. Autoantibodies in systemic sclerosis. Int Rev Immunol. 1995;12:145–157. [PubMed]
115. Salliot C, Gottenberg JE, Bengoufa D, Desmoulins F, Miceli-Richard C, Mariette X. Anticentromere antibodies identify patients with Sjögren's syndrome and autoimmune overlap syndrome. J Rheumatol. 2007;34:2253–2258. [PubMed]
116. Yan SM, Zeng XF, Zhao Y, Dong Y. [A clinical analysis of primary Sjögren's syndrome with anticentromere antibodies] Zhonghua Neike Zazhi. 2008;47:296–299. [PubMed]
117. Vlachoyiannopoulos PG, Drosos AA, Wiik A, Moutsopoulos HM. Patients with anticentromere antibodies, clinical features, diagnoses and evolution. Br J Rheumatol. 1993;32:297–301. [PubMed]
118. Nakano M, Ohuchi Y, Hasegawa H, Kuroda T, Ito S, Gejyo F. Clinical significance of anticentromere antibodies in patients with systemic lupus erythematosus. J Rheumatol. 2000;27:1403–1407. [PubMed]
119. Chan HL, Lee YS, Hong HS, Kuo TT. Anticentromere antibodies (ACA): clinical distribution and disease specificity. Clin Exp Dermatol. 1994;19:298–302. [PubMed]
120. Parveen S, Morshed SA, Nishioka M. High prevalence of antibodies to recombinant CENP-B in primary biliary cirrhosis: nuclear immunofluorescence patterns and ELISA reactivities. J Gastroenterol Hepatol. 1995;10:438–445. [PubMed]
121. Akbarali Y, Matousek-Ronck J, Hunt L, Staudt L, Reichlin M, Guthridge JM, James JA. Fine specificity mapping of autoantigens targeted by anti-centromere autoantibodies. J Autoimmun. 2006;27:272–280. [PMC free article] [PubMed]
122. Russo K, Hoch S, Dima C, Varga J, Teodorescu M. Circulating anticentromere CENP-A and CENP-B antibodies in patients with diffuse and limited systemic sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. J Rheumatol. 2000;27:142–148. [PubMed]
123. Nakamura M, Kondo H, Mori T, Komori A, Matsuyama M, Ito M, Takii Y, Koyabu M, Yokoyama T, Migita K, et al. Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis. Hepatology. 2007;45:118–127. [PubMed]
124. Klein R, Berg PA. Anti-M9 antibodies in sera from patients with primary biliary cirrhosis recognize an epitope of glycogen phosphorylase. Clin Exp Immunol. 1990;81:65–71. [PubMed]
125. Santiago M, Baron M, Miyachi K, Fritzler MJ, Abu-Hakima M, Leclercq S, Bell M, Hudson M, Mathieu JP, Taillefer S, et al. A comparison of the frequency of antibodies to cyclic citrullinated peptides using a third generation anti-CCP assay (CCP3) in systemic sclerosis, primary biliary cirrhosis and rheumatoid arthritis. Clin Rheumatol. 2008;27:77–83. [PubMed]
126. Koga T, Migita K, Miyashita T, Maeda Y, Nakamura M, Abiru S, Myoji M, Komori A, Yano K, Yatsuhashi H, et al. Determination of anti-cyclic citrullinated peptide antibodies in the sera of patients with liver diseases. Clin Exp Rheumatol. 2008;26:121–124. [PubMed]
127. Agmon-Levin N, Shapira Y, Selmi C, Barzilai O, Ram M, Szyper-Kravitz M, Sella S, Katz BS, Youinou P, Renaudineau Y, et al. A comprehensive evaluation of serum autoantibodies in primary biliary cirrhosis. J Autoimmun. 2010;34:55–58. [PubMed]
128. Li L, Chen M, Huang DY, Nishioka M. Frequency and significance of antibodies to chromatin in autoimmune hepatitis type I. J Gastroenterol Hepatol. 2000;15:1176–1182. [PubMed]
129. Czaja AJ, Shums Z, Binder WL, Lewis SJ, Nelson VJ, Norman GL. Frequency and significance of antibodies to chromatin in autoimmune hepatitis. Dig Dis Sci. 2003;48:1658–1664. [PubMed]
