Pathogenesis of autoimmune hepatitis

Biomed & Pharmacother 0 Elsevier, Paris

1999 ; 53 : 255-63

Dossier: Autoimmune diseases of the liver

Pathogenesis of autoimmune hepatitis I.G. McFarlane Institute

of Liver

Studies,

King’s

College

Hospital,

Denmark

Hill,

London

SE5 9RS, United

Kingdom

Summary -Autoimmune

hepatitis (AIH) is an idiopathic disorder affecting the hepatic parenchyma. There are no morphological features that are pathognomonic of the condition but the characteristic histological picture is that of an interface hepatitis without other changes that are more typical of other liver diseases. It is associated with hypergammaglobulinaemia, high titres of a wide range of circulating auto-antibodies, often a family history of other disorders that are thought to have an autoimmune basis, and a striking response to immunosuppressive therapy. The pathogenetic mechanisms are not yet fully understood but there is now considerable circumstantial evidence suggesting that: (a) there is an underlying genetic predisposition to the disease; (b) this may relate to several defects in immunological control of autoreactivity, with consequent loss of self-tolerance to liver auto-antigens; (c) it is likely that an initiating factor, such as a hepatotropic viral infection or an idiosyncratic reaction to a drug or other hepatotoxin, is required to induce the disease in susceptible individuals; and, (d) the final effector mechanism of tissue damage probably involves auto-antibodies reacting with liver-specific antigens expressed on hepatocyte surfaces, rather than direct T-cell cytotoxicity against hepatocytes. 0 1999 Elsevier, Paris

asialoglycoprotein

receptor / auto-antibodies / autoimmunity

/ hepatitis

Autoimmune hepatitis (AIH) is an idiopathic disease affecting the hepatic parenchyma.It is characterizedby fluctuating jaundice, hypergammaglobulinaemia(due mainly to elevatedserumIgG concentrations),circulating auto-antibodies,and endocrine abnormalities[3 11. There is a marked female preponderance (80% of affected individuals are women) and often a history of other disordersthat arethought to have an autoimmune basis, particularly thyroid disease(Hashimoto’s thyroiditis or Graves’ disease),and rheumatoid arthritis in the patientsor first-degreerelatives. There are no morphological featuresthat are pathognomonicof AIH but the characteristichistological picture is that of an interface hepatitis with a dense, predominantly lymphoplasmacytic, inflammatory infiltrate spilling out from the portal tracts into the surroundingparenchymawith piecemeal necrosis of periportal hepatocytes in the absenceof other features (such as bile duct damage) suggestiveof other liver disorders[3 I]. A striking feature of the condition is its responseto immunosuppressivetherapy. The large majority of patientsshowa rapid responseto corticosteroidswith or without azathioprine and can be maintained in remissionon relatively low dosesof thesedrugs. The disease has been recognized for more than 50 years. Initially, it was thought to have a viral etiology and it was suggestedthat the hypergammaglobu-

linaemia might be related to the production of antibodiesagainstvirus-altered liver proteins, which could then induce further injury [ 15,l lo]. Later, Mackay and colleagues [50] suggestedthat there is probably an underlying genetic predisposition for the condition and that, following an initial episodeof liver injury by any one of a variety of agents(for example, viruses, drugs, alcohol, and other hepatotoxins), liver antigens releasedfrom damagedhepatocytes could provoke a continuing, self-perpetuating and damaging immune responseleading to further hepatocellular necrosis. Building on this theme, Eddleston and Williams [ 161 postulatedthat a bystandereffect of T-lymphocyte activation following infection by a hepatotropic virus might be the stimulation of naturally occurring autoreactive B-lymphocytes to produce auto-antibodies againstnormal liver cell antigens, and that theseautoantibodies could participate in cytotoxic reactions leading to further liver damage.They envisagedthat, in normal individuals, there is a control (suppressor) mechanismthat switchesoff auto-antibody production once the virus has been eliminated. It transpiresthat this is remarkably true, with the transient appearance of both organ-specific and non-organ-specific autoantibodiesin acute hepatitisA, B and (lessfrequently) C virus infections being now well recognized [39, 54, 58, 761. They further postulated that in individuals

