Mechanisms of Loss of Tolerance to Autoantigens
Bacterial and Viral Infections
Bacterial, fungal or viral infections can instigate innate and adaptive immune responses that result in autoimmunity [21]. Migration of neutrophils to sites of infection or sterile inflammation mediated by IL‐8, IFN‐γ, C3a, C5a, and leukotriene B4 plays a key role. Neutrophil phagocytosis of microbial organisms and particles leads to release of soluble antimicrobials and formation of neutrophil extracellular traps (NETs) comprising chromatin and proteases that enmesh and kill microbes. The proteolytic function of NETs also can generate neoantigens or microbial peptide molecular mimics of autoantigens (see next section).
Superantigens are proteins produced by pathogenic bacteria and viruses that trigger non‐antigen‐specific polyclonal T‐cell activation of up to 20% of the host's T cells. These activated T cells create a cytokine storm of secreted cytokines, especially IFN‐γ, which activates macrophages to secrete proinflammatory IL‐1β, IL‐6 and TNF‐α. This proinflammatory environment could promote adaptive immune responses to autoantigens in dead or dying cells.
Molecular Mimicry of Autoantigens
Molecular mimicry is a key mechanism leading to loss of tolerance to autoantigens [21]. It is defined as the cross‐reactivity of immune responses to antigenic epitopes of microbial peptides with autoantigenic epitopes of host peptides. Molecular mimicry has been observed between human autoantigens and peptide antigens of several viral, bacterial and fungal pathogens. Xenobiotics may also function as molecular mimics for autoantigens. For example, some halogenated xenobiotics exhibit immunogenic similarity with the lipoic acid‐binding domain of pyruvate dehydrogenase complex (PDC)‐E2, the primary autoantigen in PBC. Yet molecular mimicry is an insufficient explanation for a sustained loss of tolerance, which also requires failure to control the autoimmune response. Thus, molecular mimicry represents an environmental trigger capable of progressing to autoimmunity. Molecular mimicry to adjuvants (substances that enhance immune responses to an antigen) involves nucleosomes or ribonucleoproteins released after cell death. These molecules mimic viruses by stimulating an antiviral‐like, innate immune response with production of type 1 interferon.
Neoantigens
Neoantigens, also called cryptic antigens, can elicit autoimmune responses against autoantigenic epitopes that are not immunogenic until modified by either somatic hypermutations or binding of haptens [22]. Haptens are small molecules, most often metabolites of drugs or environmental xenobiotics, that are incapable of eliciting an immune response unless bound to host carrier proteins. Hapten–carrier protein complexes elicit immune responses against a single hapten epitope and multiple autoepitopes of the carrier protein. For example, haptens generate autoimmunity against cytochrome P450 (CYP)2D6 in type 2 AIH and autoantibodies and a minority of patients with chronic HCV infection, whereas haptens bound to UDP‐glucuronosyltransferase (UGT) in those infected with HCV or hepatitis D virus, and with Addison disease, APS‐1 syndrome and some drug‐induced liver injuries result in anti‐UGT reactions. A subset of NK cells develop antigen‐specific memory to haptens, which may be important for immune responses after hapten reexposure. Oral supplements of lipoic acid act as a haptens in the immunogenicity of the lipoic acid‐binding site of PDC‐E2, the principal autoantigen in PBC. Biochemical modifications of self‐antigens can also increase the immunogenicity of autoantigens. The best example is citrullination, produced by posttranslational conversion of arginine to citrulline. Since DNA does not encode the amino acid citrulline, citrullinated self‐proteins become autoantigenic, as in RA.
Failure of Apoptosis to Conceal Autoantigens and Eliminate Autoreactive Cells
Apoptosis is normally an immunologically silent form of cell death [23]. Phagocytic removal of the corpse (efferocytosis) of apoptotic cells and blebs by APCs normally induces release of anti‐inflammatory molecules, inhibits NF‐κB stimulation of proinflammatory cytokines, and promotes secretion of anti‐inflammatory IL‐10 and TGF‐β. Failure of these normal APC mechanisms is an attractive hypothesis for the genesis of autoimmunity, because apoptotic blebs contain disproportionately high concentrations of known autoantigens. However, non‐apoptotic forms of cell death, such as necrosis or necroptosis, result in APC phagocytosis, processing and presentation of autoantigenic peptides to autoreactive T and B cells in immunogenetically susceptible persons. This is the proposed explanation for AIH after documented infections with hepatotrophic or other viruses causing hepatocyte necrosis. Defective apoptosis might also contribute to the persistence of autoreactive T and B cells in autoimmune diseases. Genetic defects in Fas (CD95), Fas‐L (CD95L) and RAS pathways cause lymphoproliferative disorders and autoimmunity due to inability to eliminate autoreactive effector cells.
Immune Deviation of Activated T Cells
Immune deviation refers to the evolution of dominant populations of effector T cells, which alter local immune responses and compromise tolerance [1]. Activated CD4 Th0 differentiate into multiple functional Th1 subsets differing in cytokine production (Figure 2.2). CD4 Th1 cells secrete IL‐2, the mitogen for all activated CD4 and CD8 T cells, as well as IFN‐γ and TNF‐α. Th1 cells activate macrophages and stimulate B cells to secrete C′‐fixing IgG2. In contrast, Th2 cells secrete IL‐4, IL‐5, IL‐10, and IL‐13 that stimulate B cells to secrete IgG, IgM and IgA antibodies, while immunosuppressing the effects of Th1 cytokines. Th1 predominance produces greater immunopathology associated with autoimmune diseases that cause tissue damage. The signature cytokines of Th1 and Th2 cells inhibit the proliferation and secretion of the cytokines of each other, resulting in a dynamic balance. Skewing of this balance contributes to either the maintenance or the loss of tolerance. The T follicular helper (Tfh) cell secretes IL‐21, which is best known for inducing differentiation of activated B cells into memory B cells and plasma cells. Additional pluripotent effects of IL‐21 impact both innate and adaptive immune functions to increase immunopathology. In innate immunity, IL‐21 increases antigen processing and presentation by APCs, activates macrophages to chemoattract neutrophils, increases NK cell cytotoxicity, including ADCC and secretion of IFN‐γ, and induces NKT cell proliferation and secretion of IFN‐γ, IL‐2, IL‐4, IL‐13, and IL‐17A. In adaptive immunity, IL‐21 induces proliferation and differentiation of Th17 cells and increases both the cytotoxicity of CD8 CTLs and their secretion of IFN‐γ and TNF‐α. Thus, polarization of immune responses toward Th1 and Tfh cells greatly increases the consequences of autoreactive T and B cell activation.
T‐cell Receptor Revision in the Periphery
The fact that the TCR repertoire selected in the thymus can be altered in the periphery helps explain the presence of rogue autoreactive T cells [24]. Surface expression of the costimulatory molecule CD40, thought to be restricted to APCs, has been observed recently on neural cells, endothelial cells, adipocytes, and subsets of CD4 and CD8 T cells. Activation of CD40 expressed by the mature CD4 Th subset, designated Th40 cells, induces RAG‐1/RAG‐2‐mediated rearrangement of both TCR α‐ and β‐chains in the periphery. This refutes early dogma of the immutability of the TCR repertoire and its antigen specificity after T cells emigrate from the thymus. The fact that Th40 cells can undergo multiple cycles of TCR revision multiplies the risk of developing autoreactive TCRs, including ones recognizing unique self‐neoantigens. The finding that adoptively transferred Th40 cells induced antigen‐specific type 1 diabetes mellitus (T1DM) in non‐obese diabetic severe combined immunodeficiency mice confirms their immunogenic function. Thus, TCR revision to recognize autoantigens represents a new paradigm, explaining autoreactive peripheral T cells.
Perpetuation of Autoimmune Diseases
The primary factor in perpetuation of autoimmune diseases is failure to immunoregulate and terminate the initial activation of B and T cells to autoantigens or their mimics [1]. Multiple factors contribute to perpetuation.
Epigenetics