130. Subasić D, Karamehić J, Ljuca F, Gavrankapetanović F, Delić-Sarac M, Eminović I, Kovacević D. Correlation of autoantibodies presence detected by IFA-anti-dsDNA, IFA-AMA and immunoblotting with corresponding data in clinical management of autoimmune diseases. Bosn J Basic Med Sci. 2008;8:86–92. [PubMed]
131. Muratori P, Granito A, Pappas G, Pendino GM, Quarneti C, Cicola R, Menichella R, Ferri S, Cassani F, Bianchi FB, et al. The serological profile of the autoimmune hepatitis/primary biliary cirrhosis overlap syndrome. Am J Gastroenterol. 2009;104:1420–1425. [PubMed]
132. Chou MJ, Lee SL, Chen TY, Tsay GJ. Specificity of antinuclear antibodies in primary biliary cirrhosis. Ann Rheum Dis. 1995;54:148–151. [PMC free article] [PubMed]
133. Tsuchiya K, Kiyosawa K, Imai H, Sodeyama T, Furuta S. Detection of anti-double and anti-single stranded DNA antibodies in chronic liver disease: significance of anti-double stranded DNA antibody in autoimmune hepatitis. J Gastroenterol. 1994;29:152–158. [PubMed]
134. Konikoff F, Swissa M, Shoenfeld Y. Autoantibodies to histones and their subfractions in chronic liver diseases. Clin Immunol Immunopathol. 1989;51:77–82. [PubMed]
135. Tishler M, Alosachie I, Barka N, Lin HC, Gershwin ME, Peter JB, Shoenfeld Y. Primary Sjögren's syndrome and primary biliary cirrhosis: differences and similarities in the autoantibody profile. Clin Exp Rheumatol. 1995;13:497–500. [PubMed]
136. Granito A, Muratori P, Muratori L, Pappas G, Cassani F, Worthington J, Ferri S, Quarneti C, Cipriano V, de Molo C, et al. Antibodies to SS-A/Ro-52kD and centromere in autoimmune liver disease: a clue to diagnosis and prognosis of primary biliary cirrhosis. Aliment Pharmacol Ther. 2007;26:831–838. [PubMed]
137. Takada K, Suzuki K, Matsumoto M, Okada M, Nakanishi T, Horikoshi H, Higuchi T, Ohsuzu F. Clinical characteristics of patients with both anti-U1RNP and anti-centromere antibodies. Scand J Rheumatol. 2008;37:360–364. [PubMed]
138. Dörner T, Held C, Trebeljahr G, Lukowsky A, Yamamoto K, Hiepe F. Serologic characteristics in primary biliary cirrhosis associated with sicca syndrome. Scand J Gastroenterol. 1994;29:655–660. [PubMed]
139. Wesierska-Gadek J, Penner E, Battezzati PM, Selmi C, Zuin M, Hitchman E, Worman HJ, Gershwin ME, Podda M, Invernizzi P. Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis. Hepatology. 2006;43:1135–1144. [PubMed]
140. Kanzler S, Bozkurt S, Herkel J, Galle PR, Dienes HP, Lohse AW. [Presence of SLA/LP autoantibodies in patients with primary biliary cirrhosis as a marker for secondary autoimmune hepatitis (overlap syndrome)] Dtsch Med Wochenschr. 2001;126:450–456. [PubMed]
141. Eyraud V, Chazouilleres O, Ballot E, Corpechot C, Poupon R, Johanet C. Significance of antibodies to soluble liver antigen/liver pancreas: a large French study. Liver Int. 2009;29:857–864. [PubMed]
142. Floreani A, Baragiotta A, Leone MG, Baldo V, Naccarato R. Primary biliary cirrhosis and hepatitis C virus infection. Am J Gastroenterol. 2003;98:2757–2762. [PubMed]
143. McFarlane BM, McSorley CG, Vergani D, McFarlane IG, Williams R. Serum autoantibodies reacting with the hepatic asialoglycoprotein receptor protein (hepatic lectin) in acute and chronic liver disorders. J Hepatol. 1986;3:196–205. [PubMed]
144. Bedlow AJ, Donaldson PT, McFarlane BM, Lombard M, McFarlane IG, Williams R. Autoreactivity to hepatocellular antigens in primary biliary cirrhosis and primary sclerosing cholangitis. J Clin Lab Immunol. 1989;30:103–109. [PubMed]
