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© Borgis - Postępy Nauk Medycznych 11/2011, s. 963-968
*Alicja Bauer
Antimitochondrial and antinuclear antibodies in primary biliary cirrhosis**
Przeciwciała antymitochondrialne i antyjądrowe w pierwotnej żółciowej marskości wątroby
Department of Biochemistry and Molecular Biology, Medical Center of Postgraduate Education, Warsaw
Head of Department: prof dr hab. Barbara Czarnocka
Streszczenie
Pierwotna żółciowa marskość (PBC) jest przewlekłą chorobą wątroby o nieznanej etiologii. Rozpoczyna sie od zmian zapalnych w małych kanalikach żółciowych, powoli doprowadzając do patologicznych zmian w tkance wątrobowej i całkowitej marskości wątroby. Przeciwciała występujące w surowicach pacjentów są przydatnym narzędziem uzupełniającym diagnozę choroby. Najbardziej czułym i swoistym markerem immunologicznym PBC są przeciwciała antimitochondrialne (AMA), skierowane przeciwko kompleksowi dehydrogenazy pirogronianowej, zlokalizowanemu w wewnętrznej błonie mitochondrialnej. Ponadto dla ok. 50% pacjentów z PBC charakterystyczne są przeciwciała przeciwjądrowe (ANA), gdzie głównymi autoantygenami są białka otoczki jądrowej: glikoproteina gp210, nukleoporyna p62 i receptor laminy B (LBR). Zwłaszcza przeciwciała skierowane przeciwko antygenom gp210 i p62 są bardzo specyficzne dla PBC i wykrywanie ich może być pomocne w diagnostyce serologicznej, zwłaszcza w przypadkach, w których nie wykryto przeciwciał przeciwmitochondrialnych. Istnieją doniesienia wskazujące na związek obecności przeciwciał skierowanych przeciwko białkom kompleksu porowego i gorszym rokowaniem w przebiegu PBC. Badania przeprowadzone w różnych regionach świata, wykazały też znaczne różnice w częstości występowania (9-45%) przeciwciał przeciwko białku gp210 w PBC. W ciągu ostatnich lat kolejne struktury jądrowe zostały zidentyfikowane jako istotne dla przeciwciał ANA w PBC. Należą do nich między innymi białko Sp100 i białka białaczki promielocytowej. Specyficzne przeciwciała przeciwjądrowe mogą stanowić nowe ważne, narzędzie w procesie diagnostycznym pacjentów z PBC.
Summary
Primary biliary cirrhosis (PBC) is a chronic liver disease of unknown etiology. It starts with inflammatory changes in the small biliary ducts and slowly develops pathological changes in the tissue, leading to complete liver cirrhosis. Serum autoantibodies are crucial tools for diagnosis of PBC. Antimitochondrial autoantibodies (AMA), directed against the 2-oxoacid-dehydrogenase complex of the inner mitochondrial membrane, are the most sensitive and specific immunologic markers of PBC. Additionally 50% of PBC patients have antinuclear antibodies (ANA). The nuclear envelope proteins have been identified as target of ANA reactivity. A part of PBC patients develops antibodies against constituents of the nuclear pore complex – gp210 protein, p62 nucleoporin and lamin B receptor (LBR). Antibodies to these antigens such as gp210 protein and p62 nucleoporin are highly specific for PBC and can aid in the serologic diagnosis, especially in cases in which antimitochondrial antibodies are not detectable. A review of several studies performed in various regions of the world showed wide differences in prevalence (9-45%) of antibodies against gp210 protein in PBC. There are reports indicating an association of positivity for antibodies against the nuclear pore complex with poor outcome of PBC. During the last years a number of another nuclear structures have been recognized as a specific targets of ANAs in PBC. These include Sp100 and promyelocytic leukemia proteins. Specific antinuclear antibodies will provide an important, novel clinical tool in diagnostic process of patients with PBC.
Introduction
Primary biliary cirrhosis is a chronic, slowly progressive cholestatic liver disease with features of an autoimmune disorder, with unknown etiology. It starts with inflammatory changes in the small biliary ducts and after developing pathological changes in the tissue, leading to complete liver cirrhosis and the necessity of liver transplantation (1-3). PBC occurs between the ages of 35-70 and affects predominantly women (1, 4).
Antimitochondrial antibodies (AMA), which are present in 90-96% of patients, are the most characteristic of this entity and can be observed long before the disease is clinically overt (5, 6). In addition, epitopes of T cells and B cells targeting mitochondrial autoantigens have been identified (7, 8).
Antinuclear antibodies may be also detected in about 50% of patients and they are relevant as a tool for diagnosis of PBC, specially in AMA-negative patients and their high specificity for PBC has been confirmed in several reports (9-11). They are directed against three components of the nuclear envelope (NE): the lamina, the pore complex (NPC) and the inner membrane (10-12). Remarkable is the high specificity of anti-NPCs antibodies for PBC, which appears to be greater than 95%. Therefore, the presence of anti-NPC antibodies can be used to confirm the diagnosis of PBC in atypical cases, especially when AMA are undetectable (11-13).
The large geographical differences in the frequency of PBC and regional difference in AMA and anti-nuclear antibodies prevalence are explained by distinct immunogenetic background in the population of PBC patients (14, 15).
Antimitochondrial antibodies
