Autoimmune hepatitis (AIH) is a chronic, progressive, necroinflammatory disease caused by loss of tolerance to hepatic autoantigens or their molecular mimics. In AIH, adaptive immune responses against hepatic autoantigens appear to require immunogenetic susceptibility, an autoreactive immune repertoire, environmental triggering, and dysfunctional immunoregulation (Fig. 1). In the absence of validated biomarkers, the diagnosis of AIH requires exclusion of other viral, genetic, or drug-induced etiologies and the presence of characteristic histological features of interface hepatitis, clinical and laboratory findings, autoantibodies, and elevated levels of immunoglobulin G (IgG). AIH is currently subclassified on the basis of autoantibodies into type 1 (antinuclear antibodies [ANA] and/or anti-smooth muscle antibodies [ASMA]) autoantibodies) and type 2 (anti-LKM-1). Appreciation of the key concepts of immunopathogenesis can aid clinicians in the choice of immunosuppressive medications and provide the background required to understand future therapies.
Immunologic Microenvironment of the Liver
The liver is an immunologic organ, and its microenvironment directly influences AIH and other liver diseases. It contains large numbers of activated Kupffer cells (KCs) and immature antigen-presenting cells (APCs) and greater concentrations of natural killer, natural killer T, and γδT cells than found in blood. It produces complement and acute phase reactant proteins, as well as circulating growth factors and cytokines. The liver normally must constrain immune reactions to food antigens, intestinal pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and xenobiotics while remaining capable of robust innate and adaptive responses against pathogens or tumors. PAMPs in portal venous blood induce production of interleukin (IL)−10, creating an immunosuppressive environment. However, excessive PAMPs or DAMPs induce secretion of proinflammatory cytokines (IL-1β, IL-6, IL-12, IL-18, and tumor necrosis factor [TNF]-α) by KCs.
Whereas KCs, liver sinusoidal endothelial cells, hepatocytes, and stellate cells can act as APCs for intrahepatic T cells, most T cell responses are activated in lymph nodes by APCs migrating from the liver after antigen exposure. Effector T cells generated in lymph nodes migrate transendothelially into portal tracts in response to chemokines, producing portal and periportal inflammatory infiltrates that mediate AIH.
Interplay of Innate and Adaptive Immunity in Pathogenesis
The immunopathogenesis AIH (Fig. 2) involves initiation by environmental triggers in persons with immunogenetic predisposition, loss of immunological tolerance to liver autoantigens due to a permissive immune repertoire with defective natural T regulatory cells (Tregs), production of an unregulated immune attack by T cells against hepatic autoantigens, and B cell production of nonorgan, non-species-specific autoantibodies and elevated levels of IgG.[2, 3]
Adaptive immunity involves activation of antigen-specific T cells and B cells (Fig. 3). APCs process antigens into peptides that fit the antigen-binding grooves of specific HLA class I and class II molecules and present these HLA-antigen complexes to T cell receptors (TCRs). TCRs of CD4 T cells respond to class II HLA-antigen complexes, whereas TCRs of CD8 T cells respond to class I HLA-antigen complexes. APCs also express costimulatory molecules needed for functional differentiation of CD4 T cell subsets and CD8 cytotoxicity. B cells produce antigen-specific antibodies (including autoantibodies) when stimulated by CD4 T helper 2 (Th2) and Th1 and act as APCs.
Tregs maintain self-tolerance and control the extent and duration of immune responses. Natural CD4 Tregs that recognize all autoantigens are generated in the thymus. Within lymphoid organs, natural Tregs prevent autoimmunity by inhibiting APCs that express HLA-autoantigen complexes. Regulation of adaptive immune responses is mediated by antigen-specific CD4-inducible T regulatory cells (iTregs), IL-10-secreting T regulatory 1 cells (Tr1), and CD4 transforming growth factor β-secreting Th3 cells (Fig. 3).
Autoantigens remain undefined in type 1 AIH, but oligoclonality of TCRs suggest they are limited in number. In type 2 AIH, both T and B cell autoantigens are present in cytochrome P450 2D6 (CYP2D6). ANA and ASMA have no apparent pathogenic role in type 1 AIH; however, identification of novel type 1 hepatic autoantigens may lead to detection of autoantibodies reacting with their epitopes. In type 2 AIH, anti-LKM1 reacts with B cell-specific epitopes in CYP2D6, but their role in pathogenesis in unclear.
Both immune and nonimmune genetic factors are involved in AIH pathogenesis.[2, 3] HLA class II DR alleles confer susceptibility or resistance to AIH (Table 1), indicating the importance of their role in presenting AIH-specific peptide antigens to CD4 T cells (Fig. 3). HLA class III genes also encode complement factors 2 and 4, TNFα/β and heat shock proteins. Single nucleotide polymorphisms in TNFα position −308 lead to unregulated expression of TNFα. Single nucleotide polymorphisms in non-HLA genes, including CTLA-4, Fas, vitamin D receptor and autoimmune regulator 1 transcription factor, also have been implicated in AIH pathogenesis and/or progression.
|DRB1*0301||North America, Europe|
|DRB1*0401||North America, Europe|
|DRB1*1501||North and South America, Europe, Japan|
|Suppressor cell dysfunction|
|Abnormal antigen-specific T cell suppression|
|Decreased quantities and functions of CD4-CD25 Tregs|
|Dysfunctional Treg control of CD4 and CD8 T cells|
|Abnormal Treg stimulation of regulatory cytokines|
|Abnormal Treg control of monocytes|
Permissive Immune Repertoire
Onset of AIH requires a permissive autoreactive immune repertoire and failure of natural Tregs to maintain tolerance to autoantigens. Once AIH is initiated, the duration, extent, and distribution of inflammation within the liver is dictated by the balance between T cell effector and deficient autoantigen-specific iTreg, Tr1, and Th3 suppressive functions.
Viral infections and xenobiotics can trigger AIH in immunologically susceptible persons. Hepatitis A virus infection is strongly associated with AIH in Argentine children and in Brazilians. The susceptibility allele for AIH is HLA class II DRB1*1301, which is also associated with protracted hepatitis A virus infections. Immune responses to drug or xenobiotic metabolites bound to self-proteins of cytochrome P450 (CYP) isoforms or uridine diphosphate glucuronosyltransferases (UGTs) may result in autoimmune reactions against CYPs or UGTs.
Deficiencies in the numbers and functions of iTregs, CD4 Tr1, or CD4 Th3 cells may play a key role in AIH pathogenesis (Table 2); however, studies in patients with well-established AIH are difficult to interpret.[3, 7] Immunosuppression can partially restore deficiencies.
The sequential steps involved in a chronic adaptive immune response provide the clinician with multiple therapeutic options to achieve remission in AIH using either conventional or alternative immunosuppressive agents (Fig. 4). The ability to generate autologous CYP2D6 antigen-specific Tregs from CD4 T cells harvested from peripheral blood sets the stage for infusions of type 2 AIH-specific iTregs to control disease. Characterization of type 1 AIH autoantigens is a prerequisite for a similar therapeutic approach. Complete understanding of the immunopathogenesis of AIH may lead to additional novel strategies for prevention and treatment.
anti-smooth muscle antibodies
cytochrome P450 2D6
danger-associated molecular pattern
inducible T regulatory cell
pathogen-associated molecular pattern
T cell receptor
tumor necrosis factor
T regulatory cell
T regulatory 1 cell
uridine diphosphate glucuronosyltransferase.