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lacking this control mechanism the liver damage might continue. It is now generally accepted that there is probably an underlying predisposition to AIH which may relate to one or more defects in the immunological processes that normally control autoreactivity. This impression is reinforced by the observation that the disease often recurs after liver transplantation, which has become a viable treatment option for end-stage or intractable AIH [79, 801. Although the disease is seen in children and young adults, overall the large majority of cases present above the age of 50 years [74, 931. It is therefore likely that some triggering factor is required to initiate the condition in susceptible individuals and that, as a consequence of defect(s) in control of autoreactivity, there is persistence of immune reactions against auto-antigens. To explain the organ-specificity of the disease, presumably such auto-antigens must be liver-specific and available to immune effector mechanisms in vivo, i.e., normally expressed on the surfaces of hepatocytes. Additionally, in order to account for the predominantly periportal localization of the liver damage in this condition, it must be presumed that either the target autoantigens are preferentially located on periportal hepatocytes or there are local factors that render periportal liver cells more susceptible to immune-mediated injury. EVIDENCE

OF AUTOIMMUNITY

IN AIH

The earliest evidence indicating that AIH probably has an autoimmune basis came from observations that the disease is associated with a wide range of circulating auto-antibodies. About 80% of patients present with significant titres of antinuclear (ANA) or smooth muscle (SMA) auto-antibodies that react, respectively, with a variety of nuclear or cytoskeletal antigens. A further 34% have so-called type 1 liver-kidney microsoma1 (LKM-1) antibodies, which react with epitopes on the cytochrome isoform P450 IID6. Additionally, up to 90% of AIH patients have perinuclear staining antineutrophil cytoplasmic (pANCA) antibodies [88]. However, with the exception of LKM-1 (which is relatively specific to AIH), all of these auto-antibodies occur in many other conditions (both hepatic and nonhepatic). Furthermore, the antigens with which they react are intracellular components which are unlikely targets of potentially tissue-damaging autoreactions in AIH - although there is evidence that cytochrome P450 epitopes may be expressed on hepatocyte plasma membranes [42]. In recent years several other auto-antibodies have been identified which appear to be more specific to liver

disease and to AIH in particular. Of greatest current interest are antibodies reacting with: (a) a liver cytosolit antigen (LCl); (b) a soluble liver antigen (SLA); and, (c) the hepatic asialoglycoprotein receptor (ASGP-R). LCl is a 60 kDa liver-specific component which appears to be predominantly located in periportal hepatocytes [ 1,641, but its identity is still unknown. SLA is an antigen which is not liver-specific but is found at highest concentration in liver and has recently been identified as glutathione-S-transferases [ 1071, although this has been disputed [ 1091. The ASGP-R is a receptor which is involved in binding and endocytosis of galactose-terminating asialoglycoproteins and is unique to hepatocytes [53,86,90]. Anti-ASGP-R auto-antibodies occur in up to 90% of AIH patients with active disease and, as with anti-SLA and anti-LCl [64], titres correlate with histologically-assessed severity of interface hepatitis [55,89]. Additionally, the ASGP-R appears to be an important target of cellular autoreactions in AIH (see below). Data on the zonal distribution of ASGP-R across the liver lobule in relation to cell surface expression of the receptor are conflicting. Studies involving measurement of asialoglycoprotein uptake in animal models involving recirculation of the ligand and under certain conditions have suggested that its distribution is predominantly perivenular [25, 27, 94, 1031, but this may be artefactual because it is well recognized that surface expression of the receptor is up-regulated by its ligand and by other stimuli [86]. Under more physiological conditions [ 111, and especially when measures are taken to avoid artificial up-regulation [56], it appears that in vivo the receptor may be preferentially expressed at high density on periportal hepatocytes. SUSCEPTIBILITY

TO AIH

It has long been recognized that there is an underlying genetic component in AIH. In addition to a family history of other autoimmune disorders (see above), the condition is strongly associated with inheritance of the HLA Al-B8-DR3 haplotype and particularly with the DR3 and DR4 allotypes [14, 49, 731. These markers (which are common in other autoimmune disorders) appear to be inherited in linkage with a generalized non-antigen-specific defect in controlling immune reactivity, resulting in an overall heightened immune responsiveness which may account for the hypergammaglobulinaemia and the high titres of both autoantibodies and antibodies against microbial antigens that are characteristic of AIH [2 1,34,66,92]. This nonantigen-specific defect can be corrected by pharmacological doses of corticosteroids, both in vitro and in vivo