The presence of autoantibodies in the serum of patients with primary biliary cirrhosis (PBC) were first suggested by Jan Mackay in 1958 (12). In the following years, PBC sera were found to manifest a characteristic pattern, when tested again animal tissues by indirect immunofluorescence (IIF) and the cytoplasmic target identified as the mitochondria. In the past 50 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 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.
The target antigen M2 is attached to the inner mitochondrial membrane (13, 16, 17) and consists of five components (17). These components have been identified in the following years on molecular bases as subunits of the 2-oxo acid dehydrogenase complex of the inner mitochondrial membrane: the pyruvate dehydrogenase complex (PDC), the 2-oxoglutarate dehydrogenase complex and the branched-chain 2-oxo acid dehydrogenase complexes (18-20). Using an original expression vector, Gershwin first identified the cDNA encoding the 70 kDa mitochondrial antigen that led to the identification of E2 subunit of pyruvate dehydrogenase complex (PDC-E2) (21). Serum antimitochondrial antibodies react against members of the 2-oxo-acid dehydrogenase complexes (2-OADC) family, including PDC-E2, the E2 subunit of branched chain 2-oxo-acid dehydrogenase complex (BCOADC-E2), the E2 subunit of the oxoglutarate dehydrogenase complex (OGDC-E2),the dihydrolipoamide dehydrogenase (E3)-binding protein (E3BP), and the E1α subunit of pyruvate dehydrogenase complex (PDC-E1α) (22). Sera of histologically proven PBC cases react only with the antigens BCOADC or OGDC, but not with PDC-E2, in 4-13% (23,24). More recently, Gershwin, Leung, and colleagues created a recombinant fusion protein (MIT3), which includes the immunodominant portions of the 3 primary targets of AMA, E2 – subunits of the pyruvate dehydrogenase complex (PDC-E2), the branched-chain 2-oxo-acid dehydrogenase complex (BCOADC-E2) and the 2-oxo-glutarate dehydrogenase complex (OGDC-E2) (25).
The major M2-antigen which is recognized by nearly 90-96% of PBC sera is the E2 component of PDC.
By indirect immunofluorescence false-positive results are quite frequent and in many cases a more sensitive and specific confirmation test, such as immunoblotting or ELISA, is required. In studies of AMA reactivity in large numbers of sera, Leung et al. have demonstrated that recombinant antigens used for immunodiagnosis are strikingly specific for PBC. Specificity and sensitivity is dramatically increased with the use of ELISA and/or immunoblot assays compared with immunofluorescence (28). Recently, it has been suggested that Luminex and an ELISA using a mixture of purified PDC and MIT3 as antigenic targets may increase sensitivity of the AMA detection systems (26, 27).
AMA positivity is considered specific for PBC, indeed it is one of the three diagnostic criteria for the disease. No proof of a pathogenic role for AMA has been obtained thus far. It is not clear how autoantibodies directed against a ubiquitous antigen might in turn produce a highly tissue-specific autoimmune injury. Studies of AMA-M2-positive individuals with initially no evidence of cholestatic liver disease of whom the majority developed fully manifested PBC over time additionally indicated that these autoantibodies may indeed be sufficiently specific very early markers development of PBC (28-30). Metcalf et al. reported that about 75% of asymptomatic individuals with serum AMA eventually developed symptoms of PBC over a 10-25-year observation period (29). Serum AMA strongly suggest the diagnosis of PBC at early stages even before the appearing of biochemical cholestasis. Although highly specific, AMA do not predict the prognosis in patients with PBC (30). 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 (28).
Furthermore, AMA will typically reappear in patients transplanted for PBC but histological features of PBC re-manifest in few cases (31).
M4 is a single antigen with molecular weight of 52 kDa. 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 (32-37). 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 (34, 38). 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. 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 (34, 36, 37), though this finding wasn’t supported by a blinded study on Dutch PBC patients conducted by Vleggaar et al (39).
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 (40-43).
AMA are non-organ- and non-species-specific, and contain IgA, IgG and IgM subclasses. Some studies have demonstrated that the different AMA IgG subclasses have different clinical significance (44).
Several possible mechanisms have been suggested regarding the generation of AMA, such as oxidative damage, molecular mimicry and changed biliary epithelial cell (BEC) apoptosis (45, 46).
Approximately 5% of well-documented PBC patients do not react with any of the mitochondrial antigens using currently available assays.
Antinuclear antibodies
Nuclear envelope protein autoantibodies

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otrzymano: 2011-09-12
zaakceptowano do druku: 2011-10-17

Adres do korespondencji:
*Alicja Bauer
Zakład Biochemii i Biologii Molekularnej Centrum Medyczne Kształcenia Podyplomowego
ul. Marymoncka 99, 01-813 Warszawa
tel.: (22) 569-38-28
e-mail: alabauer@wp.pl

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