Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease

Kalliopi Zachou; Eirini Rigopoulou; George Dalekos

doi:10.1186/1740-2557-1-2

Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease

Zachou, Kalliopi; Rigopoulou, Eirini; Dalekos, George 2004-10-15 00:00:00 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 Page 1 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 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. 1. Introduction tine clinical practice for the diagnosis and classification of Autoimmune hepatitis (AIH) is a rare chronic liver disease patients as having either 'definite' or 'probable' AIH [13]. of unknown etiology. The estimated prevalence of AIH in In addition, a diagnostic scoring system was devised to Northern European countries is approximately 160–170 provide an objective method for selection of relatively patients/10 inhabitants [1,2]. The disease predominates homogeneous groups of patients for research purposes among women and is characterized by hypergammaglob- [13]. The same group has remarkably simplified the ulinemia even in the absence of cirrhosis, characteristic descriptive set of criteria and the diagnostic scoring system autoantibodies, association with human leukocyte anti- in late 1998 (Tables 1 and 2) [6]. The diagnostic score gens (HLA) DR3 or DR4 and a favorable response to demonstrates that the presence of defined autoantibodies immunosuppressive treatment [3-5]. The onset of AIH is an integral part of the diagnosis of AIH but not its single disease is usually insidious, with unspecific symptoms, diagnostic tool [6,14]. such as, fatigue, malaise, arthralgias, and fluctuating jaun- dice, right upper quadrant pain or lethargy [5-8]. How- In recent years however, significant progress has been ever, a substantial proportion of patients may have no made in the characterization of liver-related target- obvious signs or symptoms of liver disease, while occa- autoantigens. This has led to the notion that some of the sionally the presentation may be severe and almost iden- major target-autoantigens in AIH are active enzymes of tical to an acute or fulminant episode of viral hepatitis [5- the human hepatic and non-hepatic microsomal xenobi- 8]. Although AIH brings in mind the archetypal patient otic metabolism [14-16]. The latter serve as a means to being a young female with endocrine abnormalities, there investigate this still enigmatic liver disease. This article is nowadays increasing evidence that the disease can also will focus on the data that have evolved in the course of affect males and can present at almost any age (the large the characterization of autoantibody-autoantigen "sys- majority of patients being between 50 and 70 years of age) tem" in AIH by giving the current aspects on the role and [6-12]. significance of this "system" in the differential diagnosis and study of pathogenesis of AIH. Liver histology is not pathognomonic for AIH and there is no single serologic test of sufficient specificity for the diag- 2. Classification of AIH nosis of AIH as for the diagnosis of viral hepatitis A to E. According to the pattern of autoantibodies detected in Although the presence of autoantibodies is one of the dis- AIH patients, a subclassification of the disease into three tinguishing features of AIH, there is no single autoanti- types was proposed in 1994 [17]. AIH type 1 (AIH-1) is body with the diagnostic significance and specificity that characterized by the presence of antinuclear antibodies antimitochondrial autoantibodies (AMA) demonstrate (ANA) and/or smooth muscle autoantibodies (SMA) for the diagnosis of primary biliary cirrhosis (PBC). For which may associate with perinuclear anti-neutrophil this reason, autoantibodies can not be employed as a sin- cytoplasmic antibodies (p-ANCA) [3,5,6,14,15]. AIH type gle marker for the diagnosis of AIH. It is rather a diagnosis 2 (AIH-2) is characterized by the detection of specific reached by the exclusion of other factors leading to autoantibodies against liver and kidney microsomal anti- chronic hepatitis that include viral, toxic, genetic and met- gens (anti-LKM type 1 or infrequently type 3) [14-16,18] abolic causes [6]. Under this context, it is clear that some- and/or antibodies against liver cytosol type 1 antigen times AIH may be difficult to diagnose [7,8]. In 1992, the (anti-LC1) [14,15,19]. AIH type 3 (AIH-3) is characterized International Autoimmune Hepatitis Group reported a by autoantibodies against soluble liver antigens (anti- descriptive set of criteria that could be applied in the rou- SLA) [20] or to liver-pancreas antigen (anti-LP) [21,22]. Page 2 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 Table 1: Revised Scoring System for the Diagnosis of The serological diversity of autoantibodies found in AIH Autoimmune Hepatitis . supports the aforementioned subclassification and pro- vides a framework for the scientific analysis of this heter- Parameter/Features Score ogeneous disease group [5,15]. It also demonstrates that AIH may not be a single disease with a single underlying Gender - Female/Male +2/0 mechanism but most likely is a group of diseases with a Degree of elevation above upper normal limit of similar clinical presentation [14,15]. This is further ALP vs. aminotransferases substantiated by the finding of an unusual form of AIH in - <1.5 +2 10–18% of patients with a rare autosomal recessive disor- - 1.5 – 3.0 0 der, the autoimmune polyendocrinopathy-candidiasis- - >3.0 -2 ectodermal dystrophy syndrome (APECED) [23-25]. This Total serum globulins, γ-globulins, or IgG above normal syndrome is characterized by chronic mucocuteneous - >2.0 +3 candidiasis, ectodermal dystrophy and autoimmune tis- - 1.5 – 2.0 +2 sue destruction particularly of the endocrine glands - 1.0 – 1.5 +1 (hypoparathyroidism, adrenocortical failure and gonadal - <1.0 0 failure in females) [26-29]. ANA, SMA or LKM-1 (titers by immunofluorescence on rodent tissues or HEp2-cells) - >1 : 80 +3 However, due to recent clinical, serologic and genetic - 1 : 80 +2 findings, it has been suggested that anti-SLA seropositive - 1 : 40 +1 patients do not define a subgroup of AIH, but rather - <1 : 40 0 belong to the AIH-1 group [30-32]. For this reason, subdi- - AMA positive -4 vision into AIH-1 (ANA, SMA, p-ANCA and/or anti-SLA/ Hepatitis viral markers (IgM anti-HAV, HBsAg, IgM LP positive) and AIH-2 (anti-LKM-1, anti-LKM-3 and/or anti-HBc, anti-HCV and HCV-RNA) anti-LC1 positive) is in common usage (Table 3). Apart - Positive/Negative -3/+3 Recent or current use of known or suspected from serological differences, AIH-2 seems to be clinically hepatotoxic drugs and genetically distinguishable from AIH-1 [5,8,14]. - Yes/No -4/+1 Indeed, patients with AIH-2 are younger at presentation, Average alcohol intake usually have higher levels of bilirubin and transaminases, - <25 g/day +2 and are characterized by more severe disease than patients - >60 g/day -2 Other autoimmune disease(s) in patient or first with AIH-1 [5,6,14,18,33]. In addition, contrary to what degree relatives has been recorded in patients with AIH-1, no sustained - Yes/No +2/0 remission has been observed after the discontinuation of Optional additional parameters (should be allocated immunosuppressive therapy in patients with AIH-2 only if ANA, SMA or LKM-1 are negative) [4,33]. Taking into consideration the genetic markers, it - HLA DR3, DR4, or other HLA with published association +1 with AIH) has been found that the association between HLA DR3 - Seropositivity for any of ANCA, anti-LC1, anti-SLA/LP, +2 and AIH-2 is rather weaker than that reported in AIH-1, anti-ASGPR and anti-sulfatide while an association between HLA DQ2 and AIH-2 has Liver histology been reported [14,18,33,34]. However, AIH-2 patients - Interface hepatitis +3 represent only a small proportion of the total cases of AIH - Predominant lymphoplasmacytic infiltrate +1 [3-6]. In addition, the long-term outcome of the affected - Rosetting of liver cells +1 patients appears to be similar both in AIH-1 and AIH-2 - None of the above -5 - Biliary changes -3 [6,33]. Therefore, the classification of AIH in these two - Other changes -3 major subgroups is still uncertain and controversial Response to therapy (as defined in Table 2) [6,8,13]. - Complete/Relapse +2/+3 3. Detectable Autoantibodies in AIH-1 Definite AIH if greater than 15 before treatment or greater than 17 3.1. Anti-nuclear antibodies (ANA) and smooth muscle post-treatment; probable AIH if varies between 10–15 before treatment or 12–17 post-treatment. ALP: alkaline phospatase, IgM autontibodies (SMA) anti-HAV: hepatitis A virus IgM antibody, anti-HCV: hepatitis C virus ANA and/or SMA are almost exclusively requisites for the antibody, HBsAg: surface antigen of hepatitis B virus, IgM anti-HBc: diagnosis of AIH-1 [3,5,6,14,15,30]. In typical cases of IgM antibody against the nuclear antigen of hepatitis B virus. Other AIH-1, these autoantibodies are detected in significant tit- abbreviations are the same as shown in the text. ers (≥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]. Page 3 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 Table 2: Definitions of Response to Therapy. Response Definition Complete Either or both of the following: marked improvement of or Either or both of the following: marked improvement of symptoms and return of serum AST or ALT, bilirubin and symptoms together with at least 50% improvement of all liver immunoglobulin values completely to normal within 1 year and tests during the first month of treatment, with AST or ALT sustained for at least a further 6 months on maintenance levels continuing to fall to less than twice the upper normal therapy, or liver biopsy specimen at some time during this limit within 6 months during any reductions toward period showing at most minimal activity. maintenance therapy, or a liver biopsy within 1 year showing only minimal activity. Relapse Either or both of the following: an increased in serum AST or or Reappearance of symptoms of sufficient severity to require ALT levels of greater than twice the upper normal limit or a increased (or reintroduction of) immunosuppression, liver biopsy showing active disease, with or without accompanied by any increase in serum AST or ALT levels, after reappearance of symptoms, after a "complete" response as a "complete" response as defined above. defined above. AST: aspartate aminotransferase, ALT: alanine aminotransferase. Table 3: Classification of Autoimmune Hepatitis (AIH) According to Autoantibodies Detection Type of AIH Characteristic autoantibodies AIH-1 ANA, SMA, p-ANCA anti-ASGP-R, anti-SLA/LP AIH-2 anti-LKM-1, anti-LKM-3, anti-LC1, anti-ASGP-R Abbreviations are the same as shown in the text. Typical patient with autoimmune hepati rect immunofluoerescenc (origin Figure 2 al m staining of a agnification ntinu 40×) clear e on cr antib tis type 1 visu yoo stat section dies in the serum alized by indi- s of rat liver of a Typical staining of antinuclear antibodies in the serum of a patient with autoimmune hepatitis type 1 visualized by indi- rect immunofluoerescence on cryostat sections of rat liver (original magnification 40×). slides (Figures 1 and 2) [14,15,35,36]. Different patterns of fluorescence are found by this assay due to the large var- iability of target-autoantigens in the nuclei of HEp-2 cells H p H ty Figure 1 aiEp-2 pe 1 ttern by indirect gh titer (AIH-1) cells in a female pa antinuclear antibodi immuntien ofluoerescence o t with es (ANA) of the ho autoimmu n immobil ne mo hepgeneous aititis zed that have been recognized [35-40]. Actually, ANA are High titer antinuclear antibodies (ANA) of the homogeneous found to be directed against single or double stranded pattern by indirect immunofluoerescence on immobilized DNA, tRNA, SSA-Ro, snRNPs, laminins A and C, cyclin A HEp-2 cells in a female patient with autoimmune hepatitis or histones [35-40]. Most commonly, a homogenous type 1 (AIH-1). Homogeneous ANA are frequently found in AIH-1 (original magnification 40×). (34–58%) or speckled (21–34%) immunofluoerescence pattern is demonstrable [14,15,35-37]. So far however, neither a liver-specific nuclear antigen nor a liver-disease- specific ANA has been identified. For this reason, subtyp- ing of ANA in cases of AIH-1 seems to have limited clinical The most frequent and conventional method for ANA implication and diagnostic relevance in routine clinical detection is the indirect immunofluorescence (IIF) assay practice [6,14,15,35-40]. on cryostat sections of rodent tissues and HEp-2 cells Page 4 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 as of 1:40 [14,15]. Czaja et al [41] have suggested that antibodies to actin are associated with a younger age of disease onset, the presence of HLA-A1-B8-DR3 haplotype and a greater frequency of treatment failure, death from liver disease and earlier requirement for transplantation than actin-antibody negative AIH-1 patients. 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 adminis- tration is generally safe in most cases of viral hepatitis with ANA and/or SMA, although occasionally may pro- voke mild self-limited autoimmune disorders compared to viral hepatitis patients without ANA or SMA on ra titis type 1) Figure 3 Smooth muscle antibodies by t kidney (from a female p in atient with autoimm direct immunofluoeresce une hepa- nce autoantibodies [44-46]. During immunosuppressive Smooth muscle antibodies by indirect immunofluoerescence treatment, disappearance of ANA and/or SMA is observed on rat kidney (from a female patient with autoimmune hepa- in the majority of patients with AIH-1 [47]. However, titis type 1). The immunofluorescence involves smooth mus- autoantibody status is unable to predict immediate out- cle fibers within blood vessels (original magnification 40×). come after cessation of corticosteroid administration. Additionally, neither autoantibody titers at first diagnosis nor autoantibody behaviour in the time course of the dis- ease 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 determi- nation 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 [48]. 