Pathogenesis

of autoimmune

[68-701, but whether it is a defect in ‘T-cell suppression’ (Ts) is uncertain. The question of the existence of discrete subsets of suppressor T-lymphocytes is controversial. It is recognized that control (suppression) of the immune response may be achieved through regulation by either helper/inducer (CD4) or suppressor/cytotoxic (CD8) T-cells and the term ‘Ts defect’ is used here only for convenience. There is now considerable evidence that AIH patients have circulating and liver-infiltrating (predominantly CD4+) T-cells that recognize the ASGP-R and can induce autologous B-lymphocytes to produce antiASGP-R auto-antibodies in vitro [44,45,96,97, 1061. There is also evidence to indicate that, in addition to the non-antigen-specific Ts defect, patients have a defect in controlling autoreactivity specifically to the ASGP-R. This additional, antigen-specific, Ts defect is peculiar to AIH and seems to reside in a subpopulation of CD4+ (helper/inducer) T-cells [96, 971. It is inherited in an autosomal, non-HLA-linked mode and is not correctable by immunosuppressive therapy [71]. However, it appears that predisposition to AIH does not have a simple genetic basis. Familial AIH is rare, and patients’ first- and second-degree relatives may have one or both Ts defects without developing the disease [71]. The involvement of other genetic factors has been suggested by the finding of an association of AIH with the immunoglobulin allotype Gm a+ x+ [ 1081, although this has not been confirmed [36, 1051. It has also been reported that, in common with a number of other autoimmune diseases, many AIH patients have an isolated partial deficiency of the C4 complement component which is inherited (often in linkage with HLA AlB8-DR3) in association with the silent gene C4AQ*O at the C4A locus [ 13,82,102,104]. Additionally, a highly significant association between AIH and polymorphisms in the genes of two pro-inflammatory cytokines (TNF-a and IL-RA) has very recently been described, suggesting that genetically controlled regulation of cytokine production may be involved in this disease [9]. INDUCTION

OF AIH

Given that overall the large majority of individuals who develop AIH are peri- or post-menopausal women [74, 931, it is possible that changes in hormonal regulation of the immune system may be involved in precipitating the disease in susceptible individuals. However, there is not yet any evidence to support this. On the other hand there are now several well documented instances ofAIH developing after viral clearance in subjects infected with hepatotropic viruses [29, 58, 98, 991, and devel-

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257

opment of autoimmune phenomena (including antiASGP-R auto-antibodies) associated with persistence of liver damage has been observed in woodchucks infected with woodchuck hepatitis virus [12] and in mice following murine cytomegalovirus infection [4]. In particular, during a careful long-term follow-up of first- and second-degree relatives ofAIH patients, Vent0 et al. [98,99] documented the apparently de novo development ofAIH in two subjects following asymptomatic acute hepatitis A virus (HAV), and a further two with Epstein-Barr virus (EBV), infections. All four were shown to have the antigen-specific Ts defect relating to control of autoreactivity to ASGP-R, whereas six other relatives without this defect who acquired HAV or EBV infections during the same period developed no chronic sequelae. Another potential mechanism for induction of AIH involves the concept of molecular mimicry, i.e., similarity between antigenic determinants of infectious organisms and the host [2, 5, 201. There are several examples of molecular mimicry between hepatotropic viruses and human auto-antigens [58]. Two segments of the hepatitis C virus (HCV) polyprotein have been shown to share partial amino acid sequence homology with the 33 amino acid peptide that contains the immunodominant epitopes of cytochrome P450 IID which is the target of LKM-1 auto-antibodies [52]. There is evidence that lymphocytes prepared from liver tissue from patients with anti-LKM-1 positive AIH and from patients with chronic hepatitis C recognize these epitopes [43], but other studies have failed to identify any specific HCV genotype or specific amino acid sequence in HCV associated with induction of an anti-LKM-1 response [61]. Furthermore, as noted above, antiLKM-1 positive cases comprise a very small proportion of patients with AIH and most AIH patients have no evidence of HCV infection [6, 10, 40, 541. Molecular mimicry involving hepatitis B viral (HBV) antigens may, however, account for the development of ANA and SMA in patients with HBV infections. There are sequences within the HBV-specific DNA polymerase that share identity with, respectively, an octapeptide and a hexapeptide in the nuclear mitotic apparatus and the smooth muscle regulatory protein caldesmon, the distributions of which within cells are similar to the immunofluorescent patterns seen with ANA and SMA in AIH [ 1001. It is possible that the disease may also be induced by xenobiotics. There is a wide range of drugs and other chemical agents capable of idiosyncratically inducing an AIH-like syndrome [38]. A typical example is the antibiotic minocycline, which is occasionally associ-

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ated with liver damage accompanied by many features of AIH, including hypergammaglobulinaemia, autoantibodies, and severe interface hepatitis [23, 24, 511. In most cases the liver damage resolves and the associated features disappear following withdrawal of the drug, but presumably they could persist in individuals who are predisposed to AIH. The precise mechanisms are not clearly understood but it is known that many xenobiotics or their active metabolites can bind to cellular macromolecules which are thereby altered and represent neo-antigens that appear foreign to the immune system. Immune responses against such altered self components may trigger autoreactions to their unmodified (native) counterparts. MECHANISMS

