immune responses generate multiple mechanisms of cytotoxicity in autoimmunity. Failure of thymic nTregs allows professional APC presentation of peptide autoantigens to autoreactive naive CD4 Th0 and CD8 T cells. APC class II HLA molecules, encoded by HLA‐DR, −DQ, and ‐DP alleles, present peptide autoantigens to TCRs of CD4 Th0 cells. APC class I HLA molecules, encoded by HLA‐A, ‐B and ‐C alleles, present different peptide autoantigens to TCRs of naive CD8 CTLs. APC processing of autoantigen–immunoglobulin immune complexes dramatically increases autoantigen‐specific activation of CD8 CTLs. Polymorphisms in HLA class I and II alleles determine which autoantigens are presented to TCRs. Differentiation of functional subsets of autoantigen‐specific CD4 Th cells and cytotoxic CD8 T cells depends on two factors: costimulation of HLA–antigen activated T cells and the composition of the cytokine milieu produced by local innate immune responses. Potent costimulation is mediated by binding of CD80/CD86 expressed on APCs to CD28 expressed on T cells or binding of CD40 expressed on APCs to CD154 (aka CD40 ligand, CD40L) expressed on T cells. If costimulation is absent or inadequate, antigen‐activated CD4 Th0 and CD8 T‐cell clones become anergic to subsequent reexposures to the activating peptide antigens. When local innate immune responses produce abundant proinflammatory cytokines IL‐12, IL‐6, IL‐1β and IFN‐γ, activated CD4 Th0 cells predominantly differentiate into Th1 cells, rather than Th2 cells. Secretion of other cytokines, acting alone or in combination, promotes CD4 Th0 differentiation into other CD4 T‐cell subsets. CD4 Th1 cytokines and growth factors drive the proliferation and differentiation of cytotoxic antigen‐specific CD8 CTLs. Th1 cytokines also activate tissue macrophages and induce B‐cell secretion of C′‐fixing IgG2a. IL‐4 produced by local innate immune responses favors CD4 Th0 differentiation into Th2 cells that secrete IL‐4, IL‐5, IL‐10, and IL‐13 and induce B‐cell secretion of IgG, IgM, IgA, and IgE. CD4 Th1 and Th2 cells achieve a dynamic balance by secreting signature cytokine profiles that inhibit the proliferation and cytokine secretion of the other subset. TGF‐β and IL‐6 play important roles, both alone and in combination, in the differentiation of CD4 Tfh, Th17, and iTreg cells. IL‐21, IL‐23 and RORγ, RORα promote differentiation of Th17 cells, which intensify and perpetuate tissue inflammation. Tfh and Th9 cells secrete the pluripotent cytokine IL‐21. IL‐21 is a pivotal cytokine in autoimmune disease pathogenesis mediated by autoantibodies and cytotoxic cells and cytokines. Specifically, IL‐21 induces B‐cell differentiation into plasma cells, increases proliferation of CD4 subsets, especially Th17 cells, increases resistance to iTregs and proliferation and cytokine production of NKT cells, increases NK cell cytotoxicity and ADCC of immunoglobulin‐coated target cells, and increases IFN‐γ secretion and proliferation and cytotoxicity of CD8 CTLs. IL‐9 stimulates cell proliferation and inhibits apoptosis, while IL‐13 is an anti‐inflammatory cytokine that induces IgE and enhances APC survival. Tfh cells localize within B‐cell follicles in lymph nodes and Peyer's patches where they promote selection and survival of B‐cell clones by secreting IL‐4 and IL‐21. Tfh cells play a central role in the formation of tertiary germinal centers characteristic of autoimmune diseases. CD4 iTreg cells suppress antigen‐specific T‐cell responses of all CD4 T‐cell subsets by secreting immunosuppressive IL‐10 and TGF‐β. Local secretion of IL‐23, Il‐6, IL‐1β, and TGF‐β by cytokine‐stimulated epithelial cells (e.g. cholangiocytes) transform iTregs into proinflammatory Th17 cells, defeating the immunoregulatory function of iTregs. Innate NK, NKT cells and activated macrophages and adaptive immune effector B and T cells act together to mediate target cell cytotoxicity. NK cells express killer inhibitory receptors (KIRs) that inhibit killing of normal cells but target abnormal cells requiring elimination. Activated NK cells secrete abundant IFN‐γ, a synergizing cytokine in the proinflammatory cytokine milieu. NKT cells react to lipid or glycolipid antigens presented by CD1d molecules and secrete IFN‐γ, IL‐2, IL‐4, TNF‐α, and granulocyte–macrophage colony‐stimulating factor (GM‐CSF). NK group 2 member D (NKG2D) receptors on activated macrophages, NK, NKT and γδT cells induce apoptosis by engaging MICA and MICB ligands produced by HLA class I‐like genes in abnormal cells. Activated macrophages and NK and NKT cells also express Fc receptors that mediate antibody‐dependent cellular cytotoxicity.
