The Immunobiology and Pathophysiology of Primary Biliary Cirrhosis

Abstract

Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by clinical homogeneity among patients, an overwhelming female predominance, production of a multilineage immune response to mitochondrial autoantigens, inflammation of small bile ducts, and in some patients the development of fibrosis and cirrhosis. The targets in this disease are small bile ducts, and the prototypic serologic response includes antimitochondrial antibodies (AMAs). Several key observations have greatly advanced our understanding of PBC. First, the multilineage immune response, including AMAs, is directed at the E2 component of the 2-oxo-dehydrogenase pathway, particularly PDC-E2. Second, such autoantibodies may be identified years before the clinical diagnosis of disease. Third, the autoreactive T cell precursor frequency for both CD4 and CD8 cells is significantly higher in liver and regional lymph node than in blood, so the multilineage antimitochondrial response may be required for the development of this disease. Fourth, the apotope of biliary cells contains intact PDC-E2; this apotope, in a setting that includes granulocyte macrophage colony-stimulating factor-stimulated macrophages and AMAs, produces an intense proinflammatory response. Fifth, several mouse models of PBC highlight the importance of loss of tolerance to PDC-E2 as well as a critical role for the interleukin (IL)-12 signaling pathway. Finally, genome-wide association studies suggest an important role for the IL-12 pathway in disease susceptibility. Taken together, these findings have resulted in a better understanding of the mechanism for selective biliary cell destruction and have also suggested unique pathways for therapeutic intervention.

Clonal Characteristics of Circulating B Lymphocyte Repertoire in Primary Biliary Cholangitis

“…Somatic hypermutation of the V region will occur simultaneously, resulting in affinity maturation. As observed in this study, the highly expanded and expressed clones, which also resulted in the significantly biased usage of IGHV segments in PBC patients and its subgroups, could be due to the consequence of ongoing stimulation by endogenous bile duct epithelial Ags (1,19,20). The effective treatment of PBC patients who were refractory to UDCA with rituximab, which led to B cell depletion, through the reduction of AMA-secreting B cells, the titer of AMAs and serum IgM/G/A level, as well as serum ALP level, suggests that the highly expanded and expressed B lymphocytic clones have contributed to the abnormality of peripheral B cell immunity and may be involved in the pathogenesis of PBC patients (28).…”

“…A high level of serum IgM in most PBC patients is a unique phenomenon. Studies suggested it might be a consequence of hyperactive innate immunity independent of T cells and mediated by IgM memory B cells either in the bloodstream or in the spleen (1,5,29,30). Elevated serum IgM level has been used as a diagnostic marker for PBC, and the reduction of serum IgM level has been used as a marker of disease alleviation by clinicians (28,31).…”

“…During the past decade, many genetic, environmental, and infectious factors that may contribute to the development of PBC have been studied (1,6). However, there is limited knowledge regarding the precise role of B lymphocyte clonal changes in the pathogenesis of PBC.…”

Lower Plasma Levels of IL-35 in Patients with Primary Biliary Cirrhosis

“…As important immune cells, CD4+ T cells are involved in the pathogenesis of PBC (Hirschfield and Gershwin 2013;Wang et al 2015a;Webb et al 2015). One paper reported that the concentration of Th1-related IFN-γ was increased in PBC patients but decreased after UDCA treatment, indicating the relationship of this cytokine with disease activity (Saeki et al 1995).…”

Xenobiotic Induced Model of Primary Biliary Cirrhosis

“…The typical characteristic of the disease is the presence of antimitochondrial autoantibodies (AMA), which are present in high amounts. The autoantigens to which the immune responese is directed in PBC has been identified as the E2 subunits of the 2-oxo-acid dehydrogenase complexes (2OADC-E2), including the E2 subunits of the pyruvate dehydrogenase complex (PDC-E2), branched chain 2-oxo acid dehydrogenase complex (BCOADC-E2), and 2-oxoglutarate dehydrogenase complex (OGDC-E2) (5). The immunodominant autoantigen within this group is PDC-E2 (6; 7).…”