Unmet Challenges in Immune-Mediated Hepatobiliary Diseases

Abstract

It is ironic that the liver, which serves a critical function in immune tolerance, itself becomes the victim of an autoimmune attack. Indeed, liver autoimmunity and the autoimmune diseases associated with both innate and adaptive responses to hepatocytes and/or cholangiocytes are models of human autoimmunity. For example, in primary biliary cirrhosis, there exists a well-defined and characteristic autoantibody and considerable homogeneity between patients. In autoimmune hepatitis, there are clinical characteristics that allow a rigorous subset definition and well-defined inflammatory infiltrates. In both cases, there are defects in a variety of immune pathways and including regulatory cells. In primary sclerosing cholangitis, with its characteristic overlap with inflammatory bowel disease, there are unique defects in innate immunity and particular important contribution of lymphoid homing to disease pathogenesis. In these diseases, as with other human autoimmune processes, there is the critical understanding that pathogenesis requires a genetic background, but is determined by environmental features, and indeed the concordance of these diseases in identical twins highlights the stochastic nature of immunopathology. Unfortunately, despite major advances in basic immunology and in immunopathology in these diseases, there remains a major void in therapy. The newer biologics that are so widely used in rheumatology, neurology, and gastroenterology have not yet seen success in autoimmune liver disease. Future efforts will depend on more rigorous molecular biology and systems analysis in order for successful application to be made to patients.

The epigenetics of PBC: The link between genetic susceptibility and environment

“…Several studies suggest the involvement of disturbance in epigenetic processes in autoimmune disease, PBC included. Map epigenetic modification patterns in a given cell (either of immune system or target organ) it is critically important because epigenetic biomarkers can be used for clinical prediction, diagnosis, and therapeutic development [8,11,18,45]. Moreover, epigenetic states are potentially reversible and hence candidates for pharmacological intervention [134,135].…”

“…Primary biliary cholangitis (PBC) previously known as primary biliary cirrhosis (PBC) [1][2][3][4][5][6][7][8] is a complex idiopathic autoimmune chronic liver disease characterized by an immune driven biliary injury and cholestasis [9,10]. In PBC like other inflammatory autoimmune diseases (AIDs), the decisive role of genetic factors has been widely demonstrated, as well as the exposure to certain environmental factors that could lead to immune tolerance breakdown [11][12][13][14][15].…”

The Natural History and Prognosis of Primary Biliary Cirrhosis with Clinical Features of Autoimmune Hepatitis

“…There have been extraordinary and extensive studies of the genetic basis, the immunological features, and the molecular characteristics of not only human PBC but also of several mouse models [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21].…”

Endogenous interleukin-22 protects against inflammatory bowel disease but not autoimmune cholangitis in dominant negative form of transforming growth factor beta receptor type II mice

“…These data take on significance in PBC in which, thus far, there has not been a successful translation of the critical immunological and molecular data in both human and murine models towards new therapy [38][39][40][41][42][43][44][45][46]. In addition, we should note that further attention should be placed not only on the local tissue microenvironment, but also on innate immunity, not only in PBC but also in other autoimmune diseases [35,[47][48][49].…”