Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease
© Zachou et al; licensee BioMed Central Ltd. 2004
Received: 14 December 2003
Accepted: 15 October 2004
Published: 15 October 2004
Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver characterized by hypergammaglobulinemia, characteristic autoantibodies, association with HLA DR3 or DR4 and a favorable response to immunosuppressive treatment. The etiology is unknown. The detection of non-organ and liver-related autoantibodies remains the hallmark for the diagnosis of the disease in the absence of viral, metabolic, genetic, and toxic etiology of chronic hepatitis or hepatic injury. The current classification of AIH and the several autoantibodies/target-autoantigens found in this disease are reported. Current aspects on the significance of these markers in the differential diagnosis and the study of pathogenesis of AIH are also stated. AIH is subdivided into two major types; AIH type 1 (AIH-1) and type 2 (AIH-2). AIH-1 is characterized by the detection of smooth muscle autoantibodies (SMA) and/or antinuclear antibodies (ANA). Determination of antineutrophil cytoplasmic autoantibodies (ANCA), antibodies against the asialoglycoprotein receptor (anti-ASGP-R) and antibodies against to soluble liver antigens or liver-pancreas (anti-SLA/LP) may be useful for the identification of patients who are seronegative for ANA/SMA. AIH-2 is characterized by the presence of specific autoantibodies against liver and kidney microsomal antigens (anti-LKM type 1 or infrequently anti-LKM type 3) and/or autoantibodies against liver cytosol 1 antigen (anti-LC1). Anti-LKM-1 and anti-LKM-3 autoantibodies are also detected in some patients with chronic hepatitis C (HCV) and chronic hepatitis D (HDV). Cytochrome P450 2D6 (CYP2D6) has been documented as the major target-autoantigen of anti-LKM-1 autoantibodies in both AIH-2 and HCV infection. Recent convincing data demonstrated the expression of CYP2D6 on the surface of hepatocytes suggesting a pathogenetic role of anti-LKM-1 autoantibodies for the liver damage. Family 1 of UDP-glycuronosyltransferases has been identified as the target-autoantigen of anti-LKM-3. For these reasons the distinction between AIH and chronic viral hepatitis (especially of HCV) is of particular importance. Recently, the molecular target of anti-SLA/LP and anti-LC1 autoantibodies were identified as a 50 kDa UGA-suppressor tRNA-associated protein and a liver specific enzyme, the formiminotransferase cyclodeaminase, respectively. Anti-ASGP-R and anti-LC1 autoantibodies appear to correlate closely with disease severity and response to treatment suggesting a pathogenetic role of these autoantibodies for the hepatocellular injury. In general however, autoantibodies should not be used to monitor treatment, predict AIH activity or outcome. Finally, the current aspects on a specific form of AIH that may develop in some patients with a rare genetic syndrome, the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) are also given. Autoantibodies against liver microsomes (anti-LM) are the specific autoantibodies detected in AIH as a disease component of APECED but also in cases of dihydralazine-induced hepatitis. Cytochrome P450 1A2 has been identified as the target-autoantigen of anti-LM autoantibodies in both APECED-related AIH and dihydralazine-induced hepatitis. The latter may indicate that similar autoimmune pathogenetic mechanisms can lead to liver injury in susceptible individuals irrespective of the primary defect. Characterization of the autoantigen-autoantibody repertoire continues to be an attractive and important tool to get access to the correct diagnosis and to gain insight into the as yet unresolved mystery of how hepatic tolerance is given up and AIH ensues.
Autoimmune hepatitis (AIH) is a rare chronic liver disease of unknown etiology. The estimated prevalence of AIH in Northern European countries is approximately 160–170 patients/106 inhabitants [1, 2]. The disease predominates among women and is characterized by hypergammaglobulinemia even in the absence of cirrhosis, characteristic autoantibodies, association with human leukocyte antigens (HLA) DR3 or DR4 and a favorable response to immunosuppressive treatment [3–5]. The onset of AIH disease is usually insidious, with unspecific symptoms, such as, fatigue, malaise, arthralgias, and fluctuating jaundice, right upper quadrant pain or lethargy [5–8]. However, a substantial proportion of patients may have no obvious signs or symptoms of liver disease, while occasionally the presentation may be severe and almost identical to an acute or fulminant episode of viral hepatitis [5–8]. Although AIH brings in mind the archetypal patient being a young female with endocrine abnormalities, there is nowadays increasing evidence that the disease can also affect males and can present at almost any age (the large majority of patients being between 50 and 70 years of age) [6–12].
Revised Scoring System for the Diagnosis of Autoimmune Hepatitis6.
Degree of elevation above upper normal limit of ALP vs. aminotransferases
- 1.5 – 3.0
Total serum globulins, γ-globulins, or IgG above normal
- 1.5 – 2.0
- 1.0 – 1.5
ANA, SMA or LKM-1 (titers by immunofluorescence on rodent tissues or HEp2-cells)
- >1 : 80
- 1 : 80
- 1 : 40
- <1 : 40
- AMA positive
Hepatitis viral markers (IgM anti-HAV, HBsAg, IgM anti-HBc, anti-HCV and HCV-RNA)
Recent or current use of known or suspected hepatotoxic drugs
Average alcohol intake
- <25 g/day
- >60 g/day
Other autoimmune disease(s) in patient or first degree relatives
Optional additional parameters (should be allocated only if ANA, SMA or LKM-1 are negative)
- HLA DR3, DR4, or other HLA with published association with AIH)
- Seropositivity for any of ANCA, anti-LC1, anti-SLA/LP, anti-ASGPR and anti-sulfatide
- Interface hepatitis
- Predominant lymphoplasmacytic infiltrate
- Rosetting of liver cells
- None of the above
- Biliary changes
- Other changes
Response to therapy (as defined in Table 2)
Definitions of Response to Therapy.
Either or both of the following: marked improvement of symptoms and return of serum AST or ALT, bilirubin and immunoglobulin values completely to normal within 1 year and sustained for at least a further 6 months on maintenance therapy, or liver biopsy specimen at some time during this period showing at most minimal activity.
Either or both of the following: marked improvement of symptoms together with at least 50% improvement of all liver tests during the first month of treatment, with AST or ALT levels continuing to fall to less than twice the upper normal limit within 6 months during any reductions toward maintenance therapy, or a liver biopsy within 1 year showing only minimal activity.
Either or both of the following: an increased in serum AST or ALT levels of greater than twice the upper normal limit or a liver biopsy showing active disease, with or without reappearance of symptoms, after a "complete" response as defined above.
Reappearance of symptoms of sufficient severity to require increased (or reintroduction of) immunosuppression, accompanied by any increase in serum AST or ALT levels, after a "complete" response as defined above.
In recent years however, significant progress has been made in the characterization of liver-related target-autoantigens. This has led to the notion that some of the major target-autoantigens in AIH are active enzymes of the human hepatic and non-hepatic microsomal xenobiotic metabolism [14–16]. The latter serve as a means to investigate this still enigmatic liver disease. This article will focus on the data that have evolved in the course of the characterization of autoantibody-autoantigen "system" in AIH by giving the current aspects on the role and significance of this "system" in the differential diagnosis and study of pathogenesis of AIH.
2. Classification of AIH
According to the pattern of autoantibodies detected in AIH patients, a subclassification of the disease into three types was proposed in 1994 . AIH type 1 (AIH-1) is characterized by the presence of antinuclear antibodies (ANA) and/or smooth muscle autoantibodies (SMA) which may associate with perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) [3, 5, 6, 14, 15]. AIH type 2 (AIH-2) is characterized by the detection of specific autoantibodies against liver and kidney microsomal antigens (anti-LKM type 1 or infrequently type 3) [14–16, 18] and/or antibodies against liver cytosol type 1 antigen (anti-LC1) [14, 15, 19]. AIH type 3 (AIH-3) is characterized by autoantibodies against soluble liver antigens (anti-SLA)  or to liver-pancreas antigen (anti-LP) [21, 22].
The serological diversity of autoantibodies found in AIH supports the aforementioned subclassification and provides a framework for the scientific analysis of this heterogeneous disease group [5, 15]. It also demonstrates that AIH may not be a single disease with a single underlying mechanism but most likely is a group of diseases with a similar clinical presentation [14, 15]. This is further substantiated by the finding of an unusual form of AIH in 10–18% of patients with a rare autosomal recessive disorder, the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) [23–25]. This syndrome is characterized by chronic mucocuteneous candidiasis, ectodermal dystrophy and autoimmune tissue destruction particularly of the endocrine glands (hypoparathyroidism, adrenocortical failure and gonadal failure in females) [26–29].
Classification of Autoimmune Hepatitis (AIH) According to Autoantibodies Detection
Type of AIH
ANA, SMA, p-ANCA anti-ASGP-R, anti-SLA/LP
anti-LKM-1, anti-LKM-3, anti-LC1, anti-ASGP-R
3. Detectable Autoantibodies in AIH-1
3.1. Anti-nuclear antibodies (ANA) and smooth muscle autontibodies (SMA)
ANA and/or SMA are almost exclusively requisites for the diagnosis of AIH-1 [3, 5, 6, 14, 15, 30]. In typical cases of AIH-1, these autoantibodies are detected in significant titers (≥1;80 in adults and ≥1:40 in children) in almost half of Caucasians patients with AIH-1, while ANA alone are detected in 15% and SMA alone in 35% [5, 30, 35].
ANA and/or SMA – usually in low titers – may occur in patients with chronic viral hepatitis B or C, but in most of these cases SMA lack F-actin specificity [14, 15, 42, 43]. From the clinical point of view, interferon-alpha administration is generally safe in most cases of viral hepatitis with ANA and/or SMA, although occasionally may provoke mild self-limited autoimmune disorders compared to viral hepatitis patients without ANA or SMA autoantibodies [44–46]. During immunosuppressive treatment, disappearance of ANA and/or SMA is observed in the majority of patients with AIH-1 . However, autoantibody status is unable to predict immediate outcome after cessation of corticosteroid administration. Additionally, neither autoantibody titers at first diagnosis nor autoantibody behaviour in the time course of the disease are prognostic markers for AIH-1 [14, 15, 47]. These findings indicate that ANA and SMA are not involved in the pathogenesis of AIH-1 and furthermore, their determination is more of diagnostic than prognostic value [5, 14, 15, 47].
