Immunopathogenesis: Insights for Current and Future Therapies

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1 REVIEW Immunopathogenesis: Insights for Current and Future Therapies John M. Vierling, M.D., F.A.C.P. Autoimmune hepatitis (AIH) is a chronic, progressive, necroinflammatory disease caused by loss of tolerance to hepatic autoantigens or their molecular mimics. 1 In AIH, adaptive immune responses against hepatic autoantigens appear to require immunogenetic susceptibility, an autoreactive immune repertoire, environmental triggering, and dysfunctional immunoregulation (Fig. 1). 2 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). 1 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). 3 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. 2 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 gdt 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)210, creating an immunosuppressive environment. However, excessive PAMPs or DAMPs induce secretion of proinflammatory cytokines (IL-1b, IL-6, IL-12, IL-18, and tumor necrosis factor [TNF]-a) 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-speciesspecific 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 Abbreviations: AIH, autoimmune hepatitis; ANA, antinuclear antibodies; APC, antigen-presenting cell; ASMA, anti-smooth muscle antibodies; CYP, cytochrome P450; CYP2D6, cytochrome P450 2D6; DAMP, danger-associated molecular pattern; IgG, immunoglobulin G; IL, interleukin; itreg, inducible T regulatory cell; KC, Kupffer cell; PAMP, pathogen-associated molecular pattern; TCR, T cell receptor; Th, T helper; TNF, tumor necrosis factor; Treg, T regulatory cell; Tr1, T regulatory 1 cell; UGT, uridine diphosphate glucuronosyltransferase. From the Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX. Potential conflict of interest: Nothing to report. View this article online at wileyonlinelibrary.com VC 2014 by the American Association for the Study of Liver Diseases doi: /cld Clinical Liver Disease, Vol 3, No 2, February 2014 An Official Learning Resource of AASLD

2 Figure 1 Interactions of genetics, permissive immune repertoire, immunoregulation, and environment involved in the pathogenesis of AIH. Abbreviations: SNPs, single nucleotide polymorphisms. Figure 2 Hypothetical sequence of events in the immunopathogenesis of AIH. 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. 4 Natural CD4 Tregs that recognize all autoantigens are generated in the thymus. Within lymphoid organs, natural Tregs prevent autoimmunity by 25 Clinical Liver Disease, Vol 3, No 2, February 2014 An Official Learning Resource of AASLD

3 Figure 3 Adaptive immune response of CD4 and CD8 T cells in AIH. The intense immunopathology of AIH suggests that active innate immune responses skew the adaptive response toward a CD4 Th1 profile, generating cytokines that promote proliferation and function of CD8 cytotoxic T cells. Optimal activation of both CD4 and CD8 T cells requires that APCs that express costimulatory molecules (e.g., CD80/86) engage T cell costimulatory receptors (e.g., CD28). The signature cytokines of CD4 Th1 cells inhibit the proliferation and cytokine secretion of CD4 Th2 cells. Similarly, the signature cytokines of CD4 Th2 cells inhibit proliferation and cytokine secretion by CD4 Th1 cells. Thus, a balance is established between Th1 and Th2 effects. CD4 Th0 activation also generates inducible Tregs and both Tr1 and Th3 regulatory cells. CD4 Th17 cells intensify local inflammation and tissue injury. CD4 Th1 and Th2 cytokines stimulate B cell production of antibodies, resulting in sustained elevation of IgG and autoantibodies. In AIH, autoantigen-specific itregs and Tr1 and Th3 cells may fail to terminate the autoimmune response, perpetrating progressive immunopathology. Chronic inflammation also results in non--antigen-specific activation and recruitment of macrophages, neutrophils, eosinophils, and natural killer cells. Abbreviations: IFNg, interferon g; NKT, natural killer T cells, IL, interleukin; TNF, tumor necrosis factor; MAC, macrophage; PAMPs, pathogen-associated molecular patterns; Th, Thelper. TABLE 1 HLA DRB1 Alleles Associated with AIH Susceptibility and Resistance Alleles Susceptibility Alleles DRB1*0301 DRB1*0401 DRB1*0404 DRB1*0405 DRB1*1301 Resistance Alleles DRB1*1501 DRB1*1302 Geographic Distribution North America, Europe North America, Europe Japan Japan South America North and South America, Europe, Japan South America 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 b-secreting Th3 cells (Fig. 3). 4 Autoantigens remain undefined in type 1 AIH, but oligoclonality of TCRs suggest they are limited in number. 5 In type 2 AIH, both T and B cell autoantigens are present in cytochrome P450 2D6 (CYP2D6). 3 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. Genetic Factors 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). 6 HLA class III genes also encode complement factors 2 and 4, TNFa/b and heat shock proteins. Single nucleotide polymorphisms in TNFa position 2308 lead to unregulated expression of TNFa. Single nucleotide polymorphisms in non-hla genes, 26 Clinical Liver Disease, Vol 3, No 2, February 2014 An Official Learning Resource of AASLD