145. Yoshioka M, Mizuno M, Morisue Y, Shimada M, Hirai M, Nasu J, Okada H, Sakaguchi K, Yamamoto K, Tsuji T. Anti-asialoglycoprotein receptor autoantibodies, detected by a capture-immunoassay, are associated with autoimmune liver diseases. Acta Med Okayama. 2002;56:99–105. [PubMed]
146. Löhr H, Treichel U, Poralla T, Manns M, Meyer zum Büschenfelde KH, Fleischer B. The human hepatic asialoglycoprotein receptor is a target antigen for liver-infiltrating T cells in autoimmune chronic active hepatitis and primary biliary cirrhosis. Hepatology. 1990;12:1314–1320. [PubMed]
147. Schuurman HJ, Vogten AJ, Schalm SW, Fevery J. Clinical evaluation of the liver cell membrane autoantibody assay. Digestion. 1982;23:184–193. [PubMed]
148. Meliconi R, Stancari MV, Garagnani M, Baraldini M, Stefanini GF, Miglio F, Gasbarrini G. Occurrence and significance of IgG liver membrane autoantibodies (LMA) in chronic liver diseases of different aetiology. Clin Exp Immunol. 1983;51:565–571. [PubMed]
149. Morichika S, Arima T, Nagashima H. Clinical evaluation of autoantibodies to liver cell membrane specific antigen, liver specific lipoprotein, and Tamm-Horsfall glycoprotein in autoimmune chronic active hepatitis. Gastroenterol Jpn. 1987;22:24–33. [PubMed]
150. Meliconi R, Facchini A, Miglio F, Trevisan A, Alberti A, Realdi G, Baraldini M, Gasbarrini G. Liver-specific autoantibodies in chronic hepatitis B virus infection. Clin Sci (Lond) 1985;68:123–126. [PubMed]
151. Watanabe K, Ohira H, Orikasa H, Saito K, Kanno K, Shioya Y, Obara K, Sato Y. Anti-calreticulin antibodies in patients with inflammatory bowel disease. Fukushima J Med Sci. 2006;52:1–11. [PubMed]
152. Abe K, Ohira H, Kobayashi H, Saito H, Takahashi A, Rai T, Kanno Y, Monoe K, Watanabe H, Irisawa A, et al. Breakthrough of immune self-tolerance to calreticulin induced by CpG-oligodeoxynucleotides as adjuvant. Fukushima J Med Sci. 2007;53:95–108. [PubMed]
153. Xia Q, Lu F, Yan HP, Wang HX, Feng X, Zhao Y, Liu BY, Wang J, Li P, Xue Y, et al. Autoantibody profiling of Chinese patients with autoimmune hepatitis using immunoproteomic analysis. J Proteome Res. 2008;7:1963–1970. [PubMed]
154. Lu F, Xia Q, Ma Y, Yuan G, Yan H, Qian L, Hu M, Wang M, Lu H, Wang H, et al. Serum proteomic-based analysis for the identification of a potential serological marker for autoimmune hepatitis. Biochem Biophys Res Commun. 2008;367:284–290. [PubMed]
155. Miyachi K, Matsushima H, Hankins RW, Hirakata M, Mimori T, Hosaka H, Amagasaki Y, Miyakawa H, Kako M, Shibata M, et al. A novel antibody directed against a three-dimensional configuration of a 95-kDa protein in patients with autoimmune hepatic diseases. Scand J Immunol. 1998;47:63–68. [PubMed]
156. Miyachi K, Hirano Y, Horigome T, Mimori T, Miyakawa H, Onozuka Y, Shibata M, Hirakata M, Suwa A, Hosaka H, et al. Autoantibodies from primary biliary cirrhosis patients with anti-p95c antibodies bind to recombinant p97/VCP and inhibit in vitro nuclear envelope assembly. Clin Exp Immunol. 2004;136:568–573. [PubMed]
157. Miyachi K, Hosaka H, Nakamura N, Miyakawa H, Mimori T, Shibata M, Matsushima S, Chinoh H, Horigome T, Hankins RW, et al. Anti-p97/VCP antibodies: an autoantibody marker for a subset of primary biliary cirrhosis patients with milder disease? Scand J Immunol. 2006;63:376–382. [PubMed]