3.2. Anti-neutrophil cytoplasmic autoantibodies (ANCA)
These autoantibodies are directed against cytoplasmic constituents of neutrophil granulocytes and monocytes. Classically, they are detected by IIF using ethanol-fixed granulocytes as substrate . Using the above method, two major subtypes can be distinguished. ANCA showing a diffuse or granular cytoplasmic staining (c-ANCA) and ANCA characterized by a perinuclear-staining (p-ANCA). Both c-ANCA and p-ANCA are valuable diagnostic and prognostic markers in systemic vasculitides in particular Wegener's granulomatosis and microscopic polyangiitis, respectively [48, 49]. Proteinase-3 has been identified as the major target-autoantigen of c-ANCA in cases with Wegener's granulomatosis, while myeloperoxidase is the documented autoantigen of p-ANCA in most patients with microscopic polyangiitis [48, 49]. Since then, ANCA (in most cases of p-ANCA type) were detected in a high prevalence in other inflammatory disorders of unknown aetiology such as, inflammatory bowel disease (more frequently in ulcerative colitis than in Crohn's disease) [50, 51] and primary sclerosing cholangitis (PSC), a liver disease that is frequently associated with ulcerative colitis [51, 52].
To determine the antigenic specificities of ANCA, antigen-specific enzyme linked immunosorbent assays (ELISAs) and Western blotting followed by immunodetection can be performed [14, 63]. Using these techniques it became obvious that in AIH-1 the target-autoantigens recognized are multiple including cathepsin G, catalase, alpha-enolase, lactoferrin, actin and high mobility group (HMG) non-histone chromosomal proteins HMG1 and HMG2 [14, 54, 56, 58, 62–65]. However, the determination of antigenic specificities of ANCA seems to have limited clinical relevance in patients with AIH-1 [14, 15, 54, 56].
In conclusion, the detection of ANCA may be a useful additional marker in searching for AIH-1, in particular in ANA/SMA/anti-LKM-1 negative cases of AIH. With the exception of a recent paper by Wu et al  the detection of ANCA is rather rare in chronic viral hepatitis [14, 54, 57, 60]. The latter may prove useful in the differential diagnosis between patients with AIH and those with viral hepatitis who tested positive for ANA or SMA. Furthermore, since ANCA appear to be relatively rare in PBC [54, 59], these autoantibodies may prove useful for distinguishing between genuine cases of AIH and cases of PBC with features overlapping with those of AIH . However, due to the lack of specificity for the diagnosis of AIH and to its obscure role – if any – in AIH, their routine determination is not recommended [14, 15].
3.3. Autoantibodies against the asialoglycoprotein receptor (anti-ASGP-R)
The asialoglycoprotein receptor (ASGP-R) is a liver-specific glycoprotein of the cell membrane. Its main function is the internalization of asialoglycoproteins by binding a terminal galactose residue to coated pits. Anti-ASGP-R autoantibodies are detected in 88% of patients with AIH (both types) [66, 67]. However, these autoantibodies are also found in some patients with PBC, chronic viral hepatitis B and C and alcoholic liver disease although at lower frequency and lower titers [14, 15, 66, 67].
The ASGP-R is preferentially expressed on the surface of periportal liver cells where piecemeal necrosis is found as a marker of severe inflammatory activity in patients with AIH . This finding may suggest a possible immunopathogenetic involvement of anti-ASGP-R autoantibodies in AIH . The general presumption is that target of potentially tissue-damaging autoreactions in AIH must be liver-specific and available to the immune system in vivo (e.g. expression on the surface of hepatocytes). So far, ASGP-R is the only target-autoantigen that has been positively identified and fulfils these criteria [68, 69]. Additional support to this emerged from the determinations of anti-ASGPR autoantibodies in consecutive AIH patients. The levels of anti-ASGP-R autoantibodies vary according to the inflammatory activity of the disease. In addition, anti-ASGP-R antibody titers decreased significantly in response to immunosuppression, while they reappear when the disease has relapsed [66, 70]. These autoantibodies may be diagnostically helpful when other autoantibodies are not detected and AIH is suspected. However, due to the belief that anti-ASGPR antibody represents a general marker of liver autoimmunity and the limitations in its detection (requires chemically purified ASGP-R, which is not yet widely available), its routine use is not generally recommended.
3.4. Antibodies against soluble liver antigens (anti-SLA) or to liver-pancreas antigen (anti-LP)
The anti-SLA autoantibodies were described for the first time in 1987 . They cannot be detected by IIF on common substrate. A competitive ELISA or a radioimmunoassay usually detects these autoantibodies [20, 32, 71]. SLA is found in 100000 g supernatant of liver homogenate and represent a cytosolic protein which is neither organ nor species specific . However, the highest concentrations are found in liver and kidney tissues. The anti-SLA autoantibodies are detected in patients with AIH alone or in combination with SMA and/or ANA [30–32, 73]. As noted above, similarities in the clinical profile between patients with AIH-1 (ANA and/or SMA positive) and AIH patients with anti-SLA alone in addition with an approximately 30% seropositivity overlap between anti-SLA and SMA and/or ANA suggest that anti-SLA is rather an additional important marker for the diagnosis of AIH-1, than a marker of a third type of AIH [6, 14, 30–32].
A scientific group from Tuebingen, Germany described for the first time the anti-LP autoantibodies in 1981 . The LP antigen was predominantly detected in the S100 supernatant of liver and pancreas homogenates, indicating that this antigen was a soluble protein. Until recently, anti-LP and anti-SLA autoantibodies were thought to be different [20–22]. However, Wies et al report  provides convincing evidence and confirms previous suggestions that anti-SLA and anti-LP are one and the same autoantibody (anti-SLA/LP). In addition, the same study demonstrated that the identified target-autoantigen of anti-SLA/LP autoantibodies (a 35–50 kDa protein) was neither cytokeratins 8 or 18  nor glutathione-S-transferase isoenzyme . The results from two independent groups [76, 77] were similar with those found by Wies et al . After screening of cDNA expression libraries they identified a previously unknown amino acid sequence, which presumably encodes a UGA-suppressor tRNA-associated protein, as the targen-autoantigen of anti-SLA/LP autoantibodies [76, 77]. The UGA-suppressor serine tRNA-protein complex is likely to be involved in cotranslational selenocysteine incorporation in human cells . It was then obvious that the identification of SLA/LP autoantigen would allow the establishment of a reliable, universally available diagnostic test for AIH but also it would provoke the investigation in the area of autoimmune liver diseases.
Regarding disease specificity, anti-SLA/LP autoantibodies have not been detected in patients with AIH-2, PBC, PSC, chronic viral hepatitis, alcoholic liver disease and non-hepatic autoimmune diseases by standardized ELISAs using reference autoantibody or recombinant antigen [20, 32, 73, 79]. Ballot et al  also showed that these autoantibodies are different from anti-LC1. For these reasons, anti-SLA/LP has been considered as a valuable and specific diagnostic marker of AIH [31, 32, 73, 74, 76, 77, 79]. However, a recent study from the United Kingdom  has shown that anti-SLA/LP autoantibodies can also be detected in AIH-2 and in children with PSC. These investigators used eukaryotically expressed tRNP ((Ser) Sec)/SLA as target in a radioligand assay (RLA) which is well known as a more sensitive test than ELISAs and immunoblot due to its ability to identify antibodies directed to conformational epitopes [81–83]. Their novel findings need confirmation from other research groups and particularly to address whether anti-SLA/LP reactivity is also present in adult PSC. Recent data confirmed the previous finding that patients with anti-SLA/LP display a more severe course of AIH [79, 80, 84]. The latter suggest that anti-SLA/LP may be linked to the pathogenesis of the autoimmune process although the exact function and its role in autoimmunity are so far unclear [14, 15]. From the clinical point of view however, this autoantibody may be helpful in an attempt to reduce the group of cryptogenic hepatitis and/or cirrhosis.
4. Detectable Autoantibodies in AIH-2
4.1. Autoantibodies against liver-kidney microsomes (anti-LKM)
The major target-autoantigen of anti-LKM-1 autoantibodies in AIH-2 has been identified as the cytochrome P450 2D6 (CYP2D6) [87–89]. It has been shown that anti-LKM-1 autoantibodies inhibit the enzymatic activity of CYP2D6 in vitro, but not in vivo . Epitope mapping experiments of CYP2D6 autoantigen have defined at least four different linear epitopes [91, 92]. The most immunodominant epitopes of CYP2D6 were amino acids 257–269 and 321–351, which are recognized in about 70% and 50% of AIH-2 cases, respectively [91, 92]. Two infrequent epitopes consisting of amino acids 373–389 and 410–429 are also recognized by anti-LKM-1 in some cases . Recently, Klein et al  and Kerkar et al  reported another immunodominant epitope of CYP2D6 (amino acids 193–212) recognized in about 70% and 93 % of AIH-2 patients, respectively. However, due to failure of inhibition of CYP2D6 enzymatic activity using epitope specific antibodies and since the absorption of the above linear epitopes was unable to absorb inhibitory anti-CYP2D6 autoantibodies, the existence of additional conformational epitopes on CYP2D6 autoantigen has been postulated .