4 including CTLA-4, Fas, vitamin D receptor and autoimmune regulator 1 transcription factor, also have been implicated in AIH pathogenesis and/or progression. Permissive Immune Repertoire Onset of AIH requires a permissive autoreactive immune repertoire and failure of natural Tregs to maintain tolerance to autoantigens. 2 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. 7 Environmental Factors Viral infections and xenobiotics can trigger AIH in immunologically susceptible persons. 2 Hepatitis A virus infection is strongly associated with AIH in Argentine children and in TABLE 2 Reported Defects in Immunoregulation of AIH 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 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. Immunoregulation 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 wellestablished AIH are difficult to interpret. 3,7 Immunosuppression can partially restore deficiencies. Therapeutic Implications 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). 8 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. 9 Characterization of type 1 AIH autoantigens is a prerequisite for a similar therapeutic approach. Complete understanding of Figure 4 Therapeutic targets for control of the multistep adaptive immune response in autoimmune hepatitis. Corticosteroids and azathioprine are first-line therapies to induce remission. Alternative therapies may be required for patients who fail to achieve remission using corticosteroids and azathioprine or are intolerant of these agents. Abbreviations: IVIG, intravenous immunoglobulin; APC, antigen-presenting cell. 27 Clinical Liver Disease, Vol 3, No 2, February 2014 An Official Learning Resource of AASLD

5 the immunopathogenesis of AIH may lead to additional novel strategies for prevention and treatment. 10 n CORRESPONDENCE John M. Vierling, M.D., 6620 Main Street, Suite 1425, Houston, TX vierling@bcm.edu. REFERENCES 1. Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, et al. Diagnosis and management of autoimmune hepatitis. Hepatology 2010; 51: Vierling JM. The pathogenesis of autoimmune hepatitis. In: Hirschfield GM, Heathcote EJ, eds. Autoimmune Hepatitis: A Guide for Practicing Clinicians. New York: Humana Press; 2012: Liberal R, Grant CR, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: a comprehensive review. J Autoimmun 2013;41: Vierling JM. Autoimmune hepatitis and antigen-specific T regulatory cells: when can we send in the regulators? Hepatology 2011;53: Ichiki Y, Aoki CA, Bowlus CL, Shimoda S, Ishibashi H, Gershwin ME. T cell immunity in autoimmune hepatitis. Autoimmun Rev 2005;4: Oliveira LC, Porta G, Marin ML, Bittencourt PL, Kalil J, Goldberg AC. Autoimmune hepatitis, HLA and extended haplotypes. Autoimmun Rev 2011;10: Ferri S, Lalanne C, Masi C, Muratori L. Regulatory T cell defects in adult autoimmune hepatitis. J Hepatol 2012;57: Czaja AJ. Autoimmune hepatitis: focusing on treatments other than steroids. Can J Gastroenterol 2012;26: Muratori L, Longhi MS. The interplay between regulatory and effector T cells in autoimmune hepatitis: implications for innovative treatment strategies. J Autoimmun 2013;46: Czaja AJ. Emerging opportunities for site-specific molecular and cellular interventions in autoimmune hepatitis. Dig Dis Sci 2010;55: Clinical Liver Disease, Vol 3, No 2, February 2014 An Official Learning Resource of AASLD