OF LIVER

DAMAGE

IN AIH

The development of a potentially tissue-damaging autoreaction initially requires an autopeptide to be presented in a class II MHC molecule to an uncommitted helper T-cell (TuO) by a professional antigen presenting cell (APC). Co-stimulation through ligand-ligand interactions between T,O cells and APCs leads to activation of the T,O cells and their differentiation into the functional phenotypes Tul and T,2 (figure I). Which phenotype results from this process depends on the cytokines in the microenvironment, the nature of the autopeptide, and the affinity of the binding between the T-cell receptor (TcR) and the MHC/peptide complex [81]. High affinity binding and interleukin-12 (IL-12) in the microenvironment favors differentiation into T, 1, while T,2-cells are favored by low affinity binding and IL-4. T,l cells produce IL-2 and interferon gamma (IFN-y) which promote cell-mediated cytotoxicity through activation of macrophages and cytotoxic T-lymphocytes (CTLs), which can recognize autopeptides presented by class I molecules. T,2-cells release IL-4, IL-5, and IL-10 which promote cooperation with B-cells to produce antibodies. The cytokines released by each cell type are counteractive: IFN-)I produced by T,l-cells suppresses development of T,2-cells while IL-4 and IL-10 produced by T,2-cells suppress Tnl-cells [17]. Hepatocytes do not normally express MHC class II molecules and express class I only weakly, and are therefore unlikely to act as conventional APCs. Triggering of an inflammatory response within the liver can, however, lead to up-regulation of expression of both class I and class II molecules by IL-2 and IFN-ysecreted by Tul-cells [18, 19, 411. Even under these circumstances hepatocytes are likely to function only weakly as APCs because they lack the co-stimulatory

molecules required for strong interactions with T,Ocells, but weak interactions would tend to favor differentiation of T,O into T,2-cells and the production of auto-antibodies. It is also theoretically possible that hepatocytes expressing class II molecules might be able to present auto-antigenic peptides via professional APCs which could then initiate the cascade of autoimmune responses (figure 1). Up-regulation of class I molecules could allow for presentation of autopeptides to CTLs which could damage the hepatocytes. Additionally, very recent evidence indicates that, in AIH patients, there is a significant reduction in the proportion of natural T (NT)-cells expressing killer inhibitory receptors (KIR) [67]. NT-cells are cytotoxic lymphocytes with T-cell and natural killer (NK) phenotype and function which can be activated without the need for prior antigenic challenge and can recognize unconventional antigens presented by non-classical APCs [7]. KIR expression by NT-lymphocytes is thought to play an important role in preventing CTLs from reacting with self-antigens, thereby avoiding damaging autoimmune responses. Understanding of the mechanisms involved in the initiation and perpetuation of liver damage in AIH is hampered by the lack of a naturally occurring animal model of the disease. Several models have been developed based on immunization of animals with liver proteins [48,65,87]. In most such models, the development and persistence of liver damage requires repeated immunizations or other manipulations to overcome selftolerance. This, along with other observations in animal models and patients with AIH, provides support for the concept that defective control (suppression) of liver autoreactivity is a crucial factor in AIH [46, 471. Studies in some of these models suggest that liver damage may be mediated by direct T-cell cytotoxicity against hepatocytes [35, 62, 721. But it is uncertain whether findings from studies in such artificial systems can be extrapolated to the human situation. Indeed, numerous studies in AIH patients have failed to implicate T-cell cytotoxicity as the major mechanism of liver damage but all demonstrated in vitro antibodydependent cellular cytotoxic (ADCC) reactions against hepatocytes - involving auto-antibodies to liver cell membrane antigens cooperating with a non-T (K)lymphocyte subpopulation [57,95]. Additionally, it has been shown that hepatocytes isolated from liver biopsies of patients with AIH are coated with antibodies in vivo and that this is associated with ADCC reactions and with extent of liver damage [ 1011. Antibodies binding to hepatocyte surfaces can induce tissue injury by complement-mediated cytolysis [30,