It is noteworthy to state here that depending on the geographic origin, 0–7% of patients with chronic hepatitis C – irrespective of the HCV genotype – develop anti-LKM-1 autoantibodies [6, 14, 43, 63, 96, 97]. Recently, two studies have shown a higher prevalence of anti-LKM autoantibodies (up to 10%) in a small number of children or adult patients with HCV infection [98, 99]. As stated for AIH-2, CYP2D6 is the major target autoantigen recognized by anti-LKM-1 autoantibodies in HCV patients [14, 15, 81–83, 88, 92–96]. However, we and others have failed to document CYP2D6 as the major target autoantigen of anti-LKM antibodies in HCV/anti-LKM positive sera [98, 99]. In addition, recently Miyakawa et al  identified CYP2E1 and CYP3A4 as target autoantigens of anti-LKM autoantibodies in two patients with anti-LKM-positive chronic hepatitis C. Taking together, these findings may further indicate the heterogeneous autoimmune reactions that might take place in anti-LKM positive patients with chronic hepatitis C.
The antigenic sites on CYP2D6 autoantigen recognized by anti-LKM-1 autoantibodies are different in AIH-2 and HCV/anti-LKM-1 positive cases [92–95, 101–104]. For example, the major linear epitope of 257–269 amino acids, as well as the newly reported peptide of 193–212 amino acids are recognized in 70–93% of AIH-2 patients but only in 18–50% of HCV/anti-LKM-1 positive patients [83, 93, 94, 101]. Additional support to the presence of conformation-dependent anti-LKM-1 autoantibodies in HCV/anti-LKM-1 positive serum samples has emerged from previous studies [99, 102, 105]. In the latter studies only about 30% of HCV/anti-LKM-1 positive sera reacted with 50 kDa component using Western blot assays, while additional bands at 59 kDa, 70 kDa and 80 kDa were detected [99, 102, 105]. However, even taking into account the above additional bands, no more than 45% of all sera tested reactive by Western blot. In contrast, a significant proportion of the previous negative sera tested positive for anti-LKM-1 using a specific competitive ELISA, while denaturation of the antigens prior to perform the ELISA resulted in complete loss of the signal .
Recently, the development of a more sensitive and specific assay for the detection of anti-LKM-1 autoantibodies was achieved [14, 15]. This novel assay is a quantitative RLA based on immunoprecipitation using 35S-methionine-labelled CYP2D6 antigen obtained by in vitro transcription and translation synthesis [81–83, 99, 104]. Using this assay it was shown that the anti-LKM-1 titers do not differ significantly between AIH-2 and HCV/anti-LKM-1 positive patients [81–83]. The presence of anti-LKM-1 in some patients with HCV infection led to the proposal for a further division of AIH-2 into AIH-2a (younger, predominantly female patients without evidence of HCV infection) and AIH-2b (older, predominantly male patients with HCV infection) [13, 106]. Nowadays however, after the marked improvements in the reliability and availability of tests for HCV detection such a subdivision of AIH-2 appears unreasonable and tends to be deleted. Actually, HCV/anti-LKM-1 positive patients represent cases of "true" HCV infection with autoimmune features [6, 107].
From the clinical point of view, screening for anti-LKM autoantibodies is recommended before the initiation of interferon-alpha therapy in HCV patients and if found positive a careful monitoring appears reasonable because occasionally interferon-alpha may unmask, or provoke autoimmune hepatic reactions and even "true"AIH [6, 43, 104, 108–110]. Dalekos et al  studied antibody titers and performed epitope mapping of LKM-1-positive sera from patients with chronic hepatitis C. Interestingly, a patient with a high LKM-1 titer and autoantibodies directed against an epitope of amino acids 257–269, which are preferentially recognized by patients with AIH-2, showed exacerbation of the disease under interferon-alpha treatment. In contrast to other patients with HCV infection, this patient further recognized a rarely detected epitope on the C-terminal third of the protein. These results suggest that determination and monitoring of CYP2D6 autoantibody titers by both IIF and the RLA in combination with epitope mapping of CYP2D6 in HCV/anti-LKM positive patients before the initiation of interferon-alpha treatment, might be helpful in an attempt to identify those patients at risk of developing undesired autoimmune reactions .
Besides molecular mimicry, chemical modification of self-proteins and/or immunological cross-reactivity to homologous autoantigens may also provide potential triggers for autoimmune responses. The latter has been suggested by Choudhuri et al  who have shown that in AIH-2 patients the linear epitope 321–351 of CYP2D6 cross reacts with amino acids 33–51 of carboxypeptidase-H (the target autoantigen of islet cell autoantibodies in insulin dependent diabetes mellitus), as well as, with amino acids 307–325 of 21-hydroxylase (major target autoantigen in Addison's disease). These findings possibly indicate the presence of a common motif of CYP2D6, carboxypeptidase-H and 21-hydroxylase, which may contribute through a cross reactive immune response to the development of multiple endocrinopathies in the course of AIH-2. Additional support to this hypothesis emerged from two recent studies by Kerkar et al  and Bogdanos et al . In the first study the authors were able to show the similarity and cross-reactivity between the immunodominant epitope 193–212 of CYP2D6 and homologues of two unrelated viruses (HCV 2977–2996 and CMV 121–140) . In the second study the researchers investigated whether the immunodominant epitope 252–271 of CYP2D6 in anti-LKM-1 positive AIH-2 and homologues from the NS5B and E1 proteins of the HCV polyprotein and the ICP4 of HSV-1 are targets of humoral immune response in anti-LKM-1 positive and anti-LKM-1 negative HCV infected patients and furthermore whether this response is cross-reactive . The hypothesis of molecular mimicry and cross-reactivity in LKM-1 production has not been addressed experimentally. The authors for the first time gave experimental support to the notion that molecular similarity between CYP2D6, HCV and HSV can result in LKM-1 production via a cross-reactive response in genetically susceptible individuals (interestingly only the HCV positive/LKM-1 positive patients with viral/self cross-reactivity possessed the HLA B51 allotype) . Taking together, the above studies suggest that multiple exposure to viruses mimicking self may represent an important pathway to the development of autoimmunity [94, 113].
Two possible mechanisms have been proposed for the involvement of anti-LKM-1 autoantibodies in the pathogenesis of liver injury. The first appears to be a direct binding of these autoantibodies to hepatocytes, leading to lysis of liver cells, while the second is associated with an anti-LKM-1 induction of activating liver-infiltrating T lymphocytes, which indicates the combination of B and T cell activity in the autoimmune process involved [114–117]. A prerequisite for both anti-LKM-1 production and the activation of pathogenetic mechanisms involved in liver injury, is the expression of CYP2D6 on the surface of the patients' hepatocytes. Under this context, Ma et al  showed that key residues of a major CYP2D6 epitope (316–327) are exposed on the surface of the molecule and may represent key targets for anti-CYP2D6 production. In addition, recent data provides convincing evidence that anti-LKM-1 autoantibodies recognize CYP2D6 exposed on the plasma membrane of hepatocytes from either AIH-2 or HCV/anti-LKM-1 positive patients [114, 115] suggesting a pathogenetic role for these autoantibodies in hepatic tissue damage either in AIH-2 or in some cases of HCV/anti-LKM-1 positive patients [104, 109, 110, 115].
So far, anti-LKM type 2 autoantibodies (anti-LKM-2) have been detected only in some cases of drug-induced hepatitis caused by tienilic acid [14, 63]. The target autoantigen of anti-LKM-2 has been documented as the CYP2C9 . A proposed mechanism for the induction of anti-LKM-2 could be the binding of an active metabolite of the drug to the CYP2C9 protein, which then becomes antigenic [14, 63, 72, 85].
Anti-LKM type 3 autoantibodies (anti-LKM-3) alone or in combination with anti-LKM-1 are also detected in about 5–10% of patients with AIH-2 [16, 119]. In contrast to anti-LKM-1 and anti-LKM-2 autoantibodies, which on immunofluorescence stain liver and kidney tissues only, with anti-LKM-3 additional fluorescence signals may be present with tissue from the pancreas, adrenal gland, thyroid, and stomach. Family 1 of UDP-glycuronosyltransferases (UGT1) is the main target autoantigen of anti-LKM-3 autoantibodies (molecular weight of 55 kDa) [119, 120]. These autoantibodies were first described in about 13% of patients with chronic hepatitis D, but not in patients with chronic hepatitis B or C . However, three recent reports have shown the presence of anti-LKM-3 autoantibodies in some patients with HCV infection [99, 122, 123]. These findings may further support the heterogeneous phenomenon of the HCV-induced autoimmunity.
4.2. Autoantibodies against liver cytosolic protein type 1 (anti-LC1)
In 1988 a second autoantibody marker of AIH-2 was recognized . This autoantibody was found to react to a liver cytosolic protein. The autoantibody is organ specific but not species specific and was therefore called anti-LC1 . The anti-LC1 autoantibodies are characterized by a cytoplasmic staining of the periportal hepatocytes when the IIF assay is used for their detection. The hepatocellular layer around the central veins is not stained [19, 124]. These findings indicate that the target autoantigen of anti-LC1 autoantibodies is not uniformly distributed in rodent liver tissues. They are detected in about 30% of patients with AIH-2 [19, 124] and in approximately 50% of all anti-LKM-1 positive cases . It is noteworthy that the anti-LC1 autoantibodies proved to be the only serological marker in 10% of patients with AIH .
The detection of anti-LC1 autoantibodies by IIF is obscured due to the anti-LKM-1 pattern that frequently found in most of the anti-LC1 positive sera. For these reasons other techniques such as, the ouchterlony double diffusion, immunoblot or counter-immunoelectrophoresis are required for their detection [19, 124–126]. By immunoblotting, anti-LC1 positive serum samples recognize a liver specific cytosolic protein of 58–62 kDa [124–126]. Recently the molecular target of anti-LC1 was identified as the formiminotransferase cyclodeaminase (FTCD) , which is a polymeric bifunctional enzyme involved in folate metabolism. However, another group demonstrated the arginninosuccinate lyase (ASL) as the target autoantigen of a weak precipitin line detected by the ouchterlony double diffusion assay in patients with autoimmune or viral hepatitis .