158. Kato T, Miyakawa H, Ishibashi M. Frequency and significance of anti-glutathione S-transferase autoantibody (anti-GST A1-1) in autoimmune hepatitis. J Autoimmun. 2004;22:211–216. [PubMed]
159. Pelli N, Fensom AH, Slade C, Boa F, Mieli-Vergani G, Vergani D. Argininosuccinate lyase: a new autoantigen in liver disease. Clin Exp Immunol. 1998;114:455–461. [PubMed]
160. Ikeda Y, Toda G, Hashimoto N, Aotsuka S, Yokohari R, Maruyama T, Oka H. Anticalmodulin autoantibody in liver diseases: a new antibody against a cytoskeleton-related protein. Hepatology. 1987;7:285–293. [PubMed]
161. Sakly W, Jeddi M, Ghedira I. Anti-Saccharomyces cerevisiae antibodies in primary biliary cirrhosis. Dig Dis Sci. 2008;53:1983–1987. [PubMed]
162. Fagoonee S, De Luca L, De Angelis C, Castelli A, Rizzetto M, Pellicano R. Anti-Saccharomyces cerevisiae as unusual antibodies in autoimmune hepatitis. Minerva Gastroenterol Dietol. 2009;55:37–40. [PubMed]
163. Muratori P, Muratori L, Guidi M, Maccariello S, Pappas G, Ferrari R, Gionchetti P, Campieri M, Bianchi FB. Anti-Saccharomyces cerevisiae antibodies (ASCA) and autoimmune liver diseases. Clin Exp Immunol. 2003;132:473–476. [PubMed]
164. Jensen-Jarolim E, Neumann C, Oberhuber G, Gscheidlinger R, Neuchrist C, Reinisch W, Zuberi RI, Penner E, Liu FT, Boltz-Nitulescu G. Anti-Galectin-3 IgG autoantibodies in patients with Crohn's disease characterized by means of phage display peptide libraries. J Clin Immunol. 2001;21:348–356. [PubMed]
165. Bizzaro N, Tampoia M, Villalta D, Platzgummer S, Liguori M, Tozzoli R, Tonutti E. Low specificity of anti-tissue transglutaminase antibodies in patients with primary biliary cirrhosis. J Clin Lab Anal. 2006;20:184–189. [PubMed]
166. Chatzicostas C, Roussomoustakaki M, Drygiannakis D, Niniraki M, Tzardi M, Koulentaki M, Dimoulios P, Mouzas I, Kouroumalis E. Primary biliary cirrhosis and autoimmune cholangitis are not associated with coeliac disease in Crete. BMC Gastroenterol. 2002;2:5. [PMC free article] [PubMed]
167. Volta U, De Franceschi L, Molinaro N, Cassani F, Muratori L, Lenzi M, Bianchi FB, Czaja AJ. Frequency and significance of anti-gliadin and anti-endomysial antibodies in autoimmune hepatitis. Dig Dis Sci. 1998;43:2190–2195. [PubMed]
168. Roozendaal C, de Jong MA, van den Berg AP, van Wijk RT, Limburg PC, Kallenberg CG. Clinical significance of anti-neutrophil cytoplasmic antibodies (ANCA) in autoimmune liver diseases. J Hepatol. 2000;32:734–741. [PubMed]
169. Sundewall AC, Lefvert AK, Norberg R. Characterization of anti-acetylcholine receptor antibody activity in patients with anti-mitochondrial antibodies. Clin Immunol Immunopathol. 1987;45:184–195. [PubMed]
170. Ohana M, Okazaki K, Hajiro K, Uchida K. Antilactoferrin antibodies in autoimmune liver diseases. Am J Gastroenterol. 1998;93:1334–1339. [PubMed]
171. Muratori L, Muratori P, Zauli D, Grassi A, Pappas G, Rodrigo L, Cassani F, Lenzi M, Bianchi FB. Antilactoferrin antibodies in autoimmune liver disease. Clin Exp Immunol. 2001;124:470–473. [PubMed]
172. Gabeta S, Norman GL, Gatselis N, Liaskos C, Papamichalis PA, Garagounis A, Zachou K, Rigopoulou EI, Dalekos GN. IgA anti-b2GPI antibodies in patients with autoimmune liver diseases. J Clin Immunol. 2008;28:501–511. [PubMed]
173. Zachou K, Liaskos C, Rigopoulou E, Gabeta S, Papamichalis P, Gatselis N, Georgiadou S, Dalekos GN. Presence of high avidity anticardiolipin antibodies in patients with autoimmune cholestatic liver diseases. Clin Immunol. 2006;119:203–212. [PubMed]
