The Pathogenesis of Autoimmune Liver Disease