Anti-LC1 autoantibodies have been proposed as a more specific marker of AIH-2 than anti-LKM-1 autoantibodies, since in the original reports their presence was never associated with HCV infection [19, 124]. However, a recent study by Lenzi et al  confirmed the above aspect only in the pediatric subset of their patients, while a substantial proportion of the adults with anti-LC1 autoantibodies had also markers of HCV infection. The significance of the association between anti-LC1 autoantibodies and HCV infection remains uncertain and has to be established [106, 129]. In contrast to what has been found for anti-LKM-1, the titers of anti-LC1 autoantibodies appear to parallel with disease activity . The latter may indicate a possible involvement of anti-LC1 in the pathogenesis of AIH-2. However, the clinical significance of anti-LC1 is not yet completely defined.
5. Detectable Autoantibodies in AIH in APECED
Chronic hepatitis as a disease component of APECED may develop in 10–18% of patients [14, 15, 23–25, 28, 29, 63]. APECED appears to be caused by mutations in a recently identified gene, the autoimmune regulator gene (AIRE), and represents the only known autoimmune disease with a monogenetic mutation today [26, 27, 131]. It is interesting that patients with AIH in the absence of APECED do not display mutations of the AIRE gene and are therefore genetically distinct from patients with AIH as a component of APECED .
Similar to AIH-2, hepatitis in APECED is associated with autoantibodies directed against cytochrome P450 proteins. In a large study with APECED patients, a typical LKM staining pattern and a predominant staining of the perivenous hepatocytes in the absence of staining of the kidney were observed . The latter pattern is due to autoantibodies called liver microsomal autoantibodies (anti-LM). In this study each of anti-LKM and anti-LM antibodies were found in 8% of the patients . These findings indicate that two or more different microsomal antigens are hepatic target-autoantigens in APECED.
Indeed, screening of APECED sera with recombinant antigens using Western blots has shown reactivity against four different hepatic cytochromes P450: CYP1A1, CYP1A2, CYP2A6 and CYP2B6 [23–25, 133]. CYP1A1, CYP2A6 and CYP2B6 are expressed both in liver and in kidney resulting to an LKM staining pattern, while CYP1A2 is not expressed in the kidney leading to the LM staining. Among the four autoantibodies anti-CYP2A6 were detected with the highest prevalence in a Finnish APECED patients group (15.6%), while anti-CYP1A2 were found in 6.3% . These results were confirmed by quantitative immunoprecipitation assays with recombinant 35S-labeled CYP1A2 and CYP2A6.
Detectable autoantibodies in AIH-1, AIH-2 and AIH as part of APECED
AIH-1 or AIH-2
AIH in APECED
ANA, SMA, ANCA, anti-ASGP-R anti-SLA/LP (molecular target: UGA suppressor tRNA-associated protein), anti-LKM-1 (molecular target: CYP2D6), anti-LKM-3 (molecular target: UGT1), anti-LC1 (molecular target: FTCD)
ANA, anti-LC (molecular target: unknown), anti-LKM (molecular targets: CYP2A6, CYP1A1 and CYP2B6), anti-LM (specific autoantibody; molecular target: CYP1A2)
Differential diagnosis of chronic liver diseases according to the presence or absence of autoantibodies against molecularly defined autoantigens of cytochrome P450 complex using the radioligand assay.
Chronic liver disease
AIH-2 (94–100%), HCV (0–10%)
HCV, APECED with or without hepatitis
AIH in APECED, drug induced hepatitis
AIH in APECED
Dalekos et al  using the sensitive quantitative RLA reported for the first time the presence of anti-CYP2A6 autoantibodies in about 2% of HCV-positive sera in general and in 7.5% of LKM-1-positive/HCV-positive sera. The latter further supports the low specificity of this autoantibody as a marker for AIH in APECED. Interestingly, anti-CYP2A6 autoantibodies were not detected in patients with AIH-2 who exhibit high titers of anti-LKM-1 autoantibodies . The clinical relevance of this finding in HCV infection remains to be determined.
Anti-LM autoantibodies are first described in dihydralazine-induced hepatitis . The major target autoantigen of anti-LM in both conditions (hepatitis as part of the APECED and drug-induced hepatitis) has been documented as the CYP1A2 [23–25, 133, 135]. In cases of dihydralazine-induced hepatitis the production of anti-LM autoantibodies has been attributed to adduct formation of CYP1A2 with an activated metabolite of the drug . By contrast, in APECED patients no relationship between CYP1A2 and drug usage is known. In addition, it is not known whether in APECED patients a close monitoring of anti-LM may lead to early, or even prophylactic, treatment of hepatitis as a new disease component. Evidence that autoantibodies may be found before the clinical and/or laboratory manifestation of a new disease component in APECED comes from adrenal and ovarian insufficiencies, where the respective autoantibodies are detected 2–3 years before the clinical presentation of the autoimmune components .
Another hepatic autoantigen in APECED, the aromatic-L-amino acid decarboxylase (AADC) has also been identified recently [133, 138]. This enzyme is expressed in the liver cytosol and was originally described as a β-cell autoantigen . The prevalence of anti-AADC autoantibodies is significantly increased in APECED patients with vitiligo (88%) and hepatitis (92%) [5, 14, 29]. So far, anti-AADC autoantibodies have only been reported in APECED and their role in AIH and vitiligo as disease components of APECED deserve further investigation.
6. Concluding Remarks
Differential Diagnosis of Autoimmune Hepatitis.
Other autoimmune liver diseases
- Overlap syndromes
- Primary biliary cirrhosis
- Primary sclerosing cholangitis
Chronic viral hepatitis
- Chronic hepatitis B with or without hepatitis delta
- Chronic hepatitis C
- Chronic hepatitis non A to G
Cholangiopathy due to human immunodeficiency virus infection
Alcoholic liver disease
Systemic lupus erythematosus
The detection of non-organ specific autoantibodies remains the hallmark of AIH. A step by step diagnostic application of autoantibody tests is mandatory for the evaluation of acute or chronic hepatitis of unknown cause. ANA, SMA and anti-LKM-1 autoantibodies should be first tested in patients with acute or chronic elevation of aminotransferases when virologic tests are negative and there is no current or past history for drug or alcohol abuse. Determination of ANCA, which occur in up to 90% of patients with AIH-1, may be useful in the identification of individuals who are seronegative for the above conventional autoantibody markers but should be kept in mind that this autoantibody lacks specificity. Many target autoantigens of the non-organ specific autoantibodies have been identified, but the latter has not led to the characterization of specific subpopulations of patients or changes in the treatment strategies. In addition, most of the non-organ specific autoantibodies do not seem to be involved in the pathogenesis of liver injury in AIH. Anti-LKM-1 autoantibodies could be an exception to the above aspect since recent data have demonstrated the expression of CYP2D6 on the surface of hepatocytes, while AIH-2 has not been observed in individuals who are deficient for CYP2D6. These findings provide arguments for an antigen-driven autoimmune process. It is possible that mutations in the autoantigen itself can lead to alterations in the three dimensional structure of the antigen, which induces autoimmunity.
Antibodies directed against liver-related antigens have had similar limitations. Anti-ASGP-R and anti-LC1 autoantibodies appear to correlate with disease severity and response to treatment suggesting a pathogenetic role to the hepatocellular damage. In general however, autoantibodies should not be used as a tool for monitoring of treatment or to predict AIH activity and outcome. Anti-SLA/LP autoantibodies have been considered as valuable and specific markers for the diagnosis of AIH-1. However, a recent study has shown that anti-SLA/LP autoantibodies can also be detected in AIH-2 and in children with PSC. Irrespective of the disease specificity of this marker, it is obvious that testing for anti-SLA/LP will help to reduce the group of cryptogenic liver disease, by recognizing previously misdiagnosed patients with AIH who were seronegative for ANA, SMA or anti-LKM-1.
In APECED, autoantibodies are directed against specific cytochrome P450 enzymes (e.g. CYP1A2, CYP2A6, CYP21, CYP17, and CYP11A1), that are expressed in organs affected by the disease process. These observations argue against the idea that antibodies against cytochrome P450 complex are simply epiphenomena secondary to tissue damage and that they have no relation to the etiology and pathogenesis of APECED.
It is not known what triggers autoimmunity in AIH. The hypothesis that different causes may lead to loss of tolerance against the same molecular target autoantigen seems attractive. For instance, CYP1A2 is the molecular target in dihydralazine-induced hepatitis and AIH as a component of APECED, CYP2D6 in AIH-2 and in some patients with HCV infection, CYP2A6 in APECED and in a proportion of patients with HCV infection and UGT1 in some cases of AIH-2 and chronic hepatitis D or C.
Research protocols in order to define AIH pathogenesis, disease susceptibility, determinants of disease severity, and to understand the epidemiology of AIH are future challenges in the investigational and clinical arena of this disease [139–141].
