autoimmunity requires loss of immune tolerance to self‐antigens and results from the complex interplay of genetic, epigenetic, immunologic, and environmental factors (Figure 2.1) [1]. Genetics confers susceptibility for autoimmunity, not for a specific autoimmune disease. Thus, susceptible patients often have more than one autoimmune disease [1].
While complex genetic susceptibility and environmental triggers suggest that autoimmunity results from “bad genes, bad luck,” this notion neglects the evolutionary advantage of robust immune responses to a broad array of antigens, including some autoantigens. An evolutionary survival advantage likely explains the unexpectedly high frequency of autoimmune reactions in healthy humans that fail to progress to autoimmune diseases [2].
Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are classified as autoimmune liver diseases (AILDs). However, comparison of each of these AILDs with classical autoimmune diseases reveals shared and atypical features (Table 2.1). Knowledge of the concepts of autoimmunity can aid gastroenterologists and hepatologists in management and counseling of patients with AILDs and in understanding the rationales and sites of action of future therapies. Thus, this chapter addresses five major themes: (i) innate and adaptive immunity in the context of the liver as an immune organ; (ii) generation and maintenance of tolerance to autoantigens; (iii) risk factors for autoimmunity; (iv) loss of immune tolerance to autoantigens and perpetuation of autoimmune diseases; and (v) prospects for prevention of autoimmunity and therapeutic control of autoimmune diseases.
Figure 2.1 Interaction of factors required for generation of autoimmune diseases. Autoimmune diseases, including AILDs, result from the complex interaction among factors involving genetic susceptibility, the status of the cumulative immune response repertoire, an individual's immune regulatory capacity, environmental triggers, and the influence of the microbiome.
Role of Innate and Adaptive Immunity in Autoimmunity in the Context of the Liver as an Immune Organ
Overview
The evolutionarily ancient innate immune system provides immediate responses to pathogen‐associated molecular patterns(PAMPs) and damage‐associated molecular patterns (DAMPs) associated with microbes and injured or dying cells, respectively [3]. In contrast, the adaptive immune system responds to specific peptide antigens through antigen‐specific T‐cell responses and B‐cell production of antigen‐specific antibodies [4]. It is now clear that cytokines produced by an innate immune response dictate both the type and magnitude of adaptive responses and that both innate and adaptive immunity play important roles in the immunopathogenesis of all autoimmune diseases (Table 2.2 and Figure 2.2).
Table 2.1 Comparison of classic autoimmunity with AIH, PBC or PSC.
| Classic autoimmunity | AIH | PBC | PSC |
| Disease‐specific autoantigens | Yesa | Yes | Yesb |
| Disease‐specific autoantibodies | Yes, types 1 and 2 | Definite | Yes |
| Epitope determinant spreading | Unclear | No | Unclear |
| Female predilection | Yes | Yes | No |
| Occurrence in children and adults | Yes | No, adults only | Yes |
| Polygenetic predisposition | Yes | Yes | Yes |
| HLA immunogenetic associations | Yes | Yes | Yes |
| Non‐HLA genetic associations | Yes | Yes | Yes |
| Environmental triggers | Yes | Yes | Yes |
| Tissue/organ‐specific pathology | Yes | Yes | Yes |
| Associated extrahepatic autoimmune diseases | Yes | Yes | Yes |
| Associated IBD | Yes (weak) | No | Yes (strong) |
| Response to immunosuppression | Yes | Yes | No |
| Autoantigen‐specific animal models | Yes for type 2 No for type 1 | Yes | No |
a T and B cell epitopes defined in type 2, not type 1 AIH.
b β‐Tubulin isoform 5, not rigorously tested to determine prevalence, sensitivity or specificity.
AIH, autoimmune hepatitis; IBD, inflammatory bowel disease; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis.
Innate immune inflammasome responses, especially those mediated by nucleotide‐binding oligomerization domain (NOD)‐like receptor P3 (NLRP3), occur in both innate immune cells and non‐immune cells, including hepatocytes, cholangiocytes, and hepatic stellate cells (HSCs) [5]. Thus, clinicians must embrace a new paradigm: cells or tissues are not passive “targets” of autoimmune diseases (including AILDs), but instead are active participants in the immunopathogenesis of their own injury and demise.
Innate Immunity
The innate immune system responds immediately to PAMPs, comprising microbial constituents, and to DAMPs, comprising cellular constituents from stressed, neoplastic or dying cells (Table 2.2). Both PAMPs and DAMPs bind to pattern recognition receptors (PRRs) and other receptors expressed on neutrophils, dendritic cells (DCs), activated macrophages (including Kupffer cells), and natural killer (NK) and natural killer T (NKT) cells [3]. NK cells express killer receptors for stressed, dying or neoplastic cells and Fc receptors that mediate antibody‐dependent cell‐mediated cytotoxicity (ADCC) of target cells coated with antibodies [3]. Antigen‐presenting cells (APCs) activate NKT and γδT