Etiopathogenesis of primary biliary cirrhosis

Abstract

Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver characterized by progressive bile duct destruction eventually leading to cirrhosis and liver failure. The serological hallmark of the disease is the presence of circulating antimitochondrial antibodies (AMA). These reflect the presence of autoreactive T and B cells to the culprit antigens, the E2 subunits of mitochondrial 2-oxo-acid dehydrogenase enzymes, chiefly pyruvate dehydrogenase (PDC-E2). The disease results from a combination of genetic and environmental risk factors. Genetic predisposition is indicated by the higher familial incidence of the disease particularly among siblings and the high concordance rate among monozygotic twins. Environmental triggering events appear crucial to disrupt a pre-existing unstable immune tolerance of genetic origin allowing, after a long latency, the emergence of clinical disease. Initiating mimetopes of the vulnerable epitope of the PDC-E2 autoantigen can be derived from microbes that utilize the PDC enzyme or, alternatively, environmental xenobiotics/chemical compounds that modify the structure of native proteins to make them immunogenic. A further alternative as a source of antigen is PDC-E2 derived from apoptotic cells. In the effector phase the biliary ductular cell, by reason of its proclivity to express the antigen PDC-E2 in the course of apoptosis, undergoes a multilineage immune attack comprised of CD4(+) and CD8(+) T cells and antibody. In this article, we critically review the available evidence on etiopathogenesis of PBC and present interpretations of complex data, new developments and theories, and nominate directions for future research.

Figure 1

Model of pathogenic mechanisms in primary biliary cirrhosis (PBC). PBC is initiated by an autoantigenic stimulus (upper, right) provided either by a bacterial mimic of the autoepitope of PDC-E2, a xenobiotically modified PDC-E2, or “spillage” of native mitochondrial autoantigens derived perhaps from apoptotic cells. Hyper-responsiveness of innate immunity (top, centre) can facilitate autoantigenicity; bacterial Cpg enhances IgM production and cellular expression of TLR9. Genetic susceptibility is critical overall, and depends particularly on multiple inherited deficits in immune tolerance, mostly as yet undefined. APCs that become activated (lower, right) by stimulation through TLRs present immunogenic self peptides (or mimics) via MHC Class II molecules to autoreactive CD4⁺ T lymphocytes (centre) which in turn activate CD8⁺ cytotoxic T lymphocytes and B lymphocytes that produce AMA. Treg lymphocytes (lower, centre) that normally restrain activated autoreactive T cells are deficient in PBC, thus further impeding T cell tolerance. Effector mechanisms converge on the target cell in PBC, the BEC (lower left), which can be damaged by injurious cytokines (IFN-γ) from CD4⁺ T cells, direct cytotoxicity (Fas-L, perforin, granzyme B) from CD8⁺ T cells, or transcytosis of IgA-AMA. A toxic effect might even be supplied by activated eosinophils (centre, left) by release of eosinophil MBP. BECs thus undergo apoptosis and in doing so contribute immunogenic mitochondrial PDC-E2 autoantigen to sustain a self-perpetuating autoimmunization process and, by reason of a BEC-specific anomaly of apoptosis retain PBC-E2 intact in apoptotic blebs (see text), so conferring particular vulnerability on these cells. Ags: Antigens; AMA: Antimitochondrial antibodies; ANA: Antinuclear antibodies; APC: Antigen-presenting cell; BEC: Biliary epithelial cells; CTL: Cytotoxic T lymphocytes; ICs: Immune complexes; IL: Interleukin; IFN: Interferon; IP-10: Interferon-γ-inducible protein 10; LTA: Lipoteichoic acid; LPS: Lipopolysaccharide; MIG: Monokine induced by γ-interferon; MBP: Major basic protein (primary cytotoxic granule protein); NKT: Natural killer T cells; PDC-E2: Pyruvate dehydrogenase complex E2; TGF: Transforming growth factor; TLR: Toll-like receptor; Treg: Regulatory T cells.