- Berdal JE, Ebbesen J, Rydning A: Incidence and prevalence of autoimmune liver diseases. Tidsskr Nor Laegeforen. 1998, 118: 4517-4519.PubMedGoogle Scholar
- Boberg KM, Aadland E, Jahnsen J, Raknerud N, Stiris M, Bell H: Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol. 1998, 33: 99-103.PubMedGoogle Scholar
- Manns MP, Strassburg CP: Autoimmune hepatitis: clinical challenges. Gastroenterology. 2001, 120: 1502-1517.PubMedGoogle Scholar
- Czaja AJ: Drug therapy in the management of type 1 autoimmune hepatitis. Drugs. 1999, 57: 49-68.PubMedGoogle Scholar
- Obermayer-Straub P, Strassburg CP, Manns MP: Autoimmune hepatitis. J Hepatol. 2000, 32 (Suppl 1): 181-197.PubMedGoogle Scholar
- Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, Cooksley WGE, Czaja AJ, Desmet VJ, Donaldson PT, Eddleston ALWF, Fainboim L, Heathcote J, Homberg JC, Hoofnagle JH, Kakumu S, Krawitt EL, Mackay IR, MacSween RNM, Maddrey WC, Manns MP, McFarlane IG, Meyer zum Büschenfelde K-H, Mieli-Vergani G, Nakanuma Y, Nishioka M, Penner E, Porta G, Portmann BC, Reed DW, Rodes J, Schalm SW, Scheuer PJ, Schrumpf E, Seki T, Toda G, Tsuji T, Tygstrup N, Vergani D, Zeniya M: International autoimmune hepatitis group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999, 31: 929-938.PubMedGoogle Scholar
- Krawitt EL: Can you recognize autoimmune hepatitis?. Postgrad Med. 1998, 104: 145-149. and 152PubMedGoogle Scholar
- McFarlane IG: Definition and classification of autoimmune hepatitis. Semin Liver Dis. 2002, 22: 317-324.PubMedGoogle Scholar
- Toda G, Zeniya M, Watanabe F, Imawari M, Kiyosawa K, Nishioka M, Tsuji T, Omata M: Present status of autoimmune hepatitis in Japan-correlating the characteristics with international criteria in an area with a high rate of HCV infection. Japanese National Study Group of Autoimmune hepatitis. J Hepatol. 1997, 26: 1207-1212.PubMedGoogle Scholar
- Parker DR, Kingham JGC: Type I autoimmune hepatitis is primarily a disease of later life. Q J Med. 1997, 90: 289-296.Google Scholar
- Schramm C, Kanzler S, Buschenfelde KH, Galle PR, Lohse AW: Autoimmune hepatitis in the elderly. Am J Gastroenterol. 2001, 96: 1587-1591.PubMedGoogle Scholar
- Omagari K, Kinoshita H, Kato Y, Nakata K, Kanematsu T, Kusumoto Y, Mori I, Furukawa R, Tanioka H, Tajima H, Koga M, Yano M, Kohno S: Clinical features of 89 patients with autoimmune hepatitis in Nagasaki Prefecture, Japan. J Gastroenterol. 1999, 34: 221-226.PubMedGoogle Scholar
- Johnson PJ, McFarlane IG: Meeting report of the International Autoimmune Hepatitis Group. Hepatology. 1993, 18: 998-1005.PubMedGoogle Scholar
- Dalekos GN, Zachou K, Liaskos C, Gatselis N: Autoantibodies and defined target autoantigens in autoimmune hepatitis: an overview. Eur J Intern Med. 2002, 13: 293-303.PubMedGoogle Scholar
- Strassburg CP, Manns MP: Autoantibodies and autoantigens in autoimmune hepatitis. Semin Liver Dis. 2002, 22: 339-351.PubMedGoogle Scholar
- Fabien N, Desbos A, Bienvenu J, Magdalou J: Autoantibodies directed against the UDP-glucuronotransferases in human autoimmune hepatitis. Autoimmun Rev. 2004, 3: 1-9.PubMedGoogle Scholar
- Desmet V, Gerber MA, Hoofnagle JH, Manns M, Scheuer P: Classification of chronic hepatitis: Diagnosis, grading and staging. Hepatology. 1994, 19: 1513-1520.PubMedGoogle Scholar
- Homberg JC, Abuaf N, Bernard O, Islam S, Alvarez F, Khalil SH, Poupon R, Darnis F, Levy VG, Grippon P: Chronic active hepatitis associated with anti-liver kidney microsome antibody type I: A second type of "autoimmune hepatitis". Hepatology. 1987, 7: 1333-1339.PubMedGoogle Scholar
- Martini E, Abuaf N, Cavalli F, Durand V, Johanet C, Homberg JC: Antibody to liver cytosol (anti-LC1) in patients with autoimmune hepatitis type 2. Hepatology. 1988, 8: 1662-1666.PubMedGoogle Scholar
- Manns M, Gerken G, Kyriatsoulis A, Staritz M, Meyer zum Büschenfelde K-H: Characterization of a new subgroup of autoimmune chronic active hepatitis by autoantibodies against soluble liver antigen. Lancet. 1987, i: 292-294.Google Scholar
- Berg PA, Stechemesser E, Strenz J: Hypergammaglobulinamische chronisch aktive Hepatitis mit Nachweis von Leber-Pancreas-spezifischen koplementbindenden Antikorpen. Verch Dtsch Ges Inn Med. 1981, 87: 921-927.Google Scholar
- Stechemesser E, Klein R, Berg PA: Characterization and clinical relevance of liver-pancreas antibodies in autoimmune hepatitis. Hepatology. 1993, 18: 1-9.PubMedGoogle Scholar
- Obermayer-Straub P, Perheentupa J, Braun S, Kayser A, Barut A, Loges S, Harms A, Dalekos G, Strassburg C, Manns MP: Hepatic autoantigens in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Gastroenterology. 2001, 121: 668-677.PubMedGoogle Scholar
- Clemente MG, Obermayer-Straub P, Meloni A, Strassburg CP, Arangino V, Tukey RH, De Virgiliis S, Manns MP: Cytochrome P450 1A2 is a hepatic autoantigen in autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab. 1997, 82: 1353-1361.PubMedGoogle Scholar
- Clemente MG, Meloni A, Obermayer-Straub P, Frau F, Manns MP, De Virgiliis S: Two cytochromes P450 are major hepatocellular autoantigens in autoimmune polyglandular syndrome type 1. Gastroenterology. 1998, 114: 324-328.PubMedGoogle Scholar
- The Finish-German APECED Consortium: An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet. 1997, 17: 399-403.Google Scholar
- Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N: Positional cloning of the APECED gene. Nat Genet. 1997, 17: 393-398.PubMedGoogle Scholar
- Perheentupa J: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Horm Metab Res. 1996, 28: 353-356.PubMedGoogle Scholar
- Obermayer-Straub P, Strassburg CP, Manns MP: Autoimmune polyglandular syndrome type 1. Clin Rev Allergy Immunol. 2000, 18: 167-183.PubMedGoogle Scholar
- Czaja AJ, Manns MP: The validity and importance of subtypes in autoimmune hepatitis: A point of view. Am J Gastroenterol. 1995, 90: 1206-1211.PubMedGoogle Scholar
- Kanzler S, Weidemann C, Gerken G, Lohr HF, Galle PR, Meyer zum Buschenfelde KH, Lohse AW: Clinical significance of autoantibodies to soluble liver antigen in autoimmune hepatitis. J Hepatol. 1999, 31: 635-640.PubMedGoogle Scholar
- Ballot E, Homberg JC, Johanet C: Antibodies to soluble liver antigen: an additional marker in type 1 autoimmune hepatitis. J Hepatol. 2000, 33: 208-215.PubMedGoogle Scholar
- Gregorio GV, Portman B, Reid F, Donaldson PT, Doherty DG, McCartney M, Mowat AP, Vergani D, Mieli-Vergani G: Autoimmune hepatitis in childhood: a 20 year experience. Hepatology. 1997, 25: 541-547.PubMedGoogle Scholar
- Jurado A, Cardaba B, Jara P, Cuadrado P, Hierro L, de Andres B, del Pozo V, Cortegano MI, Gallardo S, Camarena C, Barcena R, Castaner JL, Alvarez R, Lahoz C, Palomino P: Autoimmune hepatitis type 2 and hepatitis C virus infection: study of HLA antigens. J Hepatol. 1997, 26: 983-991.PubMedGoogle Scholar
- Czaja AJ, Nishioka M, Morshed SA, Haciya T: Patterns of nuclear immunofluorescence and reactivities to recombinant nuclear antigens in autoimmune hepatitis. Gastroenterology. 1994, 107: 200-207.PubMedGoogle Scholar
- Strassburg CP, Manns MP: Antinuclear antibody (ANA) patterns in hepatic and extrahepatic autoimmune disease. J Hepatol. 1999, 31: 751-PubMedGoogle Scholar
- Czaja AJ, Cassani F, Cataleta M, Valentini P, Bianchi FB: Antinuclear antibodies and patterns of nuclear immunoflorescence in type 1 autoimmune hepatitis. Dig Dis Sci. 1997, 42: 1688-1696.PubMedGoogle Scholar
- Strassburg C, Alex B, Zindy F, Gerken G, Luttig B, Meyer zum Buschenfelde KH, Brechot C, Manns MP: Identification of Cyclin A as a molecular target of antinuclear antibodies (ANA) in hepatic and non-hepatic diseases. J Hepatol. 1996, 25: 859-866.PubMedGoogle Scholar
- Czaja AJ, Morshed SA, Parveen S, Nishioka M: Antibodies to single stranded and double-stranded DNA in antinuclear antibody-positive type 1 autoimmune hepatitis. Hepatology. 1997, 26: 567-572.PubMedGoogle Scholar
- Parveen S, Morshed SA, Arima K, Nishioka M, Czaja AJ, Chow WC, Ng HS: Antibodies to Ro/La, Cenp-B, and snRNPs antigens in autoimmune hepatitis of North America versus Asia: patterns of immunofluorescence, ELISA reactivities, and HLA association. Dig Dis Sci. 1998, 43: 1322-1331.PubMedGoogle Scholar