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 cence on rat stomach (serum autoimmune hepatitis type 1) Figure 4 Smooth muscle autoantibodies by in from a female patien direct immunofluoeres- t with Wegener's granulomatosis and microscopic polyangiitis, Smooth muscle autoantibodies by indirect immunofluoeres- respectively [48,49]. Proteinase-3 has been identified as cence on rat stomach (serum from a female patient with the major target-autoantigen of c-ANCA in cases with autoimmune hepatitis type 1). The immunofluorescence Wegener's granulomatosis, while myeloperoxidase is the involves smooth muscle fibers within muscularis mucosa (original magnification 40×). 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 fre- SMA are detected by IIF on rodent liver and kidney, due to quently in ulcerative colitis than in Crohn's disease) staining of vessel walls (Fig. 3), and stomach due to stain- [50,51] and primary sclerosing cholangitis (PSC), a liver ing of the muscle layer (Fig. 4). SMA are directed against disease that is frequently associated with ulcerative colitis structures of the cytoskeleton such as actin, troponin, [51,52]. vimentin and tropomyosin. In AIH-1, SMA are predomi- nantly directed against F-actin [41]. The latter seems to be Several recent studies however, have also documented the diagnostically more relevant in pediatric patients where presence of high titers of p-ANCA in the sera of patients SMA may be the only marker of AIH-1 even in titers as low with AIH-1 (Fig. 5; prevalence range 40–96%) [53-58] Page 5 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 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 [61] the detection of ANCA is rather rare in chronic viral hepatitis [14,54,57,60]. The latter may prove useful in the differen- tial diagnosis between patients with AIH and those with viral hepatitis who tested positive for ANA or SMA. Fur- thermore, since ANCA appear to be relatively rare in PBC [54,59], these autoantibodies may prove useful for distin- guishing between genuine cases of AIH and cases of PBC with features overlapping with those of AIH [6]. However, due to the lack of specificity for the diagnosis of AIH and to its obscure role – if any – in AIH, their routine determi- nation is not recommended [14,15]. Perinuclear staining of anti-n bodi n p Figure 5 o atient with autoim l fixed es (p-ANC human granu A) by mune hepatitis type 1) in locytes (serum from an A direct eutrophil cytoplasm immunofluoerescence on etha- N ic autoanti- A negative Perinuclear staining of anti-neutrophil cytoplasmic autoanti- 3.3. Autoantibodies against the asialoglycoprotein bodies (p-ANCA) by indirect immunofluoerescence on etha- receptor (anti-ASGP-R) nol fixed human granulocytes (serum from an ANA negative The asialoglycoprotein receptor (ASGP-R) is a liver-spe- patient with autoimmune hepatitis type 1). Original magnifi- cation 40×). cific 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 and to a much lesser extent in PBC patients (prevalence also found in some patients with PBC, chronic viral range 0–39%) [54,58,59]. Occasionally, high titers of c- hepatitis B and C and alcoholic liver disease although at ANCA can be detected in AIH-1 (Dalekos GN, 2002, lower frequency and lower titers [14,15,66,67]. unpublished observations). In contrast, p-ANCA have not been detected in serum samples from patients with AIH-2 The ASGP-R is preferentially expressed on the surface of [57]. Low ANCA titers are detected infrequently in periportal liver cells where piecemeal necrosis is found as patients with alcoholic or chronic viral liver diseases a marker of severe inflammatory activity in patients with [54,57,60]. However, a recent large study in 516 patients AIH [68]. This finding may suggest a possible immun- with hepatitis C virus (HCV) infection revealed the opathogenetic involvement of anti-ASGP-R autoantibod- presence of ANCA in as high as 55.6% of patients [61]. ies in AIH [69]. The general presumption is that target of Interestingly these investigators have shown that all HCV potentially tissue-damaging autoreactions in AIH must be positive sera with ANCA had c-ANCA pattern on IIF and liver-specific and available to the immune system in vivo contained proteinase-3 specificity [61]. The clinical rele- (e.g. expression on the surface of hepatocytes). So far, vance of this finding remains to be determined. In ASGP-R is the only target-autoantigen that has been posi- patients with AIH-1, PBC or PSC the detection of ANCA tively identified and fulfils these criteria [68,69]. appears to be associated with a more severe disease course Additional support to this emerged from the determina- or the presence of cirrhosis [54,62]. The latter suggestion tions of anti-ASGPR autoantibodies in consecutive AIH however, was not confirmed by more recent studies patients. The levels of anti-ASGP-R autoantibodies vary [53,54]. according to the inflammatory activity of the disease. In addition, anti-ASGP-R antibody titers decreased signifi- To determine the antigenic specificities of ANCA, antigen- cantly in response to immunosuppression, while they specific enzyme linked immunosorbent assays (ELISAs) reappear when the disease has relapsed [66,70]. These and Western blotting followed by immunodetection can autoantibodies may be diagnostically helpful when other be performed [14,63]. Using these techniques it became autoantibodies are not detected and AIH is suspected. obvious that in AIH-1 the target-autoantigens recognized However, due to the belief that anti-ASGPR antibody rep- are multiple including cathepsin G, catalase, alpha-eno- resents a general marker of liver autoimmunity and the lase, lactoferrin, actin and high mobility group (HMG) limitations in its detection (requires chemically purified non-histone chromosomal proteins HMG1 and HMG2 ASGP-R, which is not yet widely available), its routine use [14,54,56,58,62-65]. However, the determination of anti- is not generally recommended. genic specificities of ANCA seems to have limited clinical relevance in patients with AIH-1 [14,15,54,56]. Page 6 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 3.4. Antibodies against soluble liver antigens (anti-SLA) or sons, anti-SLA/LP has been considered as a valuable and to liver-pancreas antigen (anti-LP) specific diagnostic marker of AIH [31,32,73,74,76,77,79]. The anti-SLA autoantibodies were described for the first However, a recent study from the United Kingdom [80] time in 1987 [20]. They cannot be detected by IIF on com- has shown that anti-SLA/LP autoantibodies can also be mon substrate. A competitive ELISA or a radioimmu- detected in AIH-2 and in children with PSC. These inves- noassay usually detects these autoantibodies [20,32,71]. tigators used eukaryotically expressed tRNP ((Ser) Sec)/ SLA is found in 100000 g supernatant of liver homoge- SLA as target in a radioligand assay (RLA) which is well nate and represent a cytosolic protein which is neither known as a more sensitive test than ELISAs and immuno- organ nor species specific [72]. However, the highest con- blot due to its ability to identify antibodies directed to centrations are found in liver and kidney tissues. The anti- conformational epitopes [81-83]. Their novel findings SLA autoantibodies are detected in patients with AIH need confirmation from other research groups and partic- alone or in combination with SMA and/or ANA [30- ularly to address whether anti-SLA/LP reactivity is also 32,73]. As noted above, similarities in the clinical profile present in adult PSC. Recent data confirmed the previous between patients with AIH-1 (ANA and/or SMA positive) finding that patients with anti-SLA/LP display a more and AIH patients with anti-SLA alone in addition with an severe course of AIH [79,80,84]. The latter suggest that approximately 30% seropositivity overlap between anti- anti-SLA/LP may be linked to the pathogenesis of the SLA and SMA and/or ANA suggest that anti-SLA is rather autoimmune process although the exact function and its an additional important marker for the diagnosis of AIH- role in autoimmunity are so far unclear [14,15]. From the 1, than a marker of a third type of AIH [6,14,30-32]. clinical point of view however, this autoantibody may be helpful in an attempt to reduce the group of cryptogenic A scientific group from Tuebingen, Germany described for hepatitis and/or cirrhosis. the first time the anti-LP autoantibodies in 1981 [21]. The LP antigen was predominantly detected in the S100 super- 4. Detectable Autoantibodies in AIH-2 natant of liver and pancreas homogenates, indicating that 4.1. Autoantibodies against liver-kidney microsomes (anti- this antigen was a soluble protein. Until recently, anti-LP LKM) and anti-SLA autoantibodies were thought to be different Three types of anti-LKM autoantibodies have been identi- fied [3,5,14,15,18,30,63,72,85]. The LKM type 1 [20-22]. However, Wies et al report [74] provides convinc- ing evidence and confirms previous suggestions that anti- autoantibody (anti-LKM-1) is the characteristic serologic SLA and anti-LP are one and the same autoantibody (anti- marker for the diagnosis of AIH-2 [5,18,63,72]. These SLA/LP). In addition, the same study demonstrated that autoantibodies were first described by Rizzetto et al [86], the identified target-autoantigen of anti-SLA/LP using the IIF method on rodent liver and kidney sections. autoantibodies (a 35–50 kDa protein) was neither cytok- The characteristic features of anti-LKM-1 autoantibodies eratins 8 or 18 [71] nor glutathione-S-transferase isoen- are the diffuse staining of cytoplasm of the entire liver lob- zyme [75]. The results from two independent groups ule and the exclusive staining of the P3 portion of the [76,77] were similar with those found by Wies et al [74]. proximal renal tubules (Fig. 6) [18]. Due to this staining After screening of cDNA expression libraries they identi- pattern of kidney sections anti-LKM-1 can be easily distin- fied a previously unknown amino acid sequence, which guished from AMA, which stain proximal and distal renal presumably encodes a UGA-suppressor tRNA-associated tubules (Fig. 7). Western blots with hepatic and renal protein, as the targen-autoantigen of anti-SLA/LP autoan- microsomes revealed a protein band at 50 kDa tibodies [76,77]. The UGA-suppressor serine tRNA-pro- [5,14,15,63,72,87]. tein complex is likely to be involved in cotranslational selenocysteine incorporation in human cells [78]. It was The major target-autoantigen of anti-LKM-1 autoantibod- then obvious that the identification of SLA/LP autoanti- ies in AIH-2 has been identified as the cytochrome P450 gen would allow the establishment of a reliable, univer- 2D6 (CYP2D6) [87-89]. It has been shown that anti-LKM- sally available diagnostic test for AIH but also it would 1 autoantibodies inhibit the enzymatic activity of provoke the investigation in the area of autoimmune liver CYP2D6 in vitro, but not in vivo [90]. Epitope mapping diseases. experiments of CYP2D6 autoantigen have defined at least four different linear epitopes [91,92]. The most immuno- Regarding disease specificity, anti-SLA/LP autoantibodies dominant epitopes of CYP2D6 were amino acids 257– have not been detected in patients with AIH-2, PBC, PSC, 269 and 321–351, which are recognized in about 70% chronic viral hepatitis, alcoholic liver disease and non- and 50% of AIH-2 cases, respectively [91,92]. Two infre- hepatic autoimmune diseases by standardized ELISAs quent epitopes consisting of amino acids 373–389 and using reference autoantibody or recombinant antigen 410–429 are also recognized by anti-LKM-1 in some cases [20,32,73,79]. Ballot et al [32] also showed that these [92]. Recently, Klein et al [93] and Kerkar et al [94] autoantibodies are different from anti-LC1. For these rea- reported another immunodominant epitope of CYP2D6 Page 7 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 conformational epitopes on CYP2D6 autoantigen has been postulated [95]. It is noteworthy to state here that depending on the geo- graphic 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 autoantibod- ies (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 A LKM-1) react Figure 6 ntibodies against li to the pr ver-kidney microsomes typ oximal tubules of the rat kidney e 1 (anti- [98,99]. In addition, recently Miyakawa et al [100] identi- Antibodies against liver-kidney microsomes type 1 (anti- fied CYP2E1 and CYP3A4 as target autoantigens of anti- LKM-1) react to the proximal tubules of the rat kidney. The LKM autoantibodies in two patients with anti-LKM-posi- absence of reactivity against thedistal tubules of the rat kid- tive chronic hepatitis C. Taking together, these findings ney (see also Fig. 6B) and parietal cells of the rat stomach dis- tinguishes anti-LKM-1 autoantibodies from antimitochondrial may further indicate the heterogeneous autoimmune antibodies (original magnification 40×). 