174. Pietropaolo M, Peakman M, Pietropaolo SL, Zanone MM, Foley TP Jr, Becker DJ, Trucco M. Combined analysis of GAD65 and ICA512(IA-2) autoantibodies in organ and non-organ-specific autoimmune diseases confers high specificity for insulin-dependent diabetes mellitus. J Autoimmun. 1998;11:1–10. [PubMed]
175. Fida S, Myers MA, Whittingham S, Rowley MJ, Ozaki S, Mackay IR. Autoantibodies to the transcriptional factor SOX13 in primary biliary cirrhosis compared with other diseases. J Autoimmun. 2002;19:251–257. [PubMed]
176. Nakamura H, Usa T, Motomura M, Ichikawa T, Nakao K, Kawasaki E, Tanaka M, Ishikawa K, Eguchi K. Prevalence of interrelated autoantibodies in thyroid diseases and autoimmune disorders. J Endocrinol Invest. 2008;31:861–865. [PubMed]
177. Fusconi M, Vannini A, Dall'Aglio AC, Pappas G, Cassani F, Ballardini G, Frisoni M, Grassi A, Bianchi FB, Zauli D. Anti-cyclic citrullinated peptide antibodies in type 1 autoimmune hepatitis. Aliment Pharmacol Ther. 2005;22:951–955. [PubMed]
178. Mayo I, Arizti P, Parés A, Oliva J, Doforno RA, de Sagarra MR, Rodés J, Castaño JG. Antibodies against the COOH-terminal region of E. coli ClpP protease in patients with primary biliary cirrhosis. J Hepatol. 2000;33:528–536. [PubMed]
179. Bogdanos DP, Baum H, Sharma UC, Grasso A, Ma Y, Burroughs AK, Vergani D. Antibodies against homologous microbial caseinolytic proteases P characterise primary biliary cirrhosis. J Hepatol. 2002;36:14–21. [PubMed]
180. Roesler KW, Schmider W, Kist M, Batsford S, Schiltz E, Oelke M, Tuczek A, Dettenborn T, Behringer D, Kreisel W. Identification of beta-subunit of bacterial RNA-polymerase--a non-species-specific bacterial protein--as target of antibodies in primary biliary cirrhosis. Dig Dis Sci. 2003;48:561–569. [PubMed]
181. Takiguchi J, Ohira H, Rai T, Abe K, Takahashi A, Sato Y. Anti-eosinophil peroxidase antibodies detected in patients with primary biliary cirrhosis. Hepatol Res. 2005;32:33–37. [PubMed]
182. Herkel J, Modrow JP, Bamberger S, Kanzler S, Rotter V, Cohen IR, Lohse AW. Prevalence of autoantibodies to the p53 protein in autoimmune hepatitis. Autoimmunity. 2002;35:493–496. [PubMed]
183. Kyriatsoulis A, Manns M, Gerken G, Lohse AW, Maelicke A, Wessler I, Reske K, Meyer zum Büschenfelde KH. Immunochemical characterization of anti-acetylcholine receptor antibodies in primary biliary cirrhosis. J Hepatol. 1988;6:283–290. [PubMed]
184. Sundewall AC, Lefvert AK, Olsson R. Anti-acetylcholine receptor antibodies in primary biliary cirrhosis. Acta Med Scand. 1985;217:519–525. [PubMed]
185. Invernizzi P, Battezzati PM, Crosignani A, Zermiani P, Bignotto M, Del Papa N, Zuin M, Podda M. Antibody to carbonic anhydrase II is present in primary biliary cirrhosis (PBC) irrespective of antimitochondrial antibody status. Clin Exp Immunol. 1998;114:448–454. [PubMed]
186. Ueno Y, Ishii M, Igarashi T, Mano Y, Yahagi K, Kisara N, Kobayashi Y, Niitsuma H, Kobayashi K, Shimosegawa T. Primary biliary cirrhosis with antibody against carbonic anhydrase II associates with distinct immunological backgrounds. Hepatol Res. 2001;20:18–27. [PubMed]
187. Comay D, Cauch-Dudek K, Hemphill D, Diamandis E, Wanless I, Heathcote EJ. Are antibodies to carbonic anhydrase II specific for anti-mitochondrial antibody-negative primary biliary cirrhosis? Dig Dis Sci. 2000;45:2018–2021. [PubMed]