- Czaja AJ, Cassani F, Cataleta M, Valenti P, Bianchi FB: Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis. Hepatology. 1996, 24: 1068-1073.PubMedGoogle Scholar
- Dalekos GN, Manoussakis MN, Zervou E, Tsianos EV, Moutsopoulos HM: Immunologic and viral markers in anti-HIV negative heroin addicts. Eur J Clin Invest. 1993, 23: 219-225.PubMedGoogle Scholar
- Cassani F, Cataleta M, Valentini P, Muratori P, Giostra F, Francesconi R, Muratori L, Lenzi M, Bianchi G, Zauli D, Bianchi FB: Serum autoantibodies in chronic hepatitis C: comparison with autoimmune hepatitis and impact on disease profile. Hepatology. 1997, 26: 561-566.PubMedGoogle Scholar
- Dalekos GN, Hatzis J, Tsianos EV: Dermatologic disease during interferon-alpha therapy for chronic viral hepatitis. Ann Intern Med. 1998, 128: 409-410.PubMedGoogle Scholar
- Dalekos GN, Kistis K, Boumba D, Voulgari P, Zervou EK, Drosos AA, Tsianos EV: Increased incidence of anticardiolipin antibodies in patients with hepatitis C is not associated with aetiopathogenetic link to antiphospholipid syndrome. Eur J Gastroenterol Hepatol. 2000, 12: 67-74.PubMedGoogle Scholar
- Gregorio GV, Jones H, Chouldhuri K, Vegnente A, Bortolotti F, Mieli-Vergani G, Vergani D: Autoantibody prevalence in chronic hepatitis B virus infection: effect of interferon alpha. Hepatology. 1996, 24: 308-312.Google Scholar
- Czaja AJ: Behaviour and significance of autoantibodies in type 1 autoimmune hepatitis. J Hepatol. 1999, 30: 394-401.PubMedGoogle Scholar
- Van der Woude FJ, Rasmussen N, Lobatto S, Wiik A, Permin H, van Es LA, van der Giessen M, van der Hem GK: Autoantibodies against neutrophils and monocytes tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet. 1985, i: 425-429.Google Scholar
- Falk RJ, Jennette JC: Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med. 1988, 318: 1651-1657.PubMedGoogle Scholar
- Dalekos GN, Manoussakis MN, Goussia AC, Tsianos EV, Moutsopoulos HM: Soluble interleukin-2 receptors, antineutrophil cytoplasmic antibodies and other autoantibodies in patients with ulerative colitis. Gut. 1993, 34: 658-664.PubMed CentralPubMedGoogle Scholar
- Duerr RH, Targan SR, Landers CJ, LaRusso NF, Lindsay KL, Wiesner RH, Shanahan F: Neutrophil cytoplasmic antibodies: a link between primary sclerosing cholangitis and ulcerative colitis. Gastroenterology. 1991, 100: 1385-1391.PubMedGoogle Scholar
- Pokorny CS, Norton ID, McCaughan GW, Selby WS: Anti-neutrophil cytoplasmic antibody: a prognostic indicator in primary sclerosing cholangitis. J Gastroenterol Hepatol. 1994, 9: 40-44.PubMedGoogle Scholar
- Targan SR, Landers C, Vidrich A, Czaja AJ: High titer antineutrophil cytoplasmic antibodies in type-1 autoimmune hepatitis. Gastroenterology. 1995, 108: 1159-1166.PubMedGoogle Scholar
- Roozendaal C, de Jong MA, van den Berg AP, van Wijk RT, Limburg PC, Kallenberg CGM: Clinical significance of anti-neutrophil cytoplasmic antibodies (ANCA) in autoimmune liver diseases. J Hepatol. 2000, 32: 734-741.PubMedGoogle Scholar
- Terjung B, Herzog V, Worman HJ, Gestmann I, Bauer C, Sauerbruch T, Spengler U: Atypical antineutrophil cytoplasmic antibodies with perinuclear fluorescence in chronic inflammatory bowel diseases and hepatobiliary disorders colocalize with nuclear lamina proteins. Hepatology. 1998, 28: 332-340.PubMedGoogle Scholar
- Roozendaal C, Kallenberg CGM: Anti-neutrophil cytoplasm autoantibodies (ANCA) in autoimmune liver diseases. Hepatogastroenterology. 1999, 46: 3034-3040.PubMedGoogle Scholar
- Zauli D, Ghetti S, Grassi A, Descovich C, Cassani F, Ballardini G, Muratori L, Bianchi FB: Anti-neutrophil cytoplasmic antibodies in type 1 and 2 autoimmune hepatitis. Hepatology. 1997, 25: 1105-1107.PubMedGoogle Scholar
- Lindgren S, Nilsson S, Nassberger L, Verbaan H, Wieslander J: Anti-neutrophil cytoplasmic antibodies in patients with chronic liver diseases: prevalence, antigen specificity and predictive value for diagnosis of autoimmune liver disease. Swedish Internal Medicine Liver Club. J Gastroenterol Hepatol. 2000, 15: 437-442.PubMedGoogle Scholar
- Claise C, Johanet C, Bouhnik Y, Kapel N, Homberg JC, Poupon R: Antineutrophil cytoplasmic autoantibodies in autoimmune liver and inflammatory bowel diseases. Liver. 1996, 16: 1095-1100.Google Scholar
- Dalekos GN, Tsianos EV: Antineutrophil antibodies in chronic viral hepatitis. J Hepatol (Letter). 1994, 20: 561-Google Scholar
- Wu Y-Y, Hsu T-C, Chen T-Y, Liu T-C, Liu G-Y, Lee Y-J, Tsay G-J: Proteinase 3 and dihydrolipoamide dehydrogenase (E3) are major autoantigens in hepatitis C virus (HCV) infection. Clin Exp Immunol. 2002, 128: 347-352.PubMed CentralPubMedGoogle Scholar
- Mulder AHL, Horst G, Haagsma EB, Limburg PC, Kleibeuker JH, Kallenberg GM: Prevalence and characterization of neutrophil cytoplasmic antibodies in autoimmune liver diseases. Hepatology. 1993, 17: 411-417.PubMedGoogle Scholar
- Czaja AJ, Homburger HA: Autoantibodies in liver disease. Gastroenterolgy. 2001, 120: 239-249.Google Scholar
- Sobajima J, Ozaki S, Uesugi H, Osakada F, Inoue M, Fukuda Y, Shirakawa H, Yoshida M, Rokuhara A, Imai H, Kiyosawa K, Nakao K: High mobility group (HMG) non-histone chromosomal proteins HMG1 and HMG2 are significant target antigens of perinuclear anti-neutrophil cytoplasmic antibodies in autoimmune hepatitis. Gut. 1999, 44: 867-873.PubMed CentralPubMedGoogle Scholar
- Orth T, Gerken G, Kellner R, Meyer zum Büschenfelde K-H, Mayet W-J: Actin is a target antigen of anti-neutrophil cytoplasmic antibodies (ANCA) in autoimmune hepatitis type-1. J Hepatol. 1997, 26: 37-47.PubMedGoogle Scholar
- Treichel U, McFarlane BM, Seki T, Krawitt EL, Alessi N, Stickel F, McFarlane IG, Kiyosawa K, Furuta S, Freni MA: Demographics of anti-asialoglycoprotein receptor autoantibodies in autoimmune hepatitis. Gastroenterology. 1994, 107: 799-804.PubMedGoogle Scholar
- Czaja AJ, Pfeifer KD, Decker RH, Vallari AS: Frequency and significance of antibodies to asialoglycoprotein receptor in type 1 autoimmune hepatitis. Dig Dis Sci. 1996, 41: 1733-1740.PubMedGoogle Scholar
- McFarlane BM, Sipos J, Gove CD, McFarlane IG, Williams R: Antibodies against the hepatic asialoglycoprotein receptor perfused in situ preferentially attach to periportal liver cells in the rat. Hepatology. 1990, 11: 408-415.PubMedGoogle Scholar
- McFarlane IG: Pathogenesis of autoimmune hepatitis. Biomed Pharmacother. 1999, 53: 255-263.PubMedGoogle Scholar
- Treichel U, Gerken G, Rossol S, Rotthauwe HW, Meyer zum Bunschenfelde K-H, Poralla AS: Autoantibodies against the human asialoglycoprotein receptor: effects of therapy in autoimmune and virus induced chronic active hepatitis. J Hepatol. 1993, 19: 55-63.PubMedGoogle Scholar
- Wachter B, Kyriatsoulis A, Lohse AW, Gerken G, Meyer zum Büschenfelde KH, Manns M: Characterization of liver cytokeratin as a major target antigen of anti-SLA antibodies. J Hepatol. 1990, 11: 232-239.PubMedGoogle Scholar
- Manns MP: Cytoplasmic autoantigens in autoimmune hepatitis: Molecular analysis and clinical relevance. Sem Liver Dis. 1991, 11: 205-214.Google Scholar
- Manns MP: Antibodies to soluble liver antigen: specific marker of autoimmune hepatitis. J Hepatol. 2000, 33: 326-328.PubMedGoogle Scholar
- Wies I, Brunner S, Henninger J, Herkel J, Kanzler S, Meyer zum Buschenfelde KH, Lohse AW: Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis. Lancet. 2000, 355: 1510-1515.PubMedGoogle Scholar
- Wesierska-Gadek J, Grimm R, Hitchman E, Penner E: Members of the glutathione S-transferase gene family are antigens in autoimmune hepatitis. Gastroenterology. 1998, 114: 329-335.PubMedGoogle Scholar
- Volkmann M, Martin L, Bäurle A, Heid H, Strassburg CP, Trautwein C, Fiehn W, Manns MP: Soluble liver antigen: isolation of a 35 kD recombinant protein (SLA-P35) specifically recognizing sera from patients with autoimmune hepatitis type 3. Hepatology. 2001, 33: 591-596.PubMedGoogle Scholar
- Costa M, Rodriguez-Sanchez JL, Czaja AJ, Gelpi C: Isolation and characterization of cDNA encoding the antigenic protein of the human tRNP(Ser)Sec complex recognized by autoantibodies from patients with type-1 autoimmune hepatitis. Clin Exp Immunol. 2000, 121: 364-374.PubMed CentralPubMedGoogle Scholar