Pathogenesis

of autoimmune

hepatitis

259

Figure 1. Putative pathogenetic mechanisms in autoimmune hepatitis (AIH). Various exogenous agents (e.g., viruses, toxins) can cause up-regulation of expression of HLA class I and class II in hepatocytes. This theoretically provides the potential for presentation of auto-antigenic peptides by class II molecules, either to professional antigen presenting cells (APC) or directly to resting helper T-lymphocytes (THO). The latter become activated, thereby initiating a cascade of immune responses. This can lead to activation of cytotoxic T-lymphocytes (TC) which may damage cells through recognition of the autopeptide presented by class I molecules, as well as to transformation of B-lymphocytes (B) to plasma cells (P) that can produce auto-antibodies which may also damage hepatocytes - either by complement (C) mediated cytolysis or through antibody-dependent cytotoxic (ADCC) reactions involving K-cells (K). Existing evidence suggests that, in normal individuals, this process can be switched off by some mechanism (T,) involving suppression at the helper T-cell level and that this control system is defective in patients with AIH. Direct T-cell cytotoxicity against hepatocytes has not been demonstrated in AIH patients and the available evidence suggests that ADCC reactions are the major pathway to hepatocellular damage. This is supported by the striking efficacy of prednisolone and azathioprine in AIH. Prednisolone has complex actions, predominantly at the T-cell level, but the net effect of this drug is to suppress production of immunoglobulins (including auto-antibodies) by B-cells, while azathioprine acts mainly by reducing the numbers of K (and NK)-cells. The combined actions of these two drugs thereby effectively controls the two main components of the ADCC mechanism.

601 but the available data suggest that there is no association between complement activation and liver damage in AIH [63, 1021. Also, by interfering with vital cell processes they might induce apoptosis, as has been demonstrated by Poralla et al. [78]. However, support for ADCC as perhaps the dominant mechanism comes from the observation that, as noted above, the large majority of AIH patients show a striking response to treatment with prednisolone, and that if azathioprine is added the dose of corticosteroids required to maintain remission can be substantially reduced or, in many patients, can be withdrawn altogether and remission sustained with azathioprine alone [32]. Current knowledge of the mechanism of action of glucocorticoids on the immune system suggests that, although they may

inhibit the function of NK-lymphocytes [22], they act predominantly at the T-cell level - inhibiting T,O activation by decreasing cytokine production and thereby inhibiting both CTL and antibody production [3,8,28, 37, 59, 841. Azathioprine, on the other hand, appears to act predominantly by selectively decreasing K and NK-lymphocytes [75, 77, 831. In combination, therefore, these two drugs effectively control the two main components of the ADCC reaction. Although corticosteroids can apparently correct the non-antigenspecific heightened immune responsiveness [68-701, neither of these two drugs appears to affect the postulated antigen-specific Ts defect in AIH, which may explain why many patients relapse when all treatment is withdrawn.

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CONCLUSIONS It seems very likely that there is an underlying predisposition to AIH and that this probably involves multiple genetic factors, including both specific and non-specific defect(s) in control of autoreactivity. It appears that the disease may be initiated in susceptible individuals by exogenous agents and that the liver damage is immune-mediated, but most of the available evidence is circumstantial and the mechanisms are still not clearly understood. To date there has been no evidence from studies in AIH patients pointing to direct T-cell cytotoxicity as the prime mechanism of hepatocellular injury in this disease. On the contrary, the available data suggest that this may be mediated by antibodies reacting with auto-antigens on the surfaces of liver cells, probably involving ADCC reactions. Among the putative auto-antigens that have been described, the ASGPR seems to be particularly important in AIH. It is not yet known whether it is the prime auto-antigen in this disease, but it is the only one that has so far been identified which fulfils all of the requirements for a target of potentially tissue damaging autoreactions in AIH. It is also interesting to note that the auto-antigens that have been implicated in other organ-specific autoimmune disorders such as thyroid disease, myasthenia gravis, and insulin-dependent diabetes, are receptors (for thyroid stimulating hormone, acetylcholine, and insulin respectively) that, like the ASGP-R, perform functions unique to the target tissues. If the ASGP-R is indeed preferentially expressed on the surfaces of periportal hepatocytes (see above), immune reactions against this receptor might account for the histological features of interface hepatitis which are characteristic of AIH. However, factors such as differences in oxygen tension across the liver lobules and zonal metabolic effects [26, 331 which may render periportal hepatocytes more susceptible to immune mediated damage, or cytokine gene polymorphisms [9] that may affect localized cytokine production in periportal areas [85, 911, are also likely to be important. REFERENCES 1 Abuaf N, Johanet C, Chretien P, Martini E, Soulier E, Laperche S, et al. Characterization of the liver cytosol antigen type 1 reacting with auto-antibodies in chronic active hepatitis. Hematology 1992 ; 16 : 892-8. 2 Albani S, Carson DA. A multistep molecular mimicry hypothesis for the pathogenesis of rheumatoid arthritis. Immunol Today 1996 ; 17 : 466-70. 3 Arya SK, Wong-Staal F, Gallo RC. Dexamethasone-mediated inhibition of human T-cell growth factor and gamma interferon messenger RNA. J Immunol1984 ; 133 : 273-6.

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