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 A tu Figure 7 n bules of the rat timitochondrial an kidney tibodies (origrea inact to the proximal and distal l magnification 40×) anti-LKM-1 using a specific competitive ELISA, while Antimitochondrial antibodies react to the proximal and distal denaturation of the antigens prior to perform the ELISA tubules of the rat kidney (original magnification 40 ×). In resulted in complete loss of the signal [105]. these cases there is also reactivity to the parietal cells of the rat stomach. 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 S-methionine- (amino acids 193–212) recognized in about 70% and 93 labelled CYP2D6 antigen obtained by in vitro transcrip- % of AIH-2 patients, respectively. However, due to failure tion and translation synthesis [81-83,99,104]. Using this of inhibition of CYP2D6 enzymatic activity using epitope assay it was shown that the anti-LKM-1 titers do not differ specific antibodies and since the absorption of the above significantly between AIH-2 and HCV/anti-LKM-1 posi- linear epitopes was unable to absorb inhibitory anti- tive patients [81-83]. The presence of anti-LKM-1 in some CYP2D6 autoantibodies, the existence of additional patients with HCV infection led to the proposal for a fur- Page 8 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 ther division of AIH-2 into AIH-2a (younger, predomi- only the sister suffering from AIH-2 was HSV positive, and nantly female patients without evidence of HCV her serum recognized the viral protein ICP4 in lysates of infection) and AIH-2b (older, predominantly male HSV-infected cells [111]. So far however, overall evidence patients with HCV infection) [13,106]. Nowadays how- for mimicry as a driving force of AIH is not convincing. ever, after the marked improvements in the reliability and availability of tests for HCV detection such a subdivision Besides molecular mimicry, chemical modification of self- of AIH-2 appears unreasonable and tends to be deleted. proteins and/or immunological cross-reactivity to homol- Actually, HCV/anti-LKM-1 positive patients represent ogous autoantigens may also provide potential triggers for cases of "true" HCV infection with autoimmune features autoimmune responses. The latter has been suggested by [6,107]. Choudhuri et al [112] who have shown that in AIH-2 patients the linear epitope 321–351 of CYP2D6 cross From the clinical point of view, screening for anti-LKM reacts with amino acids 33–51 of carboxypeptidase-H autoantibodies is recommended before the initiation of (the target autoantigen of islet cell autoantibodies in insu- interferon-alpha therapy in HCV patients and if found lin dependent diabetes mellitus), as well as, with amino positive a careful monitoring appears reasonable because acids 307–325 of 21-hydroxylase (major target autoanti- occasionally interferon-alpha may unmask, or provoke gen in Addison's disease). These findings possibly indicate autoimmune hepatic reactions and even "true"AIH the presence of a common motif of CYP2D6, carbox- [6,43,104,108-110]. Dalekos et al [104] studied antibody ypeptidase-H and 21-hydroxylase, which may contribute titers and performed epitope mapping of LKM-1-positive through a cross reactive immune response to the develop- sera from patients with chronic hepatitis C. Interestingly, ment of multiple endocrinopathies in the course of AIH- a patient with a high LKM-1 titer and autoantibodies 2. Additional support to this hypothesis emerged from directed against an epitope of amino acids 257–269, two recent studies by Kerkar et al [94] and Bogdanos et al which are preferentially recognized by patients with AIH- [113]. In the first study the authors were able to show the 2, showed exacerbation of the disease under interferon- similarity and cross-reactivity between the immunodomi- alpha treatment. In contrast to other patients with HCV nant epitope 193–212 of CYP2D6 and homologues of infection, this patient further recognized a rarely detected two unrelated viruses (HCV 2977–2996 and CMV 121– epitope on the C-terminal third of the protein. These 140) [94]. In the second study the researchers investigated results suggest that determination and monitoring of whether the immunodominant epitope 252–271 of CYP2D6 autoantibody titers by both IIF and the RLA in CYP2D6 in anti-LKM-1 positive AIH-2 and homologues combination with epitope mapping of CYP2D6 in HCV/ from the NS5B and E1 proteins of the HCV polyprotein anti-LKM positive patients before the initiation of and the ICP4 of HSV-1 are targets of humoral immune interferon-alpha treatment, might be helpful in an response in anti-LKM-1 positive and anti-LKM-1 negative attempt to identify those patients at risk of developing HCV infected patients and furthermore whether this undesired autoimmune reactions [104]. response is cross-reactive [113]. The hypothesis of molec- ular mimicry and cross-reactivity in LKM-1 production The mechanism(s) of the development and the patho- has not been addressed experimentally. The authors for genic role of anti-LKM-1 autoantibodies in hepatocellular the first time gave experimental support to the notion that injury are still unclear. It has been suggested that viral molecular similarity between CYP2D6, HCV and HSV can infections by herpes simplex virus (HSV) and related result in LKM-1 production via a cross-reactive response in viruses may trigger the autoantibody formation through genetically susceptible individuals (interestingly only the molecular mimicry in at least some individuals with AIH- HCV positive/LKM-1 positive patients with viral/self 2 [91]. Manns et al [91] tested 26 LKM-positive sera using cross-reactivity possessed the HLA B51 allotype) [113]. Western blot with partial sequences of recombinant Taking together, the above studies suggest that multiple CYP2D6. Eleven sera recognized a short minimal epitope exposure to viruses mimicking self may represent an of eight amino acids with the sequence DPAQPPRD. important pathway to the development of autoimmunity Twelve other clones recognized a larger epitope contain- [94,113]. ing this eight-amino acid core sequence. The search of electronic databases revealed an interesting match of the Two possible mechanisms have been proposed for the minimal epitope with the primary structure of the involvement of anti-LKM-1 autoantibodies in the patho- immediate early protein IE 175 of HSV-1 now known as genesis of liver injury. The first appears to be a direct bind- infected cell protein 4 (ICP4) of HSV-1 (Fig. 8). Sequence ing of these autoantibodies to hepatocytes, leading to lysis identity was present for the PAQPPR sequence. This of liver cells, while the second is associated with an anti- hypothesis was further supported by a case study in a pair LKM-1 induction of activating liver-infiltrating T lym- of identical twins [111]. In this study, one sister suffered phocytes, which indicates the combination of B and T cell from AIH-2 but the other one was healthy. Interestingly, activity in the autoimmune process involved [114-117]. A Page 9 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 Lin Figure 8 ear B-cell epitopes on cytochrome P450 2D6 in autoimmune hepatitis type 2 Linear B-cell epitopes on cytochrome P450 2D6 in autoimmune hepatitis type 2. The immunodominant epitope 257–269 aa shares sequence homology with the immediate early protein IE 175, a transcription factor of herpes simplex virus type 1 (now known as infected cell protein 4 or ICP4). Although this is an attractive model for the hypothesis of molecular mimicry, overall evidence for mimicry as a driving force of autoimmune hepatitis is not convincing. prerequisite for both anti-LKM-1 production and the acti- tis caused by tienilic acid [14,63]. The target autoantigen vation of pathogenetic mechanisms involved in liver of anti-LKM-2 has been documented as the CYP2C9 [85]. injury, is the expression of CYP2D6 on the surface of the A proposed mechanism for the induction of anti-LKM-2 patients' hepatocytes. Under this context, Ma et al [118] could be the binding of an active metabolite of the drug showed that key residues of a major CYP2D6 epitope to the CYP2C9 protein, which then becomes antigenic (316–327) are exposed on the surface of the molecule and [14,63,72,85]. may represent key targets for anti-CYP2D6 production. In addition, recent data provides convincing evidence that Anti-LKM type 3 autoantibodies (anti-LKM-3) alone or in anti-LKM-1 autoantibodies recognize CYP2D6 exposed combination with anti-LKM-1 are also detected in about on the plasma membrane of hepatocytes from either AIH- 5–10% of patients with AIH-2 [16,119]. In contrast to 2 or HCV/anti-LKM-1 positive patients [114,115] suggest- anti-LKM-1 and anti-LKM-2 autoantibodies, which on ing a pathogenetic role for these autoantibodies in hepatic immunofluorescence stain liver and kidney tissues only, tissue damage either in AIH-2 or in some cases of HCV/ with anti-LKM-3 additional fluorescence signals may be anti-LKM-1 positive patients [104,109,110,115]. present with tissue from the pancreas, adrenal gland, thyroid, and stomach. Family 1 of UDP-glycuronosyl- So far, anti-LKM type 2 autoantibodies (anti-LKM-2) have transferases (UGT1) is the main target autoantigen of anti- been detected only in some cases of drug-induced hepati- LKM-3 autoantibodies (molecular weight of 55 kDa) Page 10 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 [119,120]. These autoantibodies were first described in LKM-1, the titers of anti-LC1 autoantibodies appear to about 13% of patients with chronic hepatitis D, but not in parallel with disease activity [130]. The latter may indicate patients with chronic hepatitis B or C [121]. However, a possible involvement of anti-LC1 in the pathogenesis of three recent reports have shown the presence of anti-LKM- AIH-2. However, the clinical significance of anti-LC1 is 3 autoantibodies in some patients with HCV infection not yet completely defined. [99,122,123]. These findings may further support the heterogeneous phenomenon of the HCV-induced 5. Detectable Autoantibodies in AIH in APECED autoimmunity. Chronic hepatitis as a disease component of APECED may develop in 10–18% of patients [14,15,23-25,28,29,63]. 4.2. Autoantibodies against liver cytosolic protein type 1 APECED appears to be caused by mutations in a recently (anti-LC1) identified gene, the autoimmune regulator gene (AIRE), In 1988 a second autoantibody marker of AIH-2 was rec- and represents the only known autoimmune disease with ognized [19]. This autoantibody was found to react to a a monogenetic mutation today [26,27,131]. It is interest- liver cytosolic protein. The autoantibody is organ specific ing that patients with AIH in the absence of APECED do but not species specific and was therefore called anti-LC1 not display mutations of the AIRE gene and are therefore [19]. The anti-LC1 autoantibodies are characterized by a genetically distinct from patients with AIH as a compo- cytoplasmic staining of the periportal hepatocytes when nent of APECED [132]. the IIF assay is used for their detection. The hepatocellular layer around the central veins is not stained [19,124]. Similar to AIH-2, hepatitis in APECED is associated with These findings indicate that the target autoantigen of anti- autoantibodies directed against cytochrome P450 pro- LC1 autoantibodies is not uniformly distributed in rodent teins. In a large study with APECED patients, a typical liver tissues. They are detected in about 30% of patients LKM staining pattern and a predominant staining of the with AIH-2 [19,124] and in approximately 50% of all perivenous hepatocytes in the absence of staining of the anti-LKM-1 positive cases [125]. It is noteworthy that the kidney were observed [23]. The latter pattern is due to anti-LC1 autoantibodies proved to be the only serological autoantibodies called liver microsomal autoantibodies marker in 10% of patients with AIH [19]. (anti-LM). In this study each of anti-LKM and anti-LM antibodies were found in 8% of the patients [23]. These The detection of anti-LC1 autoantibodies by IIF is findings indicate that two or more different microsomal obscured due to the anti-LKM-1 pattern that frequently antigens are hepatic target-autoantigens in APECED. found in most of the anti-LC1 positive sera. For these rea- sons other techniques such as, the ouchterlony double Indeed, screening of APECED sera with recombinant anti- diffusion, immunoblot or counter-immunoelectrophore- gens using Western blots has shown reactivity against four sis are required for their detection [19,124-126]. By different hepatic cytochromes P450: CYP1A1, CYP1A2, immunoblotting, anti-LC1 positive serum samples recog- CYP2A6 and CYP2B6 [23-25,133]. CYP1A1, CYP2A6 and nize a liver specific cytosolic protein of 58–62 kDa [124- CYP2B6 are expressed both in liver and in kidney result- 126]. Recently the molecular target of anti-LC1 was iden- ing to an LKM staining pattern, while CYP1A2 is not tified as the formiminotransferase cyclodeaminase expressed in the kidney leading to the LM staining. (FTCD) [127], which is a polymeric bifunctional enzyme Among the four autoantibodies anti-CYP2A6 were involved in folate metabolism. However, another group detected with the highest prevalence in a Finnish APECED demonstrated the arginninosuccinate lyase (ASL) as the patients group (15.6%), while anti-CYP1A2 were found in target autoantigen of a weak precipitin line detected by the 6.3% [23]. These results were confirmed by quantitative ouchterlony double diffusion assay in patients with immunoprecipitation assays with recombinant S- autoimmune or viral hepatitis [128]. labeled CYP1A2 and CYP2A6. Anti-LC1 autoantibodies have been proposed as a more Contrary to a previous