and therapeutic control of autoimmune diseases. Bacterial, fungal or viral infections can instigate innate and adaptive immune responses that result in autoimmunity. Vitamin D deficiency is epidemiologically associated with risk of autoimmunity. The increasing incidence of autoimmunity and inflammatory diseases observed worldwide is correlated with changes in environmental factors, including a more modern lifestyle, improved hygiene, a Western diet, use of antibiotics, and elimination of childhood parasitic infections.
Keywords adaptive immunity; autoantigens; autoimmune liver diseases; autoimmunity prevention; immune homeostasis maintenance; immune tolerance; innate immune organ; therapeutic control
Key Points
Autoimmunity results from the complex interplay of genetic, epigenetic, immunologic, and environmental factors.
Environmental triggers initiate loss of tolerance to autoantigens in genetically susceptible individuals.
Susceptible individuals must have inflammatory innate immune responses, human leukocyte antigen (HLA) alleles capable of autoantigen presentation to autoreactive T‐cell receptors, and autoreactive B cells to develop a specific autoimmune disease.
Subsequently, additional immunologic mechanisms perpetuate chronic progressive inflammatory disease.
Novel therapies based on immunopathogenic mechanisms in autoimmunity are in development.
Introduction
Until the identification of human autoimmune diseases at the dawn of the twentieth century proved Paul Ehrlich's concept of horror autotoxicus to be correct, clinicians believed that the immune system was incapable of reactions against self‐tissues and organs. To date, over 80 human autoimmune diseases have been identified, ranging in nature from systemic to localized. The genesis of 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 |
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