- Gelpi C, Sontheimer E, Rodriguez-Sanchez J: Autoantibodies against a serine tRNA-protein complex implicated in cotranslational selenocysteine insertion. Proc Natl Acad Sci USA. 1992, 89: 9739-9743.PubMed CentralPubMedGoogle Scholar
- Baeres M, Herkel J, Czaja AJ, Wies I, Kanzler S, Cancado EL, Porta G, Nishioka M, Simon T, Daehnrich C, Schlumberger W, Galle PR, Lohse AW: Establishment of standardised SLA/LP immunoassays: specificity for autoimmune hepatitis, worldwide occurrence, and clinical characteristics. Gut. 2002, 51: 259-264.PubMed CentralPubMedGoogle Scholar
- Ma Y, Okamoto M, Thomas MG, Bogdanos DP, Lopes AR, Portmann B, Underhill J, Durr R, Mieli-Vergani G, Vergani D: Antibodies to conformantional epitopes of soluble liver antigen define a severe form of autoimmune liver disease. Hepatology. 2002, 36: 658-664.Google Scholar
- Yamamoto AM, Johanet C, Duclos-Vallee J-C, Bustarret FA, Alvarez F, Homberg JC, Bach JF: A new approach to cytochrome CYP2D6 antibody detection in autoimmune hepatitis type-2 (AIH-2) and chronic hepatitis C virus (HCV) infection: a sensitive and quantitative radioligand assay. Clin Exp Immunol. 1997, 108: 396-400.PubMed CentralPubMedGoogle Scholar
- Ma Y, Gregorio G, Gaken J, Muratori L, Bianchi FB, Mieli-Vergani G, Vergani D: Establishment of a novel radioligand assay using eukaryotically expressed cytochrome P4502D6 for the measurement of liver kidney microsomal type-1 antibody in patients with autoimmune hepatitis and hepatitis C virus infection. J Hepatol. 1997, 26: 1396-1402.PubMedGoogle Scholar
- Sugimura T, Obermayer-Straub P, Kayser A, Braun S, Loges S, Alex B, Luttig B, Johnson EF, Manns MP, Strassburg CP: A major CYP2D6 autoepitope in autoimmune hepatitis type 2 and chronic hepatitis C is a three-dimensional structure homologous to other cytochrome P450autoantigens. Autoimmunity. 2002, 35: 501-513.PubMedGoogle Scholar
- Czaja AJ, Donaldson PT, Lohse AW: Antibodies to soluble liver antigen/liver pancreas and HLA risk factors for type 1 autoimmune hepatitis. Am J Gastroenterol. 2002, 97: 413-419.PubMedGoogle Scholar
- Beaune P, Dansette PM, Mansuy D, Kiffel L, Finck M, Amar C, Leroux JP, Homberg JC: Human antiendoplasmic reticulum autoantibodies appearing in a drug-induced hepatitis directed against a human liver cytochrome P450 that hydroxylates the drug. Proc Natl Acad Sci USA. 1987, 84: 551-555.PubMed CentralPubMedGoogle Scholar
- Rizzetto M, Swana G, Doniach D: Microsomal antibodies in active chronic hepatitis and other disorders. Clin Exp Immunol. 1973, 15: 331-344.PubMed CentralPubMedGoogle Scholar
- Manns M, Johnson EF, Griffin KJ, Tan EM, Sullivan KF: The major target antigen of liver kidney microsomal autoantibodies in idiopathic autoimmune hepatitis is cytochrome P450 db1. J Clin Invest. 1989, 83: 1066-1072.PubMed CentralPubMedGoogle Scholar
- Gueguen M, Yamamoto AM, Bernard O, Alvarez F: Anti-liver kidney microsome antibody type 1 recognizes cytochrome P450 db1. Biochem Biophys Res Commun. 1989, 159: 542-547.PubMedGoogle Scholar
- Zanger UM, Hauri HP, Loeper J, Homberg JC, Meyer UA: Antibodies against human cytochrome P450 db 1 in autoimmune hepatitis type 2. Proc Natl Acad Sci USA. 1988, 85: 8256-8260.PubMed CentralPubMedGoogle Scholar
- Manns M, Zanger U, Gerken G, Sullivan KF, Meyer zum Buschenfelde KH, Meyer UA, Eichelbaum M: Patients with type II autoimmune hepatitis express functionally intact cytochrome P450 db1 that is inhibited by LKM1 autoantibodies in vitro but not in vivo. Hepatology. 1990, 12: 127-132.PubMedGoogle Scholar
- Manns MP, Griffin KJ, Sullivan KF, Johnson EF: LKM-1 autoantibodies recognize a short linear sequence in P450 2D6, a cytochrome P450 monooxygenase. J Clin Invest. 1991, 88: 1370-1378.PubMed CentralPubMedGoogle Scholar
- Yamamoto AM, Cresteil D, Boniface O, Clerc FF, Alvarez F: Identification and analysis of cytochrome P450 2D6 antigenic sites recognized by anti-liver kidney microsome type-1 antibodies (LKM1). Eur J Immunol. 1993, 23: 1105-1111.PubMedGoogle Scholar
- Klein R, Zanger UM, Berg T, Hopf U, Berg PA: Overlapping but distinct specificities of anti-liver-kidney microsomes antibodies in autoimmune hepatitis type II and hepatitis C revealed by recombinant native CYP2D6 and novel peptide epitopes. Clin Exp Immunol. 1999, 118: 290-297.PubMed CentralPubMedGoogle Scholar
- Kerkar N, Choudhuri K, Ma Y, Mahmoud A, Bogdanos DP, Muratori L, Bianchi F, Williams R, Mieli-Vergani G, Vergani D: Cytochrome P4502D6 (193–212): a new immunodominant epitope and target of virus/self cross-reactivity in liver kidney microsomal autoantibody type 1-positive liver disease. J Immunol. 2003, 170: 1481-1489.PubMedGoogle Scholar
- Duclos-Valleye JC, Hajoui O, Yamamoto AM, Jacqz-Aigrain E, Alvarez F: Conformational epitopes on CYP2D6 are recognized by liver/kidney microsomal antibodies. Gastroenterology. 1995, 108: 470-476.Google Scholar
- Nishioka M, Morshed SA, Kono K, Himoto T, Parveen S, Arima K, Watanabe S, Manns MP: Frequency and significance of antibodies to P450IID6 protein in Japanese patients with chronic hepatitis C. J Hepatol. 1997, 26: 992-1000.PubMedGoogle Scholar
- Clifford BD, Donahue D, Smith L, Cable E, Luttig B, Manns M, Bonkovsky HL: High prevalence of serological markers of autoimmunity in patients with chronic hepatitis C. Hepatology. 1995, 21: 613-619.PubMedGoogle Scholar
- Bortolotti F, Vajro P, Balli F, Giacchino R, Crivellaro C, Barbera C, Cataleta M, Muratori L, Pontisso P, Nebbia G, Zancan L, Bertolini A, Alberti A, Bianchi F: Non-organ specific autoantibodies in children with chronic hepatitis C. J Hepatol. 1996, 25: 614-620.PubMedGoogle Scholar
- Dalekos GN, Makri E, Loges S, Obermayer-Straub P, Zachou K, Tsikrikas T, Schimdt E, Papadamou G, Manns MP: Increased incidence of anti-LKM autoantibodies in a consecutive cohort of HCV patients from central Greece. Eur J Gastroenterol Hepatol. 2002, 14: 35-42.PubMedGoogle Scholar
- Miyakawa H, Kitazawa E, Kikuchi K, Fujikawa H, Kawaguchi N, Abe K, Matsushita M, Matsushima H, Igarashi T, Hankins RW, Kako M: Immunoreactivity to various human cytochrome P450 proteins of sera from patients with autoimmune hepatitis, chronic hepatitis B, and chronic hepatitis C. Autoimmunity. 2000, 33: 23-32.PubMedGoogle Scholar
- Muratori L, Lenzi M, Ma Y, Cataleta M, Mieli-Vergani G, Vergani D, Bianchi FB: Heterogeneity of liver/kidney microsomal antibody type 1 in autoimmune hepatitis and hepatitis C virus related liver disease. Gut. 1995, 37: 406-412.PubMed CentralPubMedGoogle Scholar
- Ma Y, Peakman M, Lobo-Yeo A, Wen L, Lenzi M, Gaken J, Farzaneh F, Mieli-Vergani G, Bianchi FB, Vergani D: Differences in immune recognition of cytochrome P450 2D6 by liver kidney microsomal (LKM) antibody in autoimmune hepatitis and chronic hepatitis C virus infection. Clin Exp Immunol. 1994, 97: 94-99.PubMed CentralPubMedGoogle Scholar
- Yamamoto AM, Cresteil D, Homberg JC, Alvarez F: Characterization of anti-liver-kidney microsome antibody (anti-LKM1) from hepatitis C virus-positive and -negative sera. Gastroenterology. 1993, 104: 1762-1767.PubMedGoogle Scholar
- Dalekos GN, Wedemeyer H, Obermayer-Straub P, Kayser A, Barut A, Frank H, Manns MP: Epitope mapping of cytochrome P450 2D6 autoantigen in patients with chronic hepatitis C under α-interferon treatment. J Hepatol. 1999, 30: 366-375.PubMedGoogle Scholar
- Durazzo M, Philipp T, Va Pelt FN, Luttig B, Borghesio E, Michel G, Schmidt E, Loges S, Rizzetto M, Manns MP: Heterogeneity of microsomal autoantibodies (LKM) in chronic hepatitis C and D virus infection. Gastroenterology. 1995, 108: 455-462.PubMedGoogle Scholar
- Lunel F, Abuaf N, Frangeul L, Grippon P, Perrin M, Le Coz Y, Valla D, Borotto E, Yamamoto AM, Huraux JM: Liver/kidney microsome antibody type 1 and hepatitis C virus infection. Hepatology. 1992, 16: 630-636.PubMedGoogle Scholar
- Miyakawa H, Kitazawa E, Abe K, Kawaguchi N, Fuzikawa H, Kikuchi K, Kako M, Komatsu T, Hayashi N, Kiyosawa K: Chronic hepatitis C associated with anti-liver/kidney microsome-1 antibody is not a subgroup of autoimmune hepatitis. J Gastroenterol. 1997, 32: 769-776.PubMedGoogle Scholar
- Ruiz-Moreno M, Rua MJ, Carreno V, Quironga JA, Manns M, Meyer zum Büschenfelde K-H: Autoimmune chronic active hepatitis type 2 manifested during interferon therapy in children. J Hepatol. 1991, 12: 265-266.PubMedGoogle Scholar
- Muratori L, Lenzi M, Cataleta M, Giostra F, Cassani F, Ballardini G, Zauli D, Bianchi FB: Interferon therapy in liver/kidney microsomal antibody type 1-positive patients with chronic hepatitis C. J Hepatol. 1994, 21: 199-203.PubMedGoogle Scholar
- Todros L, Saracco G, Durazzo M, Abate ML, Touscoz G, Scaglione L, Verme G, Rizzetto M: Efficacy and safety of interferon alpha therapy in chronic hepatitis C with autoantibodies to liver-kidney microsomes. Hepatology. 1995, 22: 1374-1378.PubMedGoogle Scholar
- Manns MP, Jentzsch M, Mergener K: Discordant manifestation of LKM-1 antibody positive autoimmune hepatitis in identical twins [abstract]. Hepatology. 1990, 12: 840-Google Scholar
- Choudhury K, Gregorio GV, Mieli-Vergani G, Vergani D: Immunological cross-reactivity to multiple autoantigens in patients with liver kidney microsomal type 1 autoimmune hepatitis. Hepatology. 1998, 28: 1177-1181.Google Scholar
- Bogdanos D-P, Lenzi M, Okamoto M, Rigopoulou EI, Muratori P, Ma Y, Muratori L, Tsantoulas D, Mieli-Vergani G, Bianchi FB, Vergani D: Multiple viral/self immunological cross-reactivity in liver kidney microsomal antibody positive hepatitis C virus infected patients is associated with the possession of HLA 51. Int J Immunopathol Pharmacol. 2004, 17: 83-92.PubMedGoogle Scholar
- Loeper J, Louerat-Oriou B, Duport C, Pompon D: Yeast expressed cytochrome P450 2D6 (CYP2D6) exposed on the external face of plasma membrane is functionally competent. Mol Pharmacol. 1998, 54: 8-13.PubMedGoogle Scholar
- Muratori L, Parola M, Ripalti A, Robino G, Muratori P, Bellomo G, Carini R, Lenzi M, Landini MP, Albano E, Bianchi FB: Liver/kidney microsomal antibody type 1 targets CYP2D6 on hepatocyte plasma membrane. Gut. 2000, 46: 553-561.PubMed CentralPubMedGoogle Scholar
- Lohr HF, Schlaak JF, Lohse AW, Bocher WO, Arenz M, Gerken G, Meyer Zum Buschenfelde KH: Autoreactive CD4+ LKM-specific and anticlonotypic T-cell responses in LKM-1 antibody-positive autoimmune hepatitis. Hepatology. 1996, 24: 1416-1421.PubMedGoogle Scholar
- Arenz M, Pingel S, Schirmacher P, Meyer zum Buschenfelde KH, Lohr HF: T cell receptor Vbeta chain restriction and preferred CDR3 motifs of liver-kidney microsomal antigen (LKM-1)-reactive T cells from autoimmune hepatitis patients. Liver. 2001, 21: 18-25.PubMedGoogle Scholar
- Ma Y, Thomas MG, Okamoto M, Bogdanos DP, Nagl S, Kerkar N, Lopes AR, Muratori L, Lenzi M, Bianchi FB, Mieli-Vergani G, Vergani D: Key residues of a major cytochrome P4502D6 epitope are located on the surface of the molecule. J Immunol. 2002, 169: 277-285.PubMedGoogle Scholar
- Strassburg CP, Obermayer-Straub P, Alex B, Durazzo M, Rizzetto M, Tukey RH, Manns MP: Autoantibodies against glucuronosyltransferases differ between viral hepatitis and autoimmune hepatitis. Gastroenterology. 1996, 111: 1582-1592.Google Scholar
- Philipp T, Durazzo M, Trautwein C, Alex B, Straub P, Lamb JG, Johnson EF, Tukey RH, Manns MP: LKM-3 autoantibodies in chronic hepatitis D recognize the UDP-glucuronosyl-transferases. Lancet. 1994, 344: 578-581.PubMedGoogle Scholar
- Crivelli O, Lavarini C, Chiaberge E, Amoroso A, Farci P, Negro F, Rizzetto M: Microsomal autoantibodies in chronic infection with HBsAg associated delta (d) agent. Clin Exp Immunol. 1983, 54: 232-238.PubMed CentralPubMedGoogle Scholar
- Csepregi A, Nemesanszky E, Luettig B, Obermayer-Starub P, Manns MP: LKM3 autoantibodies in hepatitis C cirrhosis: a further phenomenon of the HCV-induced autoimmunity. Am J Gastroenterol. 2001, 96: 910-911.PubMedGoogle Scholar
- Bachrich T, Thalhammer T, Jager W, Haslmayer P, Alihodzic B, Bakos S, Hitchman E, Senderowicz AM, Penner E: Characterization of autoantibodies against uridine-diphospate glucuronosyltransferase in patients with inflammatory liver diseases. Hepatology. 2001, 33: 1053-1059.PubMedGoogle Scholar
- Abuaf N, Johanet C, Chretien P, Martini E, Soulier E, Laperche S, Homberg JC: Characterization of liver cytosol antigen type 1 reacting with autoantibodies in chronic active hepatitis. Hepatology. 1992, 16: 892-898.PubMedGoogle Scholar
- Lenzi M, Manotti P, Muratori L, Cataleta M, Ballardini G, Cassani F, Bianchi FB: Liver cytosolic 1 antigen-antibody system in type 2 autoimmune hepatitis and hepatitis C virus infection. Gut. 1995, 36: 749-754.PubMed CentralPubMedGoogle Scholar
- Muratori L, Cataleta M, Muratori P, Manotti P, Lenzi M, Cassani F, Bianchi FB: Detection of anti-liver cytosol antibody type 1 (anti-LC1) by immunodiffusion, counterimmunoelectrophoresis and immunoblotting: comparison of three different techniques. J Immunol Methods. 1995, 187: 259-264.PubMedGoogle Scholar
- Lapierre P, Hajoui O, Homberg J-C, Alvarez F: Formininotransferase cyclodeaminase is organ-specific autoantigen recognized by sera of patients with autoimmune hepatitis. Gastroenterology. 1999, 116: 643-649.PubMedGoogle Scholar
- 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 CentralPubMedGoogle Scholar
- Obermayer-Straub P, Manns MP: Hepatitis C and D, retroviruses and autoimmune manifestations. J Autoimmunity. 2001, 16: 275-285.Google Scholar
- Muratori L, Cataleta M, Muratori P, Lenzi M, Bianchi FB: Liver/kidney microsomal antibody type 1 and liver cytosol antibody type 1 concentrations in type 2 autoimmune hepatitis. Gut. 1998, 42: 721-726.PubMed CentralPubMedGoogle Scholar
- Rinderle C, Christensen HM, Schweiger S, Lehrach H, Yaspo ML: AIRE encodes a nuclear protein co-localizing with cytoskeletal filaments: altered sub-cellular distribution of mutants lacking the PHD zinc fingers. Hum Mol Genet. 1999, 8: 277-290.PubMedGoogle Scholar
- Vogel A, Liermann H, Harms A, Strassburg CP, Manns MP, Obermayer-Straub P: Autoimmune regulator AIRE: evidence for genetic differences between autoimmune hepatitis and hepatitis as part of the autoimmune polyglandular syndrome type 1. Hepatology. 2001, 33: 1047-1052.PubMedGoogle Scholar
- Gebre-Medhin G, Husebye ES, Gustafsson J, Winqvist O, Goksoyr A, Rorsman F, Kampe O: Cytochrome P450IA2 and aromatic L-amino acid decarboxylase are hepatic autoantigens in autoimmune polyendocrine syndrome type I. FEBS Letters. 1997, 412: 439-445.PubMedGoogle Scholar
- Dalekos GN, Obermayer-Straub P, Bartels M, Maeda T, Kayser A, Braun S, Loges S, Schmidt E, Gershwin ME, Manns MP: Cytochrome P450 2A6: A new hepatic autoantigen in patients with chronic hepatitis C virus infection. J Hepatol. 2003, 39: 800-806.PubMedGoogle Scholar
- Bourdi M, Larrey D, Nataf J, Bernuau J, Pessayre D, Iwasaki M, Guengerich FP, Beaune PH: Anti-liver endoplasmic reticulum autoantibodies are directed against human cytochrome P450 IA2: A specific marker of dihydralazine-induced hepatitis. J Clin Invest. 1990, 85: 1967-1973.PubMed CentralPubMedGoogle Scholar
- Beaune PH, Pessayre D, Dansette P, Mansuy D, Manns MP: Autoantibodies against cytochromes P450: Role in human diseases. Adv Pharmacol. 1994, 30: 199-245.PubMedGoogle Scholar
- Ahonen P, Miettinen A, Perheentupa J: Adrenal and steroidal cell antibodies in patients with autoimmune polyglandular disease type I and risk of adrenocortical and ovarian failure. J Clin Endocrinol Metabol. 1987, 64: 494-500.Google Scholar
- Rorsman F, Husebye ES, Winquist O, Björk E, Karlsson FA, Kämpe O: Aromatic-L-aminoacid decarboxylase, a pyridoxal phosphate-dependent enzyme, is a beta-cell autoantigen. Proc Natl Acad Sci USA. 1995, 92: 8626-8629.PubMed CentralPubMedGoogle Scholar
- Kyriakou D, Alexandrakis M, Zachou K, Passam F, Stathakis N, Dalekos GN: Hemopoietic progenitor cells and bone marrow stromal cells in patients with autoimmune hepatitis type 1 and primary biliary cirrhosis. J Hepatol. 2003, 39: 679-685.PubMedGoogle Scholar
- Czaja AJ, Manns MP, McFarlane IG, Hoofnagle JH: Autoimmune hepatitis: The investigational and clinical challenges. Hepatology. 2000, 31: 1194-2000.PubMedGoogle Scholar
- Czaja AJ: Understanding the pathogenesis of autoimmune hepatitis. Am J Gastroenterol. 2001, 96: 1224-1231.PubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.