work in Sardinian patients with specific marker of AIH-2 than anti-LKM-1 autoantibodies, APECED [25], the detection of anti-CYP2A6 autoantibod- since in the original reports their presence was never asso- ies in a larger group of Finnish patients was not associated ciated with HCV infection [19,124]. However, a recent with the presence or absence of hepatitis, while anti- study by Lenzi et al [125] confirmed the above aspect only CYP1A2 autoantibodies were detected only in APECED in the pediatric subset of their patients, while a substantial patients with hepatitis [23]. These findings indicate that proportion of the adults with anti-LC1 autoantibodies anti-CYP1A2 is a specific marker for AIH as a component had also markers of HCV infection. The significance of the of APECED, albeit with a low sensitivity [23,24]. Anti- association between anti-LC1 autoantibodies and HCV CYP2A6 autoantibodies may be used as an indicator for infection remains uncertain and has to be established APECED, if they are present in a patient with AIH. In par- [106,129]. In contrast to what has been found for anti- allel with the above conclusions is the anti-LKM/LM Page 11 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 Table 4: 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 ANA, anti-LC (molecular target: unknown), anti-LKM (molecular suppressor tRNA-associated protein), anti-LKM-1 (molecular target: targets: CYP2A6, CYP1A1 and CYP2B6), anti-LM (specific autoantibody; CYP2D6), anti-LKM-3 (molecular target: UGT1), anti-LC1 (molecular molecular target: CYP1A2) target: FTCD) Abbreviations are the same as shown in the text. Table 5: 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. Anti-CYP2D6 Anti-CYP2A6 Anti-CYP1A2 Chronic liver disease + - - AIH-2 (94–100%), HCV (0–10%) - + - HCV, APECED with or without hepatitis - - + AIH in APECED, drug induced hepatitis ++ - HCV (0–7%) - + + AIH in APECED Abbreviations are the same as shown in the text. detection by IIF in about 50% of patients with AIH as part Anti-LM autoantibodies are first described in dihydrala- of the APECED and in only 11% of APECED patients zine-induced hepatitis [135]. The major target autoanti- without hepatitis [23]. The same study showed that the gen of anti-LM in both conditions (hepatitis as part of the prevalence of ANA detection in APECED patients was APECED and drug-induced hepatitis) has been docu- high (22%) but irrespective of the presence or absence of mented as the CYP1A2 [23-25,133,135]. In cases of dihy- hepatitis. Therefore ANA are not useful laboratory mark- dralazine-induced hepatitis the production of anti-LM ers for AIH in APECED [23]. To the contrary, none of the autoantibodies has been attributed to adduct formation patients' sera tested positive for anti-SLA, anti-CYP2D6 or of CYP1A2 with an activated metabolite of the drug [136]. anti-FTCD autoantibodies, which are specific markers of By contrast, in APECED patients no relationship between AIH-1 and AIH-2 [23]. On the other hand, CYP1A2 and CYP1A2 and drug usage is known. In addition, it is not CYP2A6 could not be identified as hepatic autoantigens in known whether in APECED patients a close monitoring of the disease control groups consisting of patients with idi- anti-LM may lead to early, or even prophylactic, treatment opathic AIH or patients with autoimmune rheumatic dis- of hepatitis as a new disease component. Evidence that eases [23]. These findings indicate that idiopathic AIH autoantibodies may be found before the clinical and/or and AIH in APECED are characterized by different molec- laboratory manifestation of a new disease component in ular targets of autoimmunity, which do not overlap. APECED comes from adrenal and ovarian insufficiencies, Therefore, AIH and hepatitis as part of the APECED may where the respective autoantibodies are detected 2–3 be distinguished on the basis of differences in autoanti- years before the clinical presentation of the autoimmune body profile (Tables 4 and 5). components [137]. Dalekos et al [134] using the sensitive quantitative RLA Another hepatic autoantigen in APECED, the aromatic-L- reported for the first time the presence of anti-CYP2A6 amino acid decarboxylase (AADC) has also been identi- autoantibodies in about 2% of HCV-positive sera in gen- fied recently [133,138]. This enzyme is expressed in the eral and in 7.5% of LKM-1-positive/HCV-positive sera. liver cytosol and was originally described as a β-cell The latter further supports the low specificity of this autoantigen [133]. The prevalence of anti-AADC autoan- autoantibody as a marker for AIH in APECED. tibodies is significantly increased in APECED patients Interestingly, anti-CYP2A6 autoantibodies were not with vitiligo (88%) and hepatitis (92%) [5,14,29]. So far, detected in patients with AIH-2 who exhibit high titers of anti-AADC autoantibodies have only been reported in anti-LKM-1 autoantibodies [134]. The clinical relevance APECED and their role in AIH and vitiligo as disease com- of this finding in HCV infection remains to be ponents of APECED deserve further investigation. determined. Page 12 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 Table 6: Differential Diagnosis of Autoimmune Hepatitis. have been identified, but the latter has not led to the characterization of specific subpopulations of patients or Other autoimmune liver diseases changes in the treatment strategies. In addition, most of - Overlap syndromes the non-organ specific autoantibodies do not seem to be - Primary biliary cirrhosis involved in the pathogenesis of liver injury in AIH. Anti- - Primary sclerosing cholangitis Chronic viral hepatitis LKM-1 autoantibodies could be an exception to the above - Chronic hepatitis B with or without hepatitis delta aspect since recent data have demonstrated the expression - Chronic hepatitis C of CYP2D6 on the surface of hepatocytes, while AIH-2 has - Chronic hepatitis non A to G not been observed in individuals who are deficient for Cholangiopathy due to human immunodeficiency virus infection CYP2D6. These findings provide arguments for an anti- Alcoholic liver disease gen-driven autoimmune process. It is possible that muta- Drug-induced hepatitis tions in the autoantigen itself can lead to alterations in the Non-alcoholic steatohepatitis Granulomatous hepatitis three dimensional structure of the antigen, which induces Hemochromatosis autoimmunity. α -antithrypsin deficiency Wilson's disease Antibodies directed against liver-related antigens have Systemic lupus erythematosus 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, autoan- tibodies should not be used as a tool for monitoring of 6. Concluding Remarks In clinical practice the recognition of AIH is of great treatment or to predict AIH activity and outcome. Anti- importance since most of the patients respond favorably SLA/LP autoantibodies have been considered as valuable to antiinflammatory and immunosuppressive treatment. and specific markers for the diagnosis of AIH-1. However, In addition, recent novel findings dealing with the bone a recent study has shown that anti-SLA/LP autoantibodies marrow hemopoietic progenitor cells and bone marrow can also be detected in AIH-2 and in children with PSC. stromal cells of patients with AIH suggests alternative Irrespective of the disease specificity of this marker, it is therapeutic options even in refractory cases [139]. obvious that testing for anti-SLA/LP will help to reduce Diagnostic criteria for this disease have been codified the group of cryptogenic liver disease, by recognizing pre- recently [6]. These include descriptive criteria and scoring viously misdiagnosed patients with AIH who were seron- system based on clinical, serologic and histologic features egative for ANA, SMA or anti-LKM-1. of AIH (Table 1), which contribute substantially to the differential diagnosis of the disease from other forms of In APECED, autoantibodies are directed against specific chronic hepatitis associated with autoimmune phenom- cytochrome P450 enzymes (e.g. CYP1A2, CYP2A6, ena (Table 6). The discrimination between AIH and HCV CYP21, CYP17, and CYP11A1), that are expressed in infection is of particular importance, since the immuno- organs affected by the disease process. These observations suppression used in the former can deteriorate liver dis- argue against the idea that antibodies against cytochrome ease in HCV patients, while interferon-alpha treatment P450 complex are simply epiphenomena secondary to tis- used in HCV infection may lead to exacerbation of AIH sue damage and that they have no relation to the etiology [104,108-110]. and pathogenesis of APECED. The detection of non-organ specific autoantibodies It is not known what triggers autoimmunity in AIH. The remains the hallmark of AIH. A step by step diagnostic hypothesis that different causes may lead to loss of toler- application of autoantibody tests is mandatory for the ance against the same molecular target autoantigen seems evaluation of acute or chronic hepatitis of unknown attractive. For instance, CYP1A2 is the molecular target in cause. ANA, SMA and anti-LKM-1 autoantibodies should dihydralazine-induced hepatitis and AIH as a component be first tested in patients with acute or chronic elevation of APECED, CYP2D6 in AIH-2 and in some patients with of aminotransferases when virologic tests are negative and HCV infection, CYP2A6 in APECED and in a proportion there is no current or past history for drug or alcohol of patients with HCV infection and UGT1 in some cases of abuse. Determination of ANCA, which occur in up to 90% AIH-2 and chronic hepatitis D or C. of patients with AIH-1, may be useful in the identification of individuals who are seronegative for the above conven- Research protocols in order to define AIH pathogenesis, tional autoantibody markers but should be kept in mind disease susceptibility, determinants of disease severity, that this autoantibody lacks specificity. Many target and to understand the epidemiology of AIH are future autoantigens of the non-organ specific autoantibodies Page 13 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 mune chronic active hepatitis by autoantibodies against challenges in the investigational and clinical arena of this soluble liver antigen. Lancet 1987, i:292-294. disease [139-141]. 21. Berg PA, Stechemesser E, Strenz J: Hypergammaglobulinamische chronisch aktive Hepatitis mit Nachweis von Leber-Pan- creas-spezifischen koplementbindenden Antikorpen. Verch Competing interest Dtsch Ges Inn Med 1981, 87:921-927. The author(s) declare that they have no competing 22. Stechemesser E, Klein R, Berg PA: Characterization and clinical relevance of liver-pancreas antibodies in autoimmune interests. hepatitis. Hepatology 1993, 18:1-9. 23. 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Hepatol- MP: LKM3 autoantibodies in hepatitis C cirrhosis: a further ogy 2000, 31:1194-2000. phenomenon of the HCV-induced autoimmunity. Am J 141. Czaja AJ: Understanding the pathogenesis of autoimmune Gastroenterol 2001, 96:910-911. hepatitis. Am J Gastroenterol 2001, 96:1224-1231. 123. Bachrich T, Thalhammer T, Jager W, Haslmayer P, Alihodzic B, Bakos S, Hitchman E, Senderowicz AM, Penner E: Characterization of autoantibodies against uridine-diphospate glucuronosyl- transferase in patients with inflammatory liver diseases. Hepatology 2001, 33:1053-1059. 124. 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. 125. 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. 126. 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, counterimmunoelectro- phoresis and immunoblotting: comparison of three different techniques. J Immunol Methods 1995, 187:259-264. 127. Lapierre P, Hajoui O, Homberg J-C, Alvarez F: Formininotrans- ferase cyclodeaminase is organ-specific autoantigen recog- nized by sera of patients with autoimmune hepatitis. Gastroenterology 1999, 116:643-649. 128. 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. Publish with Bio Med Central and every 129. Obermayer-Straub P, Manns MP: Hepatitis C and D, retroviruses scientist can read your work free of charge and autoimmune manifestations. J Autoimmunity 2001, 16:275-285. "BioMed Central will be the most significant development for 130. Muratori L, Cataleta M, Muratori P, Lenzi M, Bianchi FB: Liver/kid- disseminating the results of biomedical researc h in our lifetime." ney microsomal antibody type 1 and liver cytosol antibody Sir Paul Nurse, Cancer Research UK type 1 concentrations in type 2 autoimmune hepatitis. Gut 1998, 42:721-726. Your research papers will be: 131. Rinderle C, Christensen HM, Schweiger S, Lehrach H, Yaspo ML: available free of charge to the entire biomedical community AIRE encodes a nuclear protein co-localizing with cytoskele- tal filaments: altered sub-cellular distribution of mutants peer reviewed and published immediately upon acceptance lacking the PHD zinc fingers. Hum Mol Genet 1999, 8:277-290. cited in PubMed and archived on PubMed Central 132. Vogel A, Liermann H, Harms A, Strassburg CP, Manns MP, Ober- mayer-Straub P: Autoimmune regulator AIRE: evidence for yours — you keep the copyright genetic differences between autoimmune hepatitis and hep- BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 17 of 17 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Autoimmune Diseases Springer Journals http://www.deepdyve.com/lp/springer-journals/autoantibodies-and-autoantigens-in-autoimmune-hepatitis-important-BsEakcmanq

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Publisher: Springer Journals
Copyright: Copyright © 2004 by Zachou et al; licensee BioMed Central Ltd.