188. Hosoda H, Okawa-Takatsuji M, Tanaka A, Uwatoko S, Aotsuka S, Hasimoto N, Ozaki Y, Ikeda Y. Detection of autoantibody against carbonic anhydrase II in various liver diseases by enzyme-linked immunosorbent assay using appropriate conditions. Clin Chim Acta. 2004;342:71–81. [PubMed]
189. Alver A, Menteşe A, Karahan SC, Erem C, Keha EE, Arikan MK, Eminağaoğlu MS, Deger O. Increased serum anti-carbonic anhydrase II antibodies in patients with Graves' disease. Exp Clin Endocrinol Diabetes. 2007;115:287–291. [PubMed]
190. Akisawa N, Maeda T, Iwasaki S, Onishi S. Identification of an autoantibody against alpha-enolase in primary biliary cirrhosis. J Hepatol. 1997;26:845–851. [PubMed]
191. Saulot V, Vittecoq O, Charlionet R, Fardellone P, Lange C, Marvin L, Machour N, Le Loët X, Gilbert D, Tron F. Presence of autoantibodies to the glycolytic enzyme alpha-enolase in sera from patients with early rheumatoid arthritis. Arthritis Rheum. 2002;46:1196–1201. [PubMed]
192. Bogdanos DP, Gilbert D, Bianchi I, Leoni S, Mitry RR, Ma Y, Mieli-Vergani G, Vergani D. Antibodies to soluble liver antigen and alpha-enolase in patients with autoimmune hepatitis. J Autoimmune Dis. 2004;1:4. [PMC free article] [PubMed]
193. Mosca M, Chimenti D, Pratesi F, Baldini C, Anzilotti C, Bombardieri S, Migliorini P. Prevalence and clinico-serological correlations of anti-alpha-enolase, anti-C1q, and anti-dsDNA antibodies in patients with systemic lupus erythematosus. J Rheumatol. 2006;33:695–697. [PubMed]
194. Terrier B, Degand N, Guilpain P, Servettaz A, Guillevin L, Mouthon L. Alpha-enolase: a target of antibodies in infectious and autoimmune diseases. Autoimmun Rev. 2007;6:176–182. [PubMed]
195. Vermeulen N, Arijs I, Joossens S, Vermeire S, Clerens S, Van den Bergh K, Michiels G, Arckens L, Schuit F, Van Lommel L, et al. Anti-alpha-enolase antibodies in patients with inflammatory Bowel disease. Clin Chem. 2008;54:534–541. [PubMed]
196. Yamaguchi H, Miura H, Ohsumi K, Ishimi N, Taguchi H, Ishiyama N, Shiraishi Y, Yamamoto T, Ogata S. Detection and characterization of antibodies to bacterial heat-shock protein 60 in sera of patients with primary biliary cirrhosis. Microbiol Immunol. 1994;38:483–487. [PubMed]
197. Martins EB, Chapman RW, Marron K, Fleming KA. Biliary expression of heat shock protein: a non-specific feature of chronic cholestatic liver diseases. J Clin Pathol. 1996;49:53–56. [PMC free article] [PubMed]
198. Vilagut L, Parés A, Viñas O, Vila J, Jiménez de Anta MT, Rodés J. Antibodies to mycobacterial 65-kD heat shock protein cross-react with the main mitochondrial antigens in patients with primary biliary cirrhosis. Eur J Clin Invest. 1997;27:667–672. [PubMed]
199. Bogdanos DP, Pares A, Baum H, Caballeria L, Rigopoulou EI, Ma Y, Burroughs AK, Rodes J, Vergani D. Disease-specific cross-reactivity between mimicking peptides of heat shock protein of Mycobacterium gordonae and dominant epitope of E2 subunit of pyruvate dehydrogenase is common in Spanish but not British patients with primary biliary cirrhosis. J Autoimmun. 2004;22:353–362. [PubMed]
200. Shinkura N, Ikai I, Yamauchi A, Hirose T, Kawai Y, Inamoto T, Ozaki S, Iwai M, Bona C, Yamaoka Y. Autoantibodies to FK506 binding protein 12 (FKBP12) in autoimmune diseases. Autoimmunity. 1999;29:159–170. [PubMed]

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