Are Antibodies to Carbonic Anhydrase II Specific for Anti-Mitochondrial Antibody-Negative Primary Biliary Cirrhosis?

Antibodies to carbonic anhydrase II (CAII) have been reported to be specific to anti-mitochondrial antibody (AMA) -negative primary biliary cirrhosis (PBC). We examined whether antibodies to CAII are specific for AMA-negative PBC or a nonspecific response in autoimmune liver disease. Antibody assays to CAII, by western immunoblot (dilution 1:200), were performed on sera from 16 AMA-negative PBC patients, 21 AMA-positive PBC patients, 21 autoimmune hepatitis type 1 (AIH) patients, and 18 alcoholic liver disease (ALD) patients. CAII antibody activity was found in 8 of 16 (50%) of the AMA-negative PBC patients, 9 of 21 (43%) of the AMA-positive PBC group, 10 of 21 (48%) of the AIH group, and in 3 of 18 (17%) of the ALD control group. There was no difference in the prevalence of CAII antibody reactivity between the AMA-negative PBC, AMA-positive PBC, and AIH groups. In conclusion, we determined that CAII antibodies are detected with equal frequency in AMA-positive PBC and AIH. Given that CAII antibodies have been reported in other nonhepatic autoimmune diseases, we conclude that CAII antibodies are likely a nonspecific marker of autoimmunity rather than specific for AMA-negative PBC.     

Autoimmune cholangitis

Autoimmune cholangitis is the term that has been used to describe patients who have the clinical, biochemical, and histologic characteristics of primary biliary cirrhosis (PBC), but who are antinuclear antibody positive rather than anti-mitochondrial antibody (AMA) positive in their sera. The course of their disease is similar to AMA positive cases, and the associated nonhepatic autoimmune diseases are the same in both AMA-positive and AMA-negative PBC. Serial testing for AMA using highly sensitive and specific techniques over time suggests that in subjects with autoimmune cholangitis, their AMA negative status remains negative. The beneficial response to treatment with ursodeoxycholic acid is the same as for AMA-positive PBC. It may be preferable to use the term autoimmune cholangitis, further stratified by AMA status, instead of the somewhat innapropriate term primary biliary cirrhosis.     

Human leukocyte antigen Class II associations in serum antimitochondrial antibodies (AMA)-positive and AMA-negative primary biliary cirrhosis.

BACKGROUND/AIMS: An association of Class II HLA-DR8 antigen is reported in patients with serum antimitochondrial antibodies (AMA)-positive primary biliary cirrhosis (PBC); no information exists as to an association with AMA-negative PBC. We compared the frequency of HLA Class II genes in AMA-positive and AMA-negative PBC patients and healthy controls. METHODS: Genomic DNA was extracted from the blood of 154 AMA-positive and 26 AMA-negative Caucasian PBC patients and from 216 healthy Caucasian controls and tested for the alleles at two HLA Class II loci, DRbeta1 and DQbeta1. RESULTS: Higher allele frequencies of HLA-DRbeta1*08 and DQbeta1*04 were found in the AMA-positive PBC patients versus controls (14.9% vs. 6.5%, odds ratio (OR)=3.3, global P=0.03 and 14.4% vs. 6.5%, OR=2.6, global P=0.002). All patients positive for DRbeta1*0801 were positive for the DQbeta1*0402 allele, delta score=22 for AMA-positive patients, 11 for controls. In AMA-negative PBC, the frequency of DRbeta1*08 and DQbeta1*04 was 0%, significantly different from the AMA-positive patients (P=0.05, P=0.05). CONCLUSIONS: AMA response may identify a group of PBC patients with a distinctive expression of the disease with the response associated with a gene(s) in the class II region of the major histocompatibility complex on the short arm of chromosome 6.     

No prognostic significance of antimitochondrial antibody profile testing in primary biliary cirrhosis

BACKGROUND/AIMS: The rate of disease progression varies considerably between individuals with primary biliary cirrhosis (PBC). On the basis of serological subtyping 4 antimitochondrial antibody (AMA) profiles (A, B, C and D) can be defined. The finding of previous studies that profile C/D is associated with a progressive course, in contrast to profile A/B, is a question of debate. The aim of the study was to investigate whether AMA profiles predicted the course for a cohort of Dutch PBC patients. METHODOLOGY: Patients with an established diagnosis of AMA-positive PBC, AMA-negative PBC patients, non-PBC decompensated cirrhotics and healthy volunteers. Serum samples from 38 AMA-positive progressive patients, 31 AMA-positive patients without evidence of progression for at least 6 years, 5 AMA-negative PBC patients, 5 non-PBC decompensated cirrhotics and 5 healthy volunteers were assessed. AMA profiles were determined without knowledge of the clinical data. RESULTS: In the progressive AMA-positive group, 13% had profile A/B and 84% had profile C/D. In the non-progressive group, 13% had profile A/B, 77% profile C/D; 10% had no profile. During follow-up, a change from profile A/B to profile C/D or vice versa was not observed. CONCLUSIONS: This study found that not only PBC patients with AMA profile C/D but also patients with profile A/B may run a progressive course and therefore does not support the suggestion that AMA profiles can be used as independent prognostic indicator. The divergent results of this and previous studies may be explained by the selection of different patient populations.     

抗线粒体抗体阴性原发性胆汁性肝硬化患者的临床、生化和病理学特点

目的 分析抗线粒体抗体（AMA）阴性的原发性胆汁性肝硬化（PBC）患者的临床、生化和病理学特点.方法 76例PBC患者,将间接免疫荧光法测定AMA及酶联免疫吸附法检测AMA-M2均为阳性的患者归为AMA阳性组,均为阴性的为AMA阴性组.观察两组临床表现;检测血清学和免疫学指标,如血清总胆红素（TBil）、直接胆红素（DBil）、丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、碱性磷酸酶（ALP）、γ-谷氨酰转移酶（GGT）、球蛋白（GLO）、免疫球蛋白（IgG、IgM、IgA）、抗核抗体（ANA）、抗平滑肌抗体（SMA）、抗线粒体抗体（AMA）、抗可溶性酸性磷酸化核蛋白抗体（sp100）及抗核孔膜糖蛋白抗体（gp210）;行肝穿刺肝组织学检查,并进行比较.结果 76例PBC患者中,AMA阴性15例,占19.7％.AMA阴性组与AMA阳性组临床表现、肝功能各项指标、病理分期及组织学表现上比较P均＞0.05.AMA阴性组、AMA阳性组IgG中位数分别为1 780、1 590 mg/L,IgM中位数分别为384.0、481.5 mg/L,GLO中位数分别为39、42 g/L,两组比较P均＜0.05.AMA阴性组、AMA阳性组ANA阳性率分别为93.3％、23.0％,SMA阳性率分别为20.0％、1.6％,sp100阳性率分别为33.3％、24.6％,gp210阳性率分别为40.0％、29.5％,两组ANA、SMA阳性率比较P均＜0.05,但两组sp100、gp210阳性率比较P均＞0.05.结论 AMA阴性PBC的临床表现、肝功能和病理学特点与AMA阳性PBC相似,但IgG水平和SMA、ANA阳性率较高,IgM和GLO水平较低.     

Clinicopathological study of primary biliary cirrhosis negative for antimitochondrial antibodies

Abstract: Primary biliary cirrhosis (PBC) is characterized by the occurrence of antimitochondrial antibodies (AMA) and the progressive destruction of intrahepatic bile ducts, followed by biliary cirrhosis. However, there are about 5% of PBC patients who show clinicopathological features of PBC but are negative for AMA. In this study, clinicopathological features, as well as antibody reactivity against recombinant (r)-mitochondrial polypeptides, were examined in 30 AMA negative PBC patients and 38 AMA positive PBC patients, in whom the presence of AMA had been determined by indirect immunofluorescence (IF). There were few differences in the clinical and serological features between both groups. Histopathologic features, including staging, bile duct lesions and granuloma, were also similar in both groups. Among the 30 IF-tested AMA negative patients, 29 were also negative against beef heart mitochondrial proteins, but 24 reacted to one or more of the following r-polypeptides, as determined by immunoblotting: E1 alpha of pyruvate dehydrogenase complex, the E2 subunit of pyruvate dehydrogenase complex, and the branched-chain 2-oxo-acid dehydrogenase complex. The remaining six AMA-negative patients were asymptomatic, and histologically resembled having stage 1 of the disease, with relatively mild lymphocytic piecemeal necrosis. One case was positive for anti-smooth muscle antibody. The other clinicopathological features of these patients were similar to those of other AMA negative patients. The present study found that a majority of the AMA-negative patients fulfilling other clinicopathological criteria of PBC, had features similar to the AMA-positive PBC patients, and that a majority of IF AMA-negative patients were positive for r-polypeptides of the 2-oxo-acid dehydrogenase complex. It seems that nearly all the AMA negative patients possess a broad spectrum of antibody profile of AMA, in addition to clinicopathological and serological features.     

A sensitive bead assay for antimitochondrial antibodies: Chipping away at AMA-negative primary biliary cirrhosis

The antimitochondrial response in primary biliary cirrhosis (PBC) is the most highly directed and specific self-reacting antibody in human immunopathology. Originally, antimitochondrial antibodies (AMAs) were detected by indirect immunofluorescence (IIF) and found in approximately 90% of well-documented patients with PBC. The introduction of recombinant autoantigens and the use of immunoblotting have increased the sensitivity and specificity of AMAs, and they are now considered positive in approximately 95% of patients with PBC. Clearly, accurate autoantibody detection represents one of the fundamental requirements for reliable diagnostics in autoimmunity. To address the 5% of AMA-negative patients with PBC, we have generated and validated a bead assay for the detection of AMA. We enrolled 120 patients with PBC, including a non-random group of 30 rigorously proven AMA-negative patients, 50 healthy subjects, and 74 controls with autoimmune diseases (18 with primary sclerosing cholangitis, 16 with autoimmune hepatitis, and 40 with systemic lupus erythematosus). Individual bead assays were done with the three mitochondrial autoantigens, PDC-E2, BCOADC-E2, and OGDC-E2. As expected, 90 of 90 previously known AMA-positive patients remained positive with this assay but, interestingly, 20% of the rigorously defined AMA-negative patient group had antibodies to one or more of the mitochondrial autoantigens. Furthermore, 100% of these newly detected AMA-positive patients were anti-nuclear antibody (ANA) positive. CONCLUSION: The development of this assay reflects the potential for automated detection with rapid and reliable assaying and further highlights the diminished number of truly AMA-negative PBC patients.     

Patients with autoimmune hepatitis who have antimitochondrial antibodies need long-term follow-up to detect late development of primary biliary cirrhosis

Patients with autoimmune hepatitis (AIH) who have antibodies against mitochondrial proteins (AMA positive) are believed to have an autoimmune syndrome that should be managed as AIH. Of patients with AMA-positive AIH, we report on 3 individuals to demonstrate how autoimmune liver disease can progress over time. Specific features of primary biliary cirrhosis (PBC) overlapped in time in these patients. Our observations indicate the importance of careful follow up of patients with AMA-positive AIH; health care professionals that treat such patients should therefore be aware of longitudinal clinical changes that might indicate development of PBC in this setting.     

Changes in titers of antimitochondrial and antinuclear antibodies during the course of primary biliary cirrhosis

A case of primary biliary cirrhosis (PBC) in whom a complete biochemical (serum bilirubin, transaminases and alkaline phosphatase) remission was noted after combination treatment with ursodeoxycholic acid (UDCA) and corticosteroid is reported. The antimitochondrial antibody (AMA) detected by indirect immunofluorescence was initially positive, and the antinuclear antibody (ANA) was negative, but these two antibodies subsequently fluctuated independently (AMA-positive/ANA-negative, AMA-negative/ANA-negative, AMA-negative/ANA-positive, AMA-positive/ANA-positive, and again AMA-negative/ANA-positive) in spite of a lack of histopathological improvement in the liver after treatment. The clinical presentation in our case suggests that in some cases the diagnosis of PBC or so-called autoimmune cholangitis (AIC) might depend on the 'phase' of the same disease. Our results also suggest that detailed immunoreactive profiles against 2-oxo-acid dehydrogenase complex (2-OADC) enzymes by using immunoblotting, together with a serial histological examination, should provide more precise information for a diagnosis of PBC.     

Immunoreactivity to M2 proteins in antimitochondrial antibody-negative patients with primary biliary cirrhosis

Abstract Although antimitochondrial auto-antibodies are characteristically present in the serum of patients with primary biliary cirrhosis (PBC), there is a discrepancy between the positivity for antimitochondrial antibody (AMA) and that for anti-M2 auto-antibody. In an attempt to explain the discrepancy, this study investigates the relationship between the AMA titre, determined by indirect immunofluorescence, and immunoreactivity to four inner mitochondrial membrance proteins (M2 proteins) with molecular weights of 70, 50, 47, and 40 kDa in 129 patients with PBC. Antimitochondrial antibody positivity was identified in 114 (88%) of 129 patients with clinically and histologically confirmed PBC. There were no significant differences between the AMA-negative and AMA-positive groups in clinical characteristics or histologically determined disease stage. Immunoblot analysis showed that all patients had anti-M2 auto-antibodies to one or more of the four M2 proteins. Nine (60%) of the 15 AMA-negative patients had antibodies to only one M2 protein (either 70 or 47 kDa). In contrast, 34 (53%) of the 64 patients with high AMA titres ( 1: 320) had antibodies to all four M2 proteins. There was a significant rank correlation between the AMA titre and the number of antibodies to M2 proteins ( P < 0.01). These findings indicate that the AMA titre is not influenced by the immunogenicity of M2 protein but by the number of M2 proteins that elicit an antibody response and that decreased immunoreactivity to M2 proteins may induce AMA negativity in PBC serum samples.     

Primary biliary cirrhosis and autoimmune cholangiopathy

AMA are detected in the serum of 92% to 95% of patients with PBC using indirect immunofluorescent methods. AIC is the term used to describe the 5% to 8% of AMA-negative PBC patients who uniformly have ANA and SMA. Recent applications of more sensitive and specific tests to detect serum AMA have shown that most, if not all, patients with AIC actually do have AMA. Emerging evidence that AMA and mitochondrial autoantigens play important roles in the immunopathogenesis of NSDC also suggests that AIC and PBC are likely to be a single disease, exhibiting variation in the types of autoantibodies and in both the concentrations and immunoglobulin isotypes of AMA.     

Primary biliary cirrhosis--presentation and diagnosis

Primary biliary cirrhosis is predominantly seen in middle-aged women. Typical symptoms are fatigue, pruritus, and abdominal pain. Jaundice develops in the endstage disease. At presentation, about 40% of the patients are asymptomatic, but 30% to 50% already have hepatomegaly, and 15% present with splenomegaly. Even patients with fully developed liver cirrhosis may be free of symptoms. Abnormal physical signs and advanced histological stage are more frequent in symptomatic than in asymptomatic patients. Fatigue, pruritus, and Sj?gren's syndrome are more common in women than men, but other signs and symptoms do not differ in the two sexes. PBC is associated with a large variety of other diseases, like arthropathy, CREST syndrome, autoimmune thyroiditis, and so on, which in addition will or will not produce symptoms. Hepatocellular carcinoma is a rare complication in women, but more frequent in men. Diagnosis can be established by the triad antimitochondrial antibodies (AMA), cholestatic indices, and liver histology, diagnostic or compatible with PBC. When AMA are not detected, then antinuclear antibodies (autoantibodies against gp.210 and others) can be detected in 50% of AMA-negative patients. AMA titers do not correlate with the course of the disease nor histological progression. After liver transplantation, AMA recur in nearly 100%. The liver enzyme pattern in PBC patients is cholestatic: alkaline phosphatase and gammaglutamyltransferase increase to 10 or more times the upper limit of normal. The amount of enzymes does not correlate with disease progression or stage of the disease. The only prognostic factor in PBC is serum bilirubin. AMA-negative patients account for about 10% to 15%. Routine biochemical tests are not different from AMA-positive patients, but usually higher ANA, SMA, and IgG concentrations are detected. Histologically, it is PBC. The overlap-syndrome, autoimmune hepatitis-PBC presents with the histological features of autoimmune hepatitis and PBC, with AMA, ANA, or SMA. Imaging procedures are not helpful for the diagnosis of PBC, except for liver histology. Histologically, four different stages can be assessed, ranging from florid bile duct lesions, ductular proliferation, and fibrosis to liver cirrhosis. Liver histology is of interest for the assessment of the diagnosis and for staging of the disease.     

Anti-mitochondrial antibody-negative primary biliary cirrhosis

The recent development in the authors' laboratory of a sensitive bead assay able to detect AMA in 20% of otherwise AMA-negative sera seems to support the hypothesis that many AMA-negative cases of primary biliary cirrhosis (PCB) are secondary to limits in the methods used and do not represent an independent clinical entity. Clinical data demonstrate that patients without detectable serum AMA do not differ in their natural history from their seropositive counterparts. Anti-nuclear antibodies have been associated repeatedly with more severe disease and are helpful tools in the management of patients who have PBC, particularly those lacking AMA.     

Consecutive occurrence of primary biliary cirrhosis and autoimmune hepatitis: a case report and review of the literature

Autoimmune cholangiopathy is a term that describes a subset of patients with overlapping features of primary biliary cirrhosis (PBC) and autoimmune hepatitis (AH). These patients typically have cholestasis, negative antimitochondrial antibody (AMA), liver histology suggestive of PBC, and may respond clinically to corticosteroid therapy. We describe a patient who presented with typical AMA-positive, biopsy-proven PBC who responded to ursodeoxycholic acid therapy both clinically and biochemically. Approximately 3 yr later, she developed elevated transaminases with biopsy-proven antinuclear antibody (ANA) negative AH. The AMA was negative at this time. After responding to steroid therapy for the AH and after discontinuing the ursodeoxycholic acid, the patient had a clinical recurrence of PBC with renewed AMA positivity.     

Prevalence of antimitochondrial antibody in Japanese corporate workers in Kanagawa prefecture

Background The prevalence of antimitochondrial antibody (AMA) in humans and its relationship to the development of primary biliary cirrhosis (PBC) are not well known. We have estimated the frequency of AMA in the general population, and studied its association with PBC.Methods We studies 1714 corporate workers (median age, 48 years; range, 30 to 59 years) who had an annual health check from 1998 to 1999 at Kawasaki Social Insurance Hospital in Japan. We used an indirect immunofluorescence method for screening serum AMA. We applied the prevalence of AMA-positive people in the study group to the general population in Japan. Then the inferred AMA-positive population was compared to the actual number of patients with PBC in statistics published by the Japanese Government.Results AMA was detected in 11 of 1714 people (0.64%; 95% confidence interval, 0.26% to 1.02%). All these 11 sera reacted with 2-oxoacid-dehydrogenase complex by immunoblotting. Of these 11 individuals, none had subjective symptoms, all had normal serum bilirubin levels, and 6 had abnormal liver function test results. Using published statistics for the Japanese population, we inferred that there were approximately 336472 AMA-positive people in Japan from age 30 to 59 years. The number of patients with symptomatic PBC recorded by the nationwide epidemiological survey of the Japanese Government was 2459. Thus, we inferred the rate of symptomatic PBC among AMA-positive persons to be about 0.73% (2459/336472).Conclusions AMA is not a rare antibody in the general population, but few people develop recognizable PBC even if they have AMA.     

Autoimmune cholangiopathy

Currently available evidence is insufficient to classify PBC and AIC as separate diseases. The ultimate answer to the question of whether AIC, defined as AMA-negative PBC with ANA or SMA, is a disease distinct from AMA-positive PBC with or without ANA will require a detailed comparison of etiologic factors and pathogenetic mechanisms, once they are elucidated. It is intriguing to consider the suggestion of Heathcote that the term autoimmune cholangitis be adopted to describe PBC with or without detectable AMA. However, it is improbable that the venerable term PBC will be supplanted. Hepatologists will probably continue to use the terms AIC and AMA-negative PBC interchangeably, with little risk of being misunderstood.     

Antimitochondrial antibodies of immunoglobulin G3 subclass are associated with a more severe disease course in primary biliary cirrhosis.

BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) is characterised by the presence of immunoglobulin (Ig) G antimitochondrial antibodies (AMA), which are routinely detected by indirect immunofluorescence (IFL) using composite rodent tissue substrate. The IgG subclass distribution and clinical significance of IFL-detected AMA in patients with PBC have not been previously studied in detail. METHODS: We have examined IgG subclass-specific AMA detected by IFL on rodent liver, kidney and stomach tissue substrate using affinity-purified IgG subclass monospecific antisera as revealing reagents in 95 AMA-positive PBC patients from Greece. RESULTS: AMA of any of the IgG1, IgG2 or IgG3 subclasses were present in 89/95 (93.7%) patients. Among those 89, 55 (61.8%) had IgG1, 2, 3 AMA positivity; eight (9%) had IgG1, 2; seven (7.9%) had IgG2, 3; eight (9%) had IgG1, 3; nine (10.1%) had IgG1 subclass and two (2.2%) single IgG3 AMA reactivity. IgG4 AMA was absent. IgG3 titres were higher than IgG2 and IgG1 (P<0.001) and IgG1 higher than IgG2 (P<0.001). IgG3 AMA-positive patients had a histologically more advanced disease (P<0.01) and were more frequently cirrhotic compared with those who were negative (P<0.01). There was a positive correlation between AMA IgG3 titre and Mayo risk score (r=0.55, P=0.009, Spearman's correlation). CONCLUSIONS: Our findings suggest that AMA are not restricted to a specific IgG subclass. AMA of the IgG3 subclass are associated with a more severe disease course, possibly reflecting the peculiar ability of this isotype to engage mediators of damage.     

Muscle pathological features and extra-muscle involvement in idiopathic inflammatory myopathies with anti-mitochondrial antibody

ObjectiveAnti-mitochondrial antibodies (AMAs) can be detected in some idiopathic inflammatory myopathy (IIM) patients. We aimed to investigate the clinical features of IIM patients with AMAs.MethodsWe retrospectively analysed 1,167 consecutive patients with IIM for AMA-associated myositis and compared them to age- and gender-matched AMA-negative IIM patients.ResultsTwenty-nine patients (2.5%) were identified with AMA-positive myositis; eight of them had primary biliary cholangitis (PBC). There were no significant differences in skin rash, dysphagia, interstitial lung disease, and muscle strength between AMA-positive patients and AMA-negative patients. Of 23 cases, 12 (52.2%) showed immune-mediated necrotizing myopathy (IMNM)-like pathological features. amongst AMA-positive patients, 11 of 16 patients with isolated anti-AMAs were classified as IMNM which was significantly higher than that of patients with coexistent anti-AMAs and myositis-specific antibodies (p = 0.026). Moreover, subclinical cardiac involvement was significantly more common in AMA-positive patients than in AMA-negative patients (21/29 VS 33/116, p<0.001). In addition, patients without PBC had a significantly higher incidence of abnormal echocardiography findings than that of patients with PBC (p = 0.009). Patients without heart abnormalities took significantly less time to achieve disease remission and prednisone tapering to <10 mg than patients with heart abnormalities (p = 0.000 and p = 0.001, respectively).ConclusionsIMNM was a major histopathological finding in IIM patients with isolated AMAs. AMAs were significantly associated with subclinical cardiac involvement in IIM. PBC seemed to be a protective factor for abnormal echocardiography findings in AMA-positive patients. Patients without heart involvement took less time to achieve disease remission and prednisone tapering off.     

Association between the primary biliary cirrhosis specific anti-sp100 antibodies and recurrent urinary tract infection

BACKGROUND AND AIMS: Recurrent urinary tract infections (rUTI) have been suggested to be involved in the induction of anti-mitochondrial antibodies (AMA), the serological hallmark of primary biliary cirrhosis (PBC), in view of the presence of AMA in rUTI women without liver disease and conversely of a high prevalence of rUTI in women with PBC. This prompted us to investigate whether PBC-specific anti-nuclear antibodies (ANA) to sp100, gp210 and lamin B receptor (LBR) antigens may also be related to rUTI. METHODS AND SUBJECTS: PBC-specific ANA reactivities were investigated in 20 women with rUTI but without liver disease, some of whom were AMA-seropositive; 40 women with PBC, with or without rUTI; and 104 pathological and 23 healthy controls. RESULTS: Among the women with rUTI but without liver disease, 8 (80%) of 10 AMA-positive women reacted with sp100 compared with none of the 10 AMA-negative women. Among the PBC patients, 14 (74%) of 19 with rUTI and 1 (4.8%) of the 21 without rUTI reacted with sp100. None of the rUTI women without liver disease reacted with gp210 or LBR. None of 127 pathological and healthy controls had PBC-specific ANA reactivity. CONCLUSIONS: Anti-sp100 reactivity strongly correlates with AMA seropositivity in rUTI women, with or without evidence of primary biliary cirrhosis. These findings provide additional support to the notion that E. coli infection is involved in the induction of PBC-specific autoimmunity. Additional factors must be involved in the progression to overt autoimmune disease.