Subject: Biomedicine; Immunology; Internal Medicine
eISSN: 1740-2557
DOI: 10.1186/1740-2557-1-2
Publisher site: See Article on Publisher Site

Abstract

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 Page 1 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 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. 1. Introduction tine clinical practice for the diagnosis and classification of Autoimmune hepatitis (AIH) is a rare chronic liver disease patients as having either 'definite' or 'probable' AIH [13]. of unknown etiology. The estimated prevalence of AIH in In addition, a diagnostic scoring system was devised to Northern European countries is approximately 160–170 provide an objective method for selection of relatively patients/10 inhabitants [1,2]. The disease predominates homogeneous groups of patients for research purposes among women and is characterized by hypergammaglob- [13]. The same group has remarkably simplified the ulinemia even in the absence of cirrhosis, characteristic descriptive set of criteria and the diagnostic scoring system autoantibodies, association with human leukocyte anti- in late 1998 (Tables 1 and 2) [6]. The diagnostic score gens (HLA) DR3 or DR4 and a favorable response to demonstrates that the presence of defined autoantibodies immunosuppressive treatment [3-5]. The onset of AIH is an integral part of the diagnosis of AIH but not its single disease is usually insidious, with unspecific symptoms, diagnostic tool [6,14]. such as, fatigue, malaise, arthralgias, and fluctuating jaun- dice, right upper quadrant pain or lethargy [5-8]. How- In recent years however, significant progress has been ever, a substantial proportion of patients may have no made in the characterization of liver-related target- obvious signs or symptoms of liver disease, while occa- autoantigens. This has led to the notion that some of the sionally the presentation may be severe and almost iden- major target-autoantigens in AIH are active enzymes of tical to an acute or fulminant episode of viral hepatitis [5- the human hepatic and non-hepatic microsomal xenobi- 8]. Although AIH brings in mind the archetypal patient otic metabolism [14-16]. The latter serve as a means to being a young female with endocrine abnormalities, there investigate this still enigmatic liver disease. This article is nowadays increasing evidence that the disease can also will focus on the data that have evolved in the course of affect males and can present at almost any age (the large the characterization of autoantibody-autoantigen "sys- majority of patients being between 50 and 70 years of age) tem" in AIH by giving the current aspects on the role and [6-12]. significance of this "system" in the differential diagnosis and study of pathogenesis of AIH. Liver histology is not pathognomonic for AIH and there is no single serologic test of sufficient specificity for the diag- 2. Classification of AIH nosis of AIH as for the diagnosis of viral hepatitis A to E. According to the pattern of autoantibodies detected in Although the presence of autoantibodies is one of the dis- AIH patients, a subclassification of the disease into three tinguishing features of AIH, there is no single autoanti- types was proposed in 1994 [17]. AIH type 1 (AIH-1) is body with the diagnostic significance and specificity that characterized by the presence of antinuclear antibodies antimitochondrial autoantibodies (AMA) demonstrate (ANA) and/or smooth muscle autoantibodies (SMA) for the diagnosis of primary biliary cirrhosis (PBC). For which may associate with perinuclear anti-neutrophil this reason, autoantibodies can not be employed as a sin- cytoplasmic antibodies (p-ANCA) [3,5,6,14,15]. AIH type gle marker for the diagnosis of AIH. It is rather a diagnosis 2 (AIH-2) is characterized by the detection of specific reached by the exclusion of other factors leading to autoantibodies against liver and kidney microsomal anti- chronic hepatitis that include viral, toxic, genetic and met- gens (anti-LKM type 1 or infrequently type 3) [14-16,18] abolic causes [6]. Under this context, it is clear that some- and/or antibodies against liver cytosol type 1 antigen times AIH may be difficult to diagnose [7,8]. In 1992, the (anti-LC1) [14,15,19]. AIH type 3 (AIH-3) is characterized International Autoimmune Hepatitis Group reported a by autoantibodies against soluble liver antigens (anti- descriptive set of criteria that could be applied in the rou- SLA) [20] or to liver-pancreas antigen (anti-LP) [21,22]. Page 2 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 Table 1: Revised Scoring System for the Diagnosis of The serological diversity of autoantibodies found in AIH Autoimmune Hepatitis . supports the aforementioned subclassification and pro- vides a framework for the scientific analysis of this heter- Parameter/Features Score ogeneous disease group [5,15]. It also demonstrates that AIH may not be a single disease with a single underlying Gender - Female/Male +2/0 mechanism but most likely is a group of diseases with a Degree of elevation above upper normal limit of similar clinical presentation [14,15]. This is further ALP vs. aminotransferases substantiated by the finding of an unusual form of AIH in - <1.5 +2 10–18% of patients with a rare autosomal recessive disor- - 1.5 – 3.0 0 der, the autoimmune polyendocrinopathy-candidiasis- - >3.0 -2 ectodermal dystrophy syndrome (APECED) [23-25]. This Total serum globulins, γ-globulins, or IgG above normal syndrome is characterized by chronic mucocuteneous - >2.0 +3 candidiasis, ectodermal dystrophy and autoimmune tis- - 1.5 – 2.0 +2 sue destruction particularly of the endocrine glands - 1.0 – 1.5 +1 (hypoparathyroidism, adrenocortical failure and gonadal - <1.0 0 failure in females) [26-29]. ANA, SMA or LKM-1 (titers by immunofluorescence on rodent tissues or HEp2-cells) - >1 : 80 +3 However, due to recent clinical, serologic and genetic - 1 : 80 +2 findings, it has been suggested that anti-SLA seropositive - 1 : 40 +1 patients do not define a subgroup of AIH, but rather - <1 : 40 0 belong to the AIH-1 group [30-32]. For this reason, subdi- - AMA positive -4 vision into AIH-1 (ANA, SMA, p-ANCA and/or anti-SLA/ Hepatitis viral markers (IgM anti-HAV, HBsAg, IgM LP positive) and AIH-2 (anti-LKM-1, anti-LKM-3 and/or anti-HBc, anti-HCV and HCV-RNA) anti-LC1 positive) is in common usage (Table 3). Apart - Positive/Negative -3/+3 Recent or current use of known or suspected from serological differences, AIH-2 seems to be clinically hepatotoxic drugs and genetically distinguishable from AIH-1 [5,8,14]. - Yes/No -4/+1 Indeed, patients with AIH-2 are younger at presentation, Average alcohol intake usually have higher levels of bilirubin and transaminases, - <25 g/day +2 and are characterized by more severe disease than patients - >60 g/day -2 Other autoimmune disease(s) in patient or first with AIH-1 [5,6,14,18,33]. In addition, contrary to what degree relatives has been recorded in patients with AIH-1, no sustained - Yes/No +2/0 remission has been observed after the discontinuation of Optional additional parameters (should be allocated immunosuppressive therapy in patients with AIH-2 only if ANA, SMA or LKM-1 are negative) [4,33]. Taking into consideration the genetic markers, it - HLA DR3, DR4, or other HLA with published association +1 with AIH) has been found that the association between HLA DR3 - Seropositivity for any of ANCA, anti-LC1, anti-SLA/LP, +2 and AIH-2 is rather weaker than that reported in AIH-1, anti-ASGPR and anti-sulfatide while an association between HLA DQ2 and AIH-2 has Liver histology been reported [14,18,33,34]. However, AIH-2 patients - Interface hepatitis +3 represent only a small proportion of the total cases of AIH - Predominant lymphoplasmacytic infiltrate +1 [3-6]. In addition, the long-term outcome of the affected - Rosetting of liver cells +1 patients appears to be similar both in AIH-1 and AIH-2 - None of the above -5 - Biliary changes -3 [6,33]. Therefore, the classification of AIH in these two - Other changes -3 major subgroups is still uncertain and controversial Response to therapy (as defined in Table 2) [6,8,13]. - Complete/Relapse +2/+3 3. Detectable Autoantibodies in AIH-1 Definite AIH if greater than 15 before treatment or greater than 17 3.1. Anti-nuclear antibodies (ANA) and smooth muscle post-treatment; probable AIH if varies between 10–15 before treatment or 12–17 post-treatment. ALP: alkaline phospatase, IgM autontibodies (SMA) anti-HAV: hepatitis A virus IgM antibody, anti-HCV: hepatitis C virus ANA and/or SMA are almost exclusively requisites for the antibody, HBsAg: surface antigen of hepatitis B virus, IgM anti-HBc: diagnosis of AIH-1 [3,5,6,14,15,30]. In typical cases of IgM antibody against the nuclear antigen of hepatitis B virus. Other AIH-1, these autoantibodies are detected in significant tit- abbreviations are the same as shown in the text. ers (≥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]. Page 3 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 Table 2: Definitions of Response to Therapy. Response Definition Complete Either or both of the following: marked improvement of or Either or both of the following: marked improvement of symptoms and return of serum AST or ALT, bilirubin and symptoms together with at least 50% improvement of all liver immunoglobulin values completely to normal within 1 year and tests during the first month of treatment, with AST or ALT sustained for at least a further 6 months on maintenance levels continuing to fall to less than twice the upper normal therapy, or liver biopsy specimen at some time during this limit within 6 months during any reductions toward period showing at most minimal activity. maintenance therapy, or a liver biopsy within 1 year showing only minimal activity. Relapse Either or both of the following: an increased in serum AST or or Reappearance of symptoms of sufficient severity to require ALT levels of greater than twice the upper normal limit or a increased (or reintroduction of) immunosuppression, liver biopsy showing active disease, with or without accompanied by any increase in serum AST or ALT levels, after reappearance of symptoms, after a "complete" response as a "complete" response as defined above. defined above. AST: aspartate aminotransferase, ALT: alanine aminotransferase. Table 3: Classification of Autoimmune Hepatitis (AIH) According to Autoantibodies Detection Type of AIH Characteristic autoantibodies AIH-1 ANA, SMA, p-ANCA anti-ASGP-R, anti-SLA/LP AIH-2 anti-LKM-1, anti-LKM-3, anti-LC1, anti-ASGP-R Abbreviations are the same as shown in the text. Typical patient with autoimmune hepati rect immunofluoerescenc (origin Figure 2 al m staining of a agnification ntinu 40×) clear e on cr antib tis type 1 visu yoo stat section dies in the serum alized by indi- s of rat liver of a Typical staining of antinuclear antibodies in the serum of a patient with autoimmune hepatitis type 1 visualized by indi- rect immunofluoerescence on cryostat sections of rat liver (original magnification 40×). slides (Figures 1 and 2) [14,15,35,36]. Different patterns of fluorescence are found by this assay due to the large var- iability of target-autoantigens in the nuclei of HEp-2 cells H p H ty Figure 1 aiEp-2 pe 1 ttern by indirect gh titer (AIH-1) cells in a female pa antinuclear antibodi immuntien ofluoerescence o t with es (ANA) of the ho autoimmu n immobil ne mo hepgeneous aititis zed that have been recognized [35-40]. Actually, ANA are High titer antinuclear antibodies (ANA) of the homogeneous found to be directed against single or double stranded pattern by indirect immunofluoerescence on immobilized DNA, tRNA, SSA-Ro, snRNPs, laminins A and C, cyclin A HEp-2 cells in a female patient with autoimmune hepatitis or histones [35-40]. Most commonly, a homogenous type 1 (AIH-1). Homogeneous ANA are frequently found in AIH-1 (original magnification 40×). (34–58%) or speckled (21–34%) immunofluoerescence pattern is demonstrable [14,15,35-37]. So far however, neither a liver-specific nuclear antigen nor a liver-disease- specific ANA has been identified. For this reason, subtyp- ing of ANA in cases of AIH-1 seems to have limited clinical The most frequent and conventional method for ANA implication and diagnostic relevance in routine clinical detection is the indirect immunofluorescence (IIF) assay practice [6,14,15,35-40]. on cryostat sections of rodent tissues and HEp-2 cells Page 4 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 as of 1:40 [14,15]. Czaja et al [41] have suggested that antibodies to actin are associated with a younger age of disease onset, the presence of HLA-A1-B8-DR3 haplotype and a greater frequency of treatment failure, death from liver disease and earlier requirement for transplantation than actin-antibody negative AIH-1 patients. 