After exiting lymph nodes, circulating activated T cells and B cells undergo transendothelial migration to enter inflamed tissues expressing chemokines [1]. Activated T cells, B cells, and other leukocytes expressing chemokine receptors migrate through the tight junctions of endothelial cells, and their chemokine receptors mediate migration toward the cellular sources of chemokine secretion. This results in mixed inflammatory infiltrates that mediate cytotoxicity (Figure 2.2).
Role of the Liver as an Adaptive Immune Organ
In addition to the innate immune functions, the liver has important roles in adaptive immunity [6]. The normal liver is a distinct “lymphoid” compartment containing CD8 αβ T cells, activated CD4 and CD8 T cells, γδT cells, memory T cells and B cells. Indeed, the proportions of highly activated T cells in the liver exceed those in blood. In contrast, normal liver contains scant numbers of naive T cells and B cells.
Most often, antigen‐activated DCs migrate to local lymph nodes to activate non‐hepatic T cells, which subsequently circulate and enter tissues through transendothelial migration. However, hepatic DCs, LSECs, and HSCs also function as APCs for intrahepatic T‐cell activation of adaptive immunity. Hepatocytes and cholangiocytes may also serve as APCs after cytokine stimulation. CD4 T cells activated by hepatic APCs primarily differentiate into Th2 cells, secreting immunosuppressive IL‐10 and IL‐4. Frequently, CD8 T cells activated in the liver have functional deficiencies leading to premature apoptosis. However, LSECs can directly activate functional antigen‐specific CD8 CTLs in the liver by cross‐presentation of soluble exogenous antigens in class I HLA molecules.
Hepatic Kupffer cells regulate T‐cell homeostasis by inducing apoptosis of senescent T cells expressing CD95 (Fas), TNF‐apoptosis‐inducing ligand (TRAIL), and programmed cell death 1 (PD‐1) receptors. Furthermore, binding of Kupffer cell PD‐L1 to PD‐1 expressed by activated CD4 T cells induces immunosuppressive IL‐10 and reduces apoptosis of CD4 T regulatory cells (Tregs).
Mucosal invariant T (MAIT) cells have characteristics of both innate and adaptive immune cells that are relevant in AILDs [7]. MAIT cells have invariant TCR α‐chains that respond to bacterially processed vitamin B antigens presented by unique major histocompatibility complex (MHC) class I‐related molecules (MR‐1) on APCs. Normally found only in blood, gut mucosa and mesenteric lymph nodes, MAIT cells congregate in the portal tracts of patients with chronic liver diseases, including AIH, PBC, PSC, alcoholic and non‐alcoholic fatty liver diseases, and chronic hepatitis C virus (HCV) infection. Proinflammatory cytokines IL‐12 and IL‐18 activate MAIT cells to display dual characteristics of CD4 Th1 and Th17 cells by secreting interferon (IFN)‐γ, TNF‐α and IL‐17. Up to 25% express cytotoxic granzyme B, a feature of cytotoxic NK, NKT, and CD8 T cells. Importantly, MAIT cell cytokines stimulate cholangiocyte secretion of cytokines capable of transforming CD4 iTregs into proinflammatory CD4 Th17 cells (Figure 2.2).
Generation and Maintenance of Tolerance to Self‐antigens
Overview
Immune tolerance is the ability of the immune system to identify and respond to foreign or non‐self‐antigens, while aborting or controlling potentially deleterious responses to autoantigens [1]. Despite genetic variability within the population and substantial differences in environmental exposures that shape an individual's immune repertoire, the vast majority of people maintain immune tolerance to self‐antigens. As a result, autoimmune diseases are rare, even among persons with genetic susceptibility [2]. In contrast, rare monogenetic defects predictably result in the development of autoimmune diseases in early life [1]. Broadly, immune tolerance is divided into two categories: natural and inducible tolerance. In addition, natural tolerance has been subclassified as either central or peripheral, based the anatomic site of development.