Autoantigens in primary biliary cirrhosis

The automimmune liver disease primary biliary cirrhosis (PBC) is characterised by serum autoantibodies directed at mitochondrial and nuclear antigens (seen in most patients and a subset of patients, respectively). The antimitochondrial antibodies (AMA) characteristic of PBC are directed at members of the 2-oxoacid dehydrogenase components of multienzyme complexes; in particular, the E2 and E3 binding protein (E3BP) components of the pyruvate dehydrogenase complex (PDC). The presence of autoantibodies reactive with PDC-E2 and/or E3BP is strongly predictive of the presence of PBC. Therefore, the detection of these antibodies plays a very important role in the diagnosis of PBC. Originally demonstrated using immunofluorescence approaches, AMA can now be detected by the use of commercially available enzyme linked immunosorbent assays (ELISAs). Although the ELISA based approaches have advantages in terms of laboratory practicality, they are slightly less sensitive for the diagnosis of PBC than immunofluorescence (occasional patients with PBC show reactivity with PDC related antigens not present in the antigen preparations available for use with ELISA). Therefore, immunofluorescence should continue to be available as a complementary diagnostic test for use in occasional patients. In a subset of patients with PBC, autoantibodies are directed at increasingly well characterised nuclear antigens. Antinuclear antibody (ANA) positive patients are typically AMA negative. There are no significant differences in disease phenotype between AMA positive and AMA negative groups. At present, the clinical detection of ANA is mostly by Hep2 immunofluorescence, although ELISA kits for individual nuclear antigens are increasingly becoming available.     

Complement profile in primary biliary cirrhosis

PBC is a chronic progressive liver disease of unknown etiology. Several abnormalities found in PBC support the hypothesis that it may be considered an autoimmune disease. Despite the complex and interesting relationship that exists between autoimmune disorders and the complement system, very few reports on the level of the serum complement component in PBC have been published, and most of these comprised only a few patients or analyzed only a scant number of the complement components. In the present study, sera of 73 PBC patients were analyzed for the levels of 10 complement components. It was found that the levels of most of the serum complement components, including C1q, C2, C3, C5, C7, properdin and factor B were significantly elevated in patients with PBC in comparison to healthy controls. The level of C4 was slightly lower than that of the normal controls (p = 0.019), while the levels of C6 and C8 were within the normal range. The number of PBC patients with serum levels of C4 and C6 < 60% of normal pooled serum was higher than in the respective control groups (6/69 compared with 0/26 and 4/71 compared with 0/27, respectively). However, the difference was not statistically significant. Thus, our study shows alterations in the levels of most complement components in PBC, the reasons for which are discussed.     

Solving the primary biliary cirrhosis puzzle: The emerging image of immunopathology in primary biliary cirrhosis

The role of adaptive as well as innate immune responses in the pathology of primary biliary cirrhosis (PBC) has been a major subject of investigation. Primary biliary cirrhosis is an autoimmune liver disease involving the destruction of small bile ducts, which eventually leads to liver cirrhosis. Adaptive immune responses involving autoantibody production by B cells and autoreactive T cells have been labeled as the most probable mediators of tissue destruction. Autoantibody production against mitochondrial antigens is used as a key diagnostic marker in PBC, being present in 90-95% of patient sera. Besides blood, these antimitochondrial antibodies are found in liver, bile, saliva, and urine of patients and target mitochondrial autoantigens that are well conserved between species. One possible mechanism of antibody-mediated tissue destruction is via the transcytosis of immunoglobulin A antimitochondrial antibodies through biliary epithelium. Another mechanism may involve the recognition by antimitochondrial antibodies of the mitochondrial autoantigens abnormally expressed on patient biliary epithelium. The second component of the adaptive immune response in PBC involves T cells, which comprise a large fraction of infiltrating leukocytes in diseased livers. Autoreactive CD4⁺ and CD8⁺ T cells recognizing mitochondrial antigens targeted by antimitochondrial antibodies have been isolated with specificity for epitopes that overlap with those of B cells. Cytokines production of such infiltrates indicates the involvement of both T_H1 and T_H2 responses in the diseased tissue. Besides adaptive responses, innate immunity effector mechanisms involving eosinophils, macrophages, and B cells hyperresponsive to bacterial DNA CpG motifs has been implicated in the pathology of PBC. Despite research efforts, the etiology of PBC still remains elusive, although theories involving the participation of genetic factors, molecular mimicry due to microorganisms, and a role for modification of native autoantigens by xenobiotics have been proposed.     

The enigma of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease characterized by a striking predominance in female patients (with most cases diagnosed between ages 40 and 60 yr) as well as serum auto-antibodies to mitochondrial antigens, elevated serum immunoglobulin M, progressive destruction of intrahepatic bile ducts, and, ultimately, liver cirrhosis and failure (1). The precise mechanisms leading to selective destruction of biliary epithelial cells lining intrahepatic bile ducts are still unknown, although numerous immunomediated pathways have been proposed. Genetic background appears to be important in determining susceptibility to the disease (2), but no clear association with alleles in the major histocompatibility complex has been identified. Molecular mimicry either by infections (3) or xenobiotics (4) has been proposed to be capable of breaking tolerance in genetically predisposed individuals, thus leading to onset of PBC. This article describes and discusses the available data regarding the immunomediated pathogenesis of PBC (with particular attention to auto-antibodies and autoreactive T-cells) and presents the recent evidence indicating a role for either xenobiotic chemicals or novel infectious agents in the induction of the disease.     

The diagnosis of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic liver disease characterized by the immune mediated destruction of small intrahepatic bile duct epithelial cells leading to cholestasis and cirrhosis. The autoimmune basis of PBC is supported by the highly specific anti-mitochondrial antibodies (AMAs) and autoreactive T cells, the former being the basis for diagnosis in the vast majority of cases. Although a rare disease, the incidence rates of PBC have been increasing, possibly due to increased testing and diagnosis as opposed to a true increase in disease incidence. Presently, most cases are asymptomatic and only suspected based upon routine liver tests. Those with symptoms typically complain of pruritus and fatigue. The diagnosis of PBC is based on the presence of at least 2 of 3 key criteria including a persistently elevated serum alkaline phosphatase, the presence of serum AMAs, and liver histology consistent with PBC. Anti-nuclear antibodies specific to PBC are useful in cases in which AMAs are not detected and may indicate a more aggressive course. Ursodeoxycholic acid is the only proven therapy for PBC and in most cases can delay or prevent disease progression. However, a subgroup of patients does not adequately respond to ursodeoxycholic acid and for whom new therapies are needed.     

Geographic clusters of primary biliary cirrhosis

Genetic and environmental factors have been widely suggested to contribute to the pathogenesis of primary biliary cirrhosis (PBC), an autoimmune disease of unknown etiology leading to destruction of small bile ducts. Interestingly, epidemiologic data indicate a variable prevalence of the disease in different geographical areas. The study of clusters of PBC may provide clues as to possible triggers in the induction of immunopathology. We report herein four such unique PBC clusters that suggest the presence of both genetic and environmental factors in the induction of PBC. The first cluster is represented by a family of ten siblings of Palestinian origin that have an extraordinary frequency of PBC (with 5/8 sisters having the disease). Second, we describe the cases of a husband and wife, both having PBC. A family in which PBC was diagnosed in two genetically unrelated individuals, who lived in the same household, represents the third cluster. Fourth, we report a high prevalence of PBC cases in a very small area in Alaska. Although these data are anedoctal, the study of a large number of such clusters may provide a tool to estimate the roles of genetics and environment in the induction of autoimmunity.     

Pregnancy in women with primary biliary cirrhosis

Background & AimsPrimary biliary cirrhosis (PBC) may present in all decades of life, also in childbearing age. Data on maternal and fetal outcome is limited. We aimed to investigate the impact of pregnancy and childbirth on the disease course and possible effects of PBC on fetal outcome.MethodsRetrospective study of local cases and a compact review of published reports between 1950 and 2014.ResultsOur cases along with literature review provided 98 pregnancies in 72 PBC patients. PBC was diagnosed during pregnancy in 26 (36%) patients and 46 (64%) had the diagnosis before conception. Twenty-four (30%) of the pregnancies were associated with biochemical flares and 55 (70%) with clinical improvement or stabilization. De novo onset or worsening of pruritus was seen in 49% (45/92). No maternal deaths were reported. Post-partum disease activation was observed in 60% (53/88). One patient was referred for liver transplantation after delivery. A miscarriage rate of 24% and three stillbirths were reported. Most patients were treated with ursodeoxycholic acid (UDCA) during breastfeeding and 12 patients also received UDCA during the first trimester without any identified side effects.ConclusionMost women with PBC maintain a stable disease during pregnancy, but post-partum biochemical flares are common. Symptomatic pruritus may be challenging in pregnant PBC patients. UDCA appears to be safe during pregnancy and breastfeeding. A successful pregnancy outcome is a realistic expectation for women with PBC.     

Anti-pyruvate dehydrogenase autoantibodies in primary biliary cirrhosis

Antimitochondrial antibodies (AMA) may be detected in 95% of patients with primary biliary cirrhosis (PBC). The target autoantigens for the AMA were recently identified as four closely related metabolic enzymes located in the mitochondria. We have purified the pyruvate dehydrogenase (PDH) enzyme from bovine heart, showing that all PBC sera reacted with a 74-kd band. PDH was utilized to establish an ELISA assay for detecting the relevant antibodies. One hundred twelve of 120 sera from patients with PBC (95%) reacted with the PDH but none of the 201 control sera, including normal subjects and a panel of sera from other patients with liver diseases, showed similar reactivity. In 77% of the PBC sera the anti-PDH antibody isotype was identified as a combination of IgG and IgM, while in 18% only IgM was detected. In 5% of the sera the isotype was confined to IgG. PBC sera specifically inhibited the PDH enzyme activity. The enzyme inhibition correlated with the anti-PDH antibody titers. Thus, PDH seems to be one of the major target epitopes for AMA observed in sera of patients with PBC.     

Familial primary biliary cirrhosis in Hiroshima.

Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by the presence of anti-mitochondrial antibodies and chronic inflammatory destruction of septal and intrahepatic bile ducts. Although there are no obvious associations of PBC with MHC class I or class II genes, there appears to be a significant increased risk of developing disease within families. Clearly, a combination of genetic and environmental factors play a role in disease pathogenesis, although the relative contributions of each are unclear. In this study, we have taken advantage of the well-defined health-care system in Hiroshima prefecture, where PBC is a reportable disease. In the period 1988-1997, 156 new patients with PBC in a total population of 2,873,000 were diagnosed. These patients included 18 subjects that were derived from eight different families in which more than one family member had a history of PBC; this reflects a frequency of 5.1% and further shows that the prevalence of PBC is greatly increased in family members. Of interest, the median age of onset of PBC in second generation patients was much younger (33.4+/-10.8 years) compared to median disease onset in general patients with PBC in Hiroshima (55.6+/-12 years). In fact, it was striking that the onset of disease in family members often occurred within a few years of each other. We also noted that sera of affected members had similar AMA reactive profiles against recombinant PDC-E2, BCKD-E2 and OGDC-E2; the major autoantigens of PBC. Similar HLA types were found within affected members of a pedigree but the data is limited because of absence of similar typing of unaffected members. The increased family history of PBC, and the earlier onset of disease in second generation members, suggests that environmental agents are an important risk factor for the development of disease. We suggest that genomic analysis in familial PBC will be important to identify the mechanisms of genetic susceptibility.     

Chromolipid-induced portal lymphadenopathy in primary biliary cirrhosis

Yellow or brown granules of chromolipid, often called Hamazaki-Wesenberg bodies, have previously been described in the sinuses of lymph nodes. They have been seen in normal nodes and nodes showing non-specific reactive changes; particular interest has been shown in a suggested association with sarcoidosis. We describe two patients, both with primary biliary cirrhosis, in whom the accumulation of large numbers of such bodies in the sinuses of lymph nodes of the porta hepatis led to a prominent lymphadenopathy.     

Serum protein levels in primary biliary cirrhosis

Serum levels of albumin, transferrin, alpha(2)-macroglobulin, beta(1)C/beta(1)A, IgA, IgG, and IgM have been determined in 73 patients with primary biliary cirrhosis and in age- and sex-matched controls. A highly significant fall in albumin was demonstrated, and there were highly significant increases in alpha(2)-macroglobulin and all three immunoglobulin levels. Transferrin and beta(1)/Cbeta(1)A levels were unchanged. No significant correlations were found between the titre of antimitochondrial antibody, the duration of symptoms, and any of the serum proteins estimated. A highly significant positive correlation was present between serum albumin and transferrin levels in both patient and control groups.     

Anti-acetylcholine receptor antibodies in primary biliary cirrhosis

Low concentrations of acetylcholine receptor antibodies were found in 16 out of 17 patients with primary biliary cirrhosis. Seven patients were treated or had been treated with penicillamine. Ten untreated patients had antibody levels corresponding to those found in the treated group. Our data support the presence of receptor antibodies of both IgG and IgM class.