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 adminis- tration is generally safe in most cases of viral hepatitis with ANA and/or SMA, although occasionally may pro- voke mild self-limited autoimmune disorders compared to viral hepatitis patients without ANA or SMA on ra titis type 1) Figure 3 Smooth muscle antibodies by t kidney (from a female p in atient with autoimm direct immunofluoeresce une hepa- nce autoantibodies [44-46]. During immunosuppressive Smooth muscle antibodies by indirect immunofluoerescence treatment, disappearance of ANA and/or SMA is observed on rat kidney (from a female patient with autoimmune hepa- in the majority of patients with AIH-1 [47]. However, titis type 1). The immunofluorescence involves smooth mus- autoantibody status is unable to predict immediate out- cle fibers within blood vessels (original magnification 40×). come after cessation of corticosteroid administration. Additionally, neither autoantibody titers at first diagnosis nor autoantibody behaviour in the time course of the dis- ease 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 determi- nation 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 [48]. 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 cence on rat stomach (serum autoimmune hepatitis type 1) Figure 4 Smooth muscle autoantibodies by in from a female patien direct immunofluoeres- t with Wegener's granulomatosis and microscopic polyangiitis, Smooth muscle autoantibodies by indirect immunofluoeres- respectively [48,49]. Proteinase-3 has been identified as cence on rat stomach (serum from a female patient with the major target-autoantigen of c-ANCA in cases with autoimmune hepatitis type 1). The immunofluorescence Wegener's granulomatosis, while myeloperoxidase is the involves smooth muscle fibers within muscularis mucosa (original magnification 40×). 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 fre- SMA are detected by IIF on rodent liver and kidney, due to quently in ulcerative colitis than in Crohn's disease) staining of vessel walls (Fig. 3), and stomach due to stain- [50,51] and primary sclerosing cholangitis (PSC), a liver ing of the muscle layer (Fig. 4). SMA are directed against disease that is frequently associated with ulcerative colitis structures of the cytoskeleton such as actin, troponin, [51,52]. vimentin and tropomyosin. In AIH-1, SMA are predomi- nantly directed against F-actin [41]. The latter seems to be Several recent studies however, have also documented the diagnostically more relevant in pediatric patients where presence of high titers of p-ANCA in the sera of patients SMA may be the only marker of AIH-1 even in titers as low with AIH-1 (Fig. 5; prevalence range 40–96%) [53-58] Page 5 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 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 [61] the detection of ANCA is rather rare in chronic viral hepatitis [14,54,57,60]. The latter may prove useful in the differen- tial diagnosis between patients with AIH and those with viral hepatitis who tested positive for ANA or SMA. Fur- thermore, since ANCA appear to be relatively rare in PBC [54,59], these autoantibodies may prove useful for distin- guishing between genuine cases of AIH and cases of PBC with features overlapping with those of AIH [6]. However, due to the lack of specificity for the diagnosis of AIH and to its obscure role – if any – in AIH, their routine determi- nation is not recommended [14,15]. Perinuclear staining of anti-n bodi n p Figure 5 o atient with autoim l fixed es (p-ANC human granu A) by mune hepatitis type 1) in locytes (serum from an A direct eutrophil cytoplasm immunofluoerescence on etha- N ic autoanti- A negative Perinuclear staining of anti-neutrophil cytoplasmic autoanti- 3.3. Autoantibodies against the asialoglycoprotein bodies (p-ANCA) by indirect immunofluoerescence on etha- receptor (anti-ASGP-R) nol fixed human granulocytes (serum from an ANA negative The asialoglycoprotein receptor (ASGP-R) is a liver-spe- patient with autoimmune hepatitis type 1). Original magnifi- cation 40×). cific 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 and to a much lesser extent in PBC patients (prevalence also found in some patients with PBC, chronic viral range 0–39%) [54,58,59]. Occasionally, high titers of c- hepatitis B and C and alcoholic liver disease although at ANCA can be detected in AIH-1 (Dalekos GN, 2002, lower frequency and lower titers [14,15,66,67]. unpublished observations). In contrast, p-ANCA have not been detected in serum samples from patients with AIH-2 The ASGP-R is preferentially expressed on the surface of [57]. Low ANCA titers are detected infrequently in periportal liver cells where piecemeal necrosis is found as patients with alcoholic or chronic viral liver diseases a marker of severe inflammatory activity in patients with [54,57,60]. However, a recent large study in 516 patients AIH [68]. This finding may suggest a possible immun- with hepatitis C virus (HCV) infection revealed the opathogenetic involvement of anti-ASGP-R autoantibod- presence of ANCA in as high as 55.6% of patients [61]. ies in AIH [69]. The general presumption is that target of Interestingly these investigators have shown that all HCV potentially tissue-damaging autoreactions in AIH must be positive sera with ANCA had c-ANCA pattern on IIF and liver-specific and available to the immune system in vivo contained proteinase-3 specificity [61]. The clinical rele- (e.g. expression on the surface of hepatocytes). So far, vance of this finding remains to be determined. In ASGP-R is the only target-autoantigen that has been posi- patients with AIH-1, PBC or PSC the detection of ANCA tively identified and fulfils these criteria [68,69]. appears to be associated with a more severe disease course Additional support to this emerged from the determina- or the presence of cirrhosis [54,62]. The latter suggestion tions of anti-ASGPR autoantibodies in consecutive AIH however, was not confirmed by more recent studies patients. The levels of anti-ASGP-R autoantibodies vary [53,54]. according to the inflammatory activity of the disease. In addition, anti-ASGP-R antibody titers decreased signifi- To determine the antigenic specificities of ANCA, antigen- cantly in response to immunosuppression, while they specific enzyme linked immunosorbent assays (ELISAs) reappear when the disease has relapsed [66,70]. These and Western blotting followed by immunodetection can autoantibodies may be diagnostically helpful when other be performed [14,63]. Using these techniques it became autoantibodies are not detected and AIH is suspected. obvious that in AIH-1 the target-autoantigens recognized However, due to the belief that anti-ASGPR antibody rep- are multiple including cathepsin G, catalase, alpha-eno- resents a general marker of liver autoimmunity and the lase, lactoferrin, actin and high mobility group (HMG) limitations in its detection (requires chemically purified non-histone chromosomal proteins HMG1 and HMG2 ASGP-R, which is not yet widely available), its routine use [14,54,56,58,62-65]. However, the determination of anti- is not generally recommended. genic specificities of ANCA seems to have limited clinical relevance in patients with AIH-1 [14,15,54,56]. Page 6 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 3.4. Antibodies against soluble liver antigens (anti-SLA) or sons, anti-SLA/LP has been considered as a valuable and to liver-pancreas antigen (anti-LP) specific diagnostic marker of AIH [31,32,73,74,76,77,79]. The anti-SLA autoantibodies were described for the first However, a recent study from the United Kingdom [80] time in 1987 [20]. They cannot be detected by IIF on com- has shown that anti-SLA/LP autoantibodies can also be mon substrate. A competitive ELISA or a radioimmu- detected in AIH-2 and in children with PSC. These inves- noassay usually detects these autoantibodies [20,32,71]. tigators used eukaryotically expressed tRNP ((Ser) Sec)/ SLA is found in 100000 g supernatant of liver homoge- SLA as target in a radioligand assay (RLA) which is well nate and represent a cytosolic protein which is neither known as a more sensitive test than ELISAs and immuno- organ nor species specific [72]. However, the highest con- blot due to its ability to identify antibodies directed to centrations are found in liver and kidney tissues. The anti- conformational epitopes [81-83]. Their novel findings SLA autoantibodies are detected in patients with AIH need confirmation from other research groups and partic- alone or in combination with SMA and/or ANA [30- ularly to address whether anti-SLA/LP reactivity is also 32,73]. As noted above, similarities in the clinical profile present in adult PSC. Recent data confirmed the previous between patients with AIH-1 (ANA and/or SMA positive) finding that patients with anti-SLA/LP display a more and AIH patients with anti-SLA alone in addition with an severe course of AIH [79,80,84]. The latter suggest that approximately 30% seropositivity overlap between anti- anti-SLA/LP may be linked to the pathogenesis of the SLA and SMA and/or ANA suggest that anti-SLA is rather autoimmune process although the exact function and its an additional important marker for the diagnosis of AIH- role in autoimmunity are so far unclear [14,15]. From the 1, than a marker of a third type of AIH [6,14,30-32]. clinical point of view however, this autoantibody may be helpful in an attempt to reduce the group of cryptogenic A scientific group from Tuebingen, Germany described for hepatitis and/or cirrhosis. the first time the anti-LP autoantibodies in 1981 [21]. The LP antigen was predominantly detected in the S100 super- 4. Detectable Autoantibodies in AIH-2 natant of liver and pancreas homogenates, indicating that 4.1. Autoantibodies against liver-kidney microsomes (anti- this antigen was a soluble protein. Until recently, anti-LP LKM) and anti-SLA autoantibodies were thought to be different Three types of anti-LKM autoantibodies have been identi- fied [3,5,14,15,18,30,63,72,85]. The LKM type 1 [20-22]. However, Wies et al report [74] provides convinc- ing evidence and confirms previous suggestions that anti- autoantibody (anti-LKM-1) is the characteristic serologic SLA and anti-LP are one and the same autoantibody (anti- marker for the diagnosis of AIH-2 [5,18,63,72]. These SLA/LP). In addition, the same study demonstrated that autoantibodies were first described by Rizzetto et al [86], the identified target-autoantigen of anti-SLA/LP using the IIF method on rodent liver and kidney sections. autoantibodies (a 35–50 kDa protein) was neither cytok- The characteristic features of anti-LKM-1 autoantibodies eratins 8 or 18 [71] nor glutathione-S-transferase isoen- are the diffuse staining of cytoplasm of the entire liver lob- zyme [75]. The results from two independent groups ule and the exclusive staining of the P3 portion of the [76,77] were similar with those found by Wies et al [74]. proximal renal tubules (Fig. 6) [18]. Due to this staining After screening of cDNA expression libraries they identi- pattern of kidney sections anti-LKM-1 can be easily distin- fied a previously unknown amino acid sequence, which guished from AMA, which stain proximal and distal renal presumably encodes a UGA-suppressor tRNA-associated tubules (Fig. 7). Western blots with hepatic and renal protein, as the targen-autoantigen of anti-SLA/LP autoan- microsomes revealed a protein band at 50 kDa tibodies [76,77]. The UGA-suppressor serine tRNA-pro- [5,14,15,63,72,87]. tein complex is likely to be involved in cotranslational selenocysteine incorporation in human cells [78]. It was The major target-autoantigen of anti-LKM-1 autoantibod- then obvious that the identification of SLA/LP autoanti- ies in AIH-2 has been identified as the cytochrome P450 gen would allow the establishment of a reliable, univer- 2D6 (CYP2D6) [87-89]. It has been shown that anti-LKM- sally available diagnostic test for AIH but also it would 1 autoantibodies inhibit the enzymatic activity of provoke the investigation in the area of autoimmune liver CYP2D6 in vitro, but not in vivo [90]. Epitope mapping diseases. experiments of CYP2D6 autoantigen have defined at least four different linear epitopes [91,92]. The most immuno- Regarding disease specificity, anti-SLA/LP autoantibodies dominant epitopes of CYP2D6 were amino acids 257– have not been detected in patients with AIH-2, PBC, PSC, 269 and 321–351, which are recognized in about 70% chronic viral hepatitis, alcoholic liver disease and non- and 50% of AIH-2 cases, respectively [91,92]. Two infre- hepatic autoimmune diseases by standardized ELISAs quent epitopes consisting of amino acids 373–389 and using reference autoantibody or recombinant antigen 410–429 are also recognized by anti-LKM-1 in some cases [20,32,73,79]. Ballot et al [32] also showed that these [92]. Recently, Klein et al [93] and Kerkar et al [94] autoantibodies are different from anti-LC1. For these rea- reported another immunodominant epitope of CYP2D6 Page 7 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 conformational epitopes on CYP2D6 autoantigen has been postulated [95]. It is noteworthy to state here that depending on the geo- graphic 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 autoantibod- ies (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 A LKM-1) react Figure 6 ntibodies against li to the pr ver-kidney microsomes typ oximal tubules of the rat kidney e 1 (anti- [98,99]. In addition, recently Miyakawa et al [100] identi- Antibodies against liver-kidney microsomes type 1 (anti- fied CYP2E1 and CYP3A4 as target autoantigens of anti- LKM-1) react to the proximal tubules of the rat kidney. The LKM autoantibodies in two patients with anti-LKM-posi- absence of reactivity against thedistal tubules of the rat kid- tive chronic hepatitis C. Taking together, these findings ney (see also Fig. 6B) and parietal cells of the rat stomach dis- tinguishes anti-LKM-1 autoantibodies from antimitochondrial may further indicate the heterogeneous autoimmune antibodies (original magnification 40×). 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 A tu Figure 7 n bules of the rat timitochondrial an kidney tibodies (origrea inact to the proximal and distal l magnification 40×) anti-LKM-1 using a specific competitive ELISA, while Antimitochondrial antibodies react to the proximal and distal denaturation of the antigens prior to perform the ELISA tubules of the rat kidney (original magnification 40 ×). In resulted in complete loss of the signal [105]. these cases there is also reactivity to the parietal cells of the rat stomach. 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 S-methionine- (amino acids 193–212) recognized in about 70% and 93 labelled CYP2D6 antigen obtained by in vitro transcrip- % of AIH-2 patients, respectively. However, due to failure tion and translation synthesis [81-83,99,104]. Using this of inhibition of CYP2D6 enzymatic activity using epitope assay it was shown that the anti-LKM-1 titers do not differ specific antibodies and since the absorption of the above significantly between AIH-2 and HCV/anti-LKM-1 posi- linear epitopes was unable to absorb inhibitory anti- tive patients [81-83]. The presence of anti-LKM-1 in some CYP2D6 autoantibodies, the existence of additional patients with HCV infection led to the proposal for a fur- Page 8 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 ther division of AIH-2 into AIH-2a (younger, predomi- only the sister suffering from AIH-2 was HSV positive, and nantly female patients without evidence of HCV her serum recognized the viral protein ICP4 in lysates of infection) and AIH-2b (older, predominantly male HSV-infected cells [111]. So far however, overall evidence patients with HCV infection) [13,106]. Nowadays how- for mimicry as a driving force of AIH is not convincing. ever, after the marked improvements in the reliability and availability of tests for HCV detection such a subdivision Besides molecular mimicry, chemical modification of self- of AIH-2 appears unreasonable and tends to be deleted. proteins and/or immunological cross-reactivity to homol- Actually, HCV/anti-LKM-1 positive patients represent ogous autoantigens may also provide potential triggers for cases of "true" HCV infection with autoimmune features autoimmune responses. The latter has been suggested by [6,107]. Choudhuri et al [112] who have shown that in AIH-2 patients the linear epitope 321–351 of CYP2D6 cross From the clinical point of view, screening for anti-LKM reacts with amino acids 33–51 of carboxypeptidase-H autoantibodies is recommended before the initiation of (the target autoantigen of islet cell autoantibodies in insu- interferon-alpha therapy in HCV patients and if found lin dependent diabetes mellitus), as well as, with amino positive a careful monitoring appears reasonable because acids 307–325 of 21-hydroxylase (major target autoanti- occasionally interferon-alpha may unmask, or provoke gen in Addison's disease). These findings possibly indicate autoimmune hepatic reactions and even "true"AIH the presence of a common motif of CYP2D6, carbox- [6,43,104,108-110]. Dalekos et al [104] studied antibody ypeptidase-H and 21-hydroxylase, which may contribute titers and performed epitope mapping of LKM-1-positive through a cross reactive immune response to the develop- sera from patients with chronic hepatitis C. Interestingly, ment of multiple endocrinopathies in the course of AIH- a patient with a high LKM-1 titer and autoantibodies 2. Additional support to this hypothesis emerged from directed against an epitope of amino acids 257–269, two recent studies by Kerkar et al [94] and Bogdanos et al which are preferentially recognized by patients with AIH- [113]. In the first study the authors were able to show the 2, showed exacerbation of the disease under interferon- similarity and cross-reactivity between the immunodomi- alpha treatment. In contrast to other patients with HCV nant epitope 193–212 of CYP2D6 and homologues of infection, this patient further recognized a rarely detected two unrelated viruses (HCV 2977–2996 and CMV 121– epitope on the C-terminal third of the protein. These 140) [94]. In the second study the researchers investigated results suggest that determination and monitoring of whether the immunodominant epitope 252–271 of CYP2D6 autoantibody titers by both IIF and the RLA in CYP2D6 in anti-LKM-1 positive AIH-2 and homologues combination with epitope mapping of CYP2D6 in HCV/ from the NS5B and E1 proteins of the HCV polyprotein anti-LKM positive patients before the initiation of and the ICP4 of HSV-1 are targets of humoral immune interferon-alpha treatment, might be helpful in an response in anti-LKM-1 positive and anti-LKM-1 negative attempt to identify those patients at risk of developing HCV infected patients and furthermore whether this undesired autoimmune reactions [104]. response is cross-reactive [113]. The hypothesis of molec- ular mimicry and cross-reactivity in LKM-1 production The mechanism(s) of the development and the patho- has not been addressed experimentally. The authors for genic role of anti-LKM-1 autoantibodies in hepatocellular the first time gave experimental support to the notion that injury are still unclear. It has been suggested that viral molecular similarity between CYP2D6, HCV and HSV can infections by herpes simplex virus (HSV) and related result in LKM-1 production via a cross-reactive response in viruses may trigger the autoantibody formation through genetically susceptible individuals (interestingly only the molecular mimicry in at least some individuals with AIH- HCV positive/LKM-1 positive patients with viral/self 2 [91]. Manns et al [91] tested 26 LKM-positive sera using cross-reactivity possessed the HLA B51 allotype) [113]. Western blot with partial sequences of recombinant Taking together, the above studies suggest that multiple CYP2D6. Eleven sera recognized a short minimal epitope exposure to viruses mimicking self may represent an of eight amino acids with the sequence DPAQPPRD. important pathway to the development of autoimmunity Twelve other clones recognized a larger epitope contain- [94,113]. ing this eight-amino acid core sequence. The search of electronic databases revealed an interesting match of the Two possible mechanisms have been proposed for the minimal epitope with the primary structure of the involvement of anti-LKM-1 autoantibodies in the patho- immediate early protein IE 175 of HSV-1 now known as genesis of liver injury. The first appears to be a direct bind- infected cell protein 4 (ICP4) of HSV-1 (Fig. 8). Sequence ing of these autoantibodies to hepatocytes, leading to lysis identity was present for the PAQPPR sequence. This of liver cells, while the second is associated with an anti- hypothesis was further supported by a case study in a pair LKM-1 induction of activating liver-infiltrating T lym- of identical twins [111]. In this study, one sister suffered phocytes, which indicates the combination of B and T cell from AIH-2 but the other one was healthy. Interestingly, activity in the autoimmune process involved [114-117]. A Page 9 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 Lin Figure 8 ear B-cell epitopes on cytochrome P450 2D6 in autoimmune hepatitis type 2 Linear B-cell epitopes on cytochrome P450 2D6 in autoimmune hepatitis type 2. The immunodominant epitope 257–269 aa shares sequence homology with the immediate early protein IE 175, a transcription factor of herpes simplex virus type 1 (now known as infected cell protein 4 or ICP4). Although this is an attractive model for the hypothesis of molecular mimicry, overall evidence for mimicry as a driving force of autoimmune hepatitis is not convincing. prerequisite for both anti-LKM-1 production and the acti- tis caused by tienilic acid [14,63]. The target autoantigen vation of pathogenetic mechanisms involved in liver of anti-LKM-2 has been documented as the CYP2C9 [85]. injury, is the expression of CYP2D6 on the surface of the A proposed mechanism for the induction of anti-LKM-2 patients' hepatocytes. Under this context, Ma et al [118] could be the binding of an active metabolite of the drug showed that key residues of a major CYP2D6 epitope to the CYP2C9 protein, which then becomes antigenic (316–327) are exposed on the surface of the molecule and [14,63,72,85]. may represent key targets for anti-CYP2D6 production. In addition, recent data provides convincing evidence that Anti-LKM type 3 autoantibodies (anti-LKM-3) alone or in anti-LKM-1 autoantibodies recognize CYP2D6 exposed combination with anti-LKM-1 are also detected in about on the plasma membrane of hepatocytes from either AIH- 5–10% of patients with AIH-2 [16,119]. In contrast to 2 or HCV/anti-LKM-1 positive patients [114,115] suggest- anti-LKM-1 and anti-LKM-2 autoantibodies, which on ing a pathogenetic role for these autoantibodies in hepatic immunofluorescence stain liver and kidney tissues only, tissue damage either in AIH-2 or in some cases of HCV/ with anti-LKM-3 additional fluorescence signals may be anti-LKM-1 positive patients [104,109,110,115]. present with tissue from the pancreas, adrenal gland, thyroid, and stomach. Family 1 of UDP-glycuronosyl- So far, anti-LKM type 2 autoantibodies (anti-LKM-2) have transferases (UGT1) is the main target autoantigen of anti- been detected only in some cases of drug-induced hepati- LKM-3 autoantibodies (molecular weight of 55 kDa) Page 10 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 [119,120]. These autoantibodies were first described in LKM-1, the titers of anti-LC1 autoantibodies appear to about 13% of patients with chronic hepatitis D, but not in parallel with disease activity [130]. The latter may indicate patients with chronic hepatitis B or C [121]. However, a possible involvement of anti-LC1 in the pathogenesis of three recent reports have shown the presence of anti-LKM- AIH-2. However, the clinical significance of anti-LC1 is 3 autoantibodies in some patients with HCV infection not yet completely defined. [99,122,123]. These findings may further support the heterogeneous phenomenon of the HCV-induced 5. Detectable Autoantibodies in AIH in APECED autoimmunity. Chronic hepatitis as a disease component of APECED may develop in 10–18% of patients [14,15,23-25,28,29,63]. 4.2. Autoantibodies against liver cytosolic protein type 1 APECED appears to be caused by mutations in a recently (anti-LC1) identified gene, the autoimmune regulator gene (AIRE), In 1988 a second autoantibody marker of AIH-2 was rec- and represents the only known autoimmune disease with ognized [19]. This autoantibody was found to react to a a monogenetic mutation today [26,27,131]. It is interest- liver cytosolic protein. The autoantibody is organ specific ing that patients with AIH in the absence of APECED do but not species specific and was therefore called anti-LC1 not display mutations of the AIRE gene and are therefore [19]. The anti-LC1 autoantibodies are characterized by a genetically distinct from patients with AIH as a compo- cytoplasmic staining of the periportal hepatocytes when nent of APECED [132]. the IIF assay is used for their detection. The hepatocellular layer around the central veins is not stained [19,124]. Similar to AIH-2, hepatitis in APECED is associated with These findings indicate that the target autoantigen of anti- autoantibodies directed against cytochrome P450 pro- LC1 autoantibodies is not uniformly distributed in rodent teins. In a large study with APECED patients, a typical liver tissues. They are detected in about 30% of patients LKM staining pattern and a predominant staining of the with AIH-2 [19,124] and in approximately 50% of all perivenous hepatocytes in the absence of staining of the anti-LKM-1 positive cases [125]. It is noteworthy that the kidney were observed [23]. The latter pattern is due to anti-LC1 autoantibodies proved to be the only serological autoantibodies called liver microsomal autoantibodies marker in 10% of patients with AIH [19]. (anti-LM). In this study each of anti-LKM and anti-LM antibodies were found in 8% of the patients [23]. These The detection of anti-LC1 autoantibodies by IIF is findings indicate that two or more different microsomal obscured due to the anti-LKM-1 pattern that frequently antigens are hepatic target-autoantigens in APECED. found in most of the anti-LC1 positive sera. For these rea- sons other techniques such as, the ouchterlony double Indeed, screening of APECED sera with recombinant anti- diffusion, immunoblot or counter-immunoelectrophore- gens using Western blots has shown reactivity against four sis are required for their detection [19,124-126]. By different hepatic cytochromes P450: CYP1A1, CYP1A2, immunoblotting, anti-LC1 positive serum samples recog- CYP2A6 and CYP2B6 [23-25,133]. CYP1A1, CYP2A6 and nize a liver specific cytosolic protein of 58–62 kDa [124- CYP2B6 are expressed both in liver and in kidney result- 126]. Recently the molecular target of anti-LC1 was iden- ing to an LKM staining pattern, while CYP1A2 is not tified as the formiminotransferase cyclodeaminase expressed in the kidney leading to the LM staining. (FTCD) [127], which is a polymeric bifunctional enzyme Among the four autoantibodies anti-CYP2A6 were involved in folate metabolism. However, another group detected with the highest prevalence in a Finnish APECED demonstrated the arginninosuccinate lyase (ASL) as the patients group (15.6%), while anti-CYP1A2 were found in target autoantigen of a weak precipitin line detected by the 6.3% [23]. These results were confirmed by quantitative ouchterlony double diffusion assay in patients with immunoprecipitation assays with recombinant S- autoimmune or viral hepatitis [128]. labeled CYP1A2 and CYP2A6. Anti-LC1 autoantibodies have been proposed as a more Contrary to a previous work in Sardinian patients with specific marker of AIH-2 than anti-LKM-1 autoantibodies, APECED [25], the detection of anti-CYP2A6 autoantibod- since in the original reports their presence was never asso- ies in a larger group of Finnish patients was not associated ciated with HCV infection [19,124]. However, a recent with the presence or absence of hepatitis, while anti- study by Lenzi et al [125] confirmed the above aspect only CYP1A2 autoantibodies were detected only in APECED in the pediatric subset of their patients, while a substantial patients with hepatitis [23]. These findings indicate that proportion of the adults with anti-LC1 autoantibodies anti-CYP1A2 is a specific marker for AIH as a component had also markers of HCV infection. The significance of the of APECED, albeit with a low sensitivity [23,24]. Anti- association between anti-LC1 autoantibodies and HCV CYP2A6 autoantibodies may be used as an indicator for infection remains uncertain and has to be established APECED, if they are present in a patient with AIH. In par- [106,129]. In contrast to what has been found for anti- allel with the above conclusions is the anti-LKM/LM Page 11 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 Table 4: 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 ANA, anti-LC (molecular target: unknown), anti-LKM (molecular suppressor tRNA-associated protein), anti-LKM-1 (molecular target: targets: CYP2A6, CYP1A1 and CYP2B6), anti-LM (specific autoantibody; CYP2D6), anti-LKM-3 (molecular target: UGT1), anti-LC1 (molecular molecular target: CYP1A2) target: FTCD) Abbreviations are the same as shown in the text. Table 5: 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. Anti-CYP2D6 Anti-CYP2A6 Anti-CYP1A2 Chronic liver disease + - - AIH-2 (94–100%), HCV (0–10%) - + - HCV, APECED with or without hepatitis - - + AIH in APECED, drug induced hepatitis ++ - HCV (0–7%) - + + AIH in APECED Abbreviations are the same as shown in the text. detection by IIF in about 50% of patients with AIH as part Anti-LM autoantibodies are first described in dihydrala- of the APECED and in only 11% of APECED patients zine-induced hepatitis [135]. The major target autoanti- without hepatitis [23]. The same study showed that the gen of anti-LM in both conditions (hepatitis as part of the prevalence of ANA detection in APECED patients was APECED and drug-induced hepatitis) has been docu- high (22%) but irrespective of the presence or absence of mented as the CYP1A2 [23-25,133,135]. In cases of dihy- hepatitis. Therefore ANA are not useful laboratory mark- dralazine-induced hepatitis the production of anti-LM ers for AIH in APECED [23]. To the contrary, none of the autoantibodies has been attributed to adduct formation patients' sera tested positive for anti-SLA, anti-CYP2D6 or of CYP1A2 with an activated metabolite of the drug [136]. anti-FTCD autoantibodies, which are specific markers of By contrast, in APECED patients no relationship between AIH-1 and AIH-2 [23]. On the other hand, CYP1A2 and CYP1A2 and drug usage is known. In addition, it is not CYP2A6 could not be identified as hepatic autoantigens in known whether in APECED patients a close monitoring of the disease control groups consisting of patients with idi- anti-LM may lead to early, or even prophylactic, treatment opathic AIH or patients with autoimmune rheumatic dis- of hepatitis as a new disease component. Evidence that eases [23]. These findings indicate that idiopathic AIH autoantibodies may be found before the clinical and/or and AIH in APECED are characterized by different molec- laboratory manifestation of a new disease component in ular targets of autoimmunity, which do not overlap. APECED comes from adrenal and ovarian insufficiencies, Therefore, AIH and hepatitis as part of the APECED may where the respective autoantibodies are detected 2–3 be distinguished on the basis of differences in autoanti- years before the clinical presentation of the autoimmune body profile (Tables 4 and 5). components [137]. Dalekos et al [134] using the sensitive quantitative RLA Another hepatic autoantigen in APECED, the aromatic-L- reported for the first time the presence of anti-CYP2A6 amino acid decarboxylase (AADC) has also been identi- autoantibodies in about 2% of HCV-positive sera in gen- fied recently [133,138]. This enzyme is expressed in the eral and in 7.5% of LKM-1-positive/HCV-positive sera. liver cytosol and was originally described as a β-cell The latter further supports the low specificity of this autoantigen [133]. The prevalence of anti-AADC autoan- autoantibody as a marker for AIH in APECED. tibodies is significantly increased in APECED patients Interestingly, anti-CYP2A6 autoantibodies were not with vitiligo (88%) and hepatitis (92%) [5,14,29]. So far, detected in patients with AIH-2 who exhibit high titers of anti-AADC autoantibodies have only been reported in anti-LKM-1 autoantibodies [134]. The clinical relevance APECED and their role in AIH and vitiligo as disease com- of this finding in HCV infection remains to be ponents of APECED deserve further investigation. determined. Page 12 of 17 (page number not for citation purposes) Journal of Autoimmune Diseases 2004, 1:2 http://www.jautoimdis.com/content/1/1/2 Table 6: Differential Diagnosis of Autoimmune Hepatitis. have been identified, but the latter has not led to the characterization of specific subpopulations of patients or Other autoimmune liver diseases changes in the treatment strategies. In addition, most of - Overlap syndromes the non-organ specific autoantibodies do not seem to be - Primary biliary cirrhosis involved in the pathogenesis of liver injury in AIH. Anti- - Primary sclerosing cholangitis Chronic viral hepatitis LKM-1 autoantibodies could be an exception to the above - Chronic hepatitis B with or without hepatitis delta aspect since recent data have demonstrated the expression - Chronic hepatitis C of CYP2D6 on the surface of hepatocytes, while AIH-2 has - Chronic hepatitis non A to G not been observed in individuals who are deficient for Cholangiopathy due to human immunodeficiency virus infection CYP2D6. These findings provide arguments for an anti- Alcoholic liver disease gen-driven autoimmune process. It is possible that muta- Drug-induced hepatitis tions in the autoantigen itself can lead to alterations in the Non-alcoholic steatohepatitis Granulomatous hepatitis three dimensional structure of the antigen, which induces Hemochromatosis autoimmunity. α -antithrypsin deficiency Wilson's disease Antibodies directed against liver-related antigens have Systemic lupus erythematosus 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, autoan- tibodies should not be used as a tool for monitoring of 6. Concluding Remarks In clinical practice the recognition of AIH is of great treatment or to predict AIH activity and outcome. Anti- importance since most of the patients respond favorably SLA/LP autoantibodies have been considered as valuable to antiinflammatory and immunosuppressive treatment. and specific markers for the diagnosis of AIH-1. However, In addition, recent novel findings dealing with the bone a recent study has shown that anti-SLA/LP autoantibodies marrow hemopoietic progenitor cells and bone marrow can also be detected in AIH-2 and in children with PSC. stromal cells of patients with AIH suggests alternative Irrespective of the disease specificity of this marker, it is therapeutic options even in refractory cases [139]. obvious that testing for anti-SLA/LP will help to reduce Diagnostic criteria for this disease have been codified the group of cryptogenic liver disease, by recognizing pre- recently [6]. These include descriptive criteria and scoring viously misdiagnosed patients with AIH who were seron- system based on clinical, serologic and histologic features egative for ANA, SMA or anti-LKM-1. of AIH (Table 1), which contribute substantially to the differential diagnosis of the disease from other forms of In APECED, autoantibodies are directed against specific chronic hepatitis associated with autoimmune phenom- cytochrome P450 enzymes (e.g. CYP1A2, CYP2A6, ena (Table 6). The discrimination between AIH and HCV CYP21, CYP17, and CYP11A1), that are expressed in infection is of particular importance, since the immuno- organs affected by the disease process. These observations suppression used in the former can deteriorate liver dis- argue against the idea that antibodies against cytochrome ease in HCV patients, while interferon-alpha treatment P450 complex are simply epiphenomena secondary to tis- used in HCV infection may lead to exacerbation of AIH sue damage and that they have no relation to the etiology [104,108-110]. and pathogenesis of APECED. The detection of non-organ specific autoantibodies It is not known what triggers autoimmunity in AIH. The remains the hallmark of AIH. A step by step diagnostic hypothesis that different causes may lead to loss of toler- application of autoantibody tests is mandatory for the ance against the same molecular target autoantigen seems evaluation of acute or chronic hepatitis of unknown attractive. For instance, CYP1A2 is the molecular target in cause. ANA, SMA and anti-LKM-1 autoantibodies should dihydralazine-induced hepatitis and AIH as a component be first tested in patients with acute or chronic elevation of APECED, CYP2D6 in AIH-2 and in some patients with of aminotransferases when virologic tests are negative and HCV infection, CYP2A6 in APECED and in a proportion there is no current or past history for drug or alcohol of patients with HCV infection and UGT1 in some cases of abuse. Determination of ANCA, which occur in up to 90% AIH-2 and chronic hepatitis D or C. of patients with AIH-1, may be useful in the identification of individuals who are seronegative for the above conven- Research protocols in order to define AIH pathogenesis, tional autoantibody markers but should be kept in mind disease susceptibility, determinants of disease severity, that this autoantibody lacks specificity. 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Muratori L, Cataleta M, Muratori P, Lenzi M, Bianchi FB: Liver/kid- disseminating the results of biomedical researc h in our lifetime." ney microsomal antibody type 1 and liver cytosol antibody Sir Paul Nurse, Cancer Research UK type 1 concentrations in type 2 autoimmune hepatitis. Gut 1998, 42:721-726. Your research papers will be: 131. Rinderle C, Christensen HM, Schweiger S, Lehrach H, Yaspo ML: available free of charge to the entire biomedical community AIRE encodes a nuclear protein co-localizing with cytoskele- tal filaments: altered sub-cellular distribution of mutants peer reviewed and published immediately upon acceptance lacking the PHD zinc fingers. Hum Mol Genet 1999, 8:277-290. cited in PubMed and archived on PubMed Central 132. Vogel A, Liermann H, Harms A, Strassburg CP, Manns MP, Ober- mayer-Straub P: Autoimmune regulator AIRE: evidence for yours — you keep the copyright genetic differences between autoimmune hepatitis and hep- BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 17 of 17 (page number not for citation purposes)

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Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease

Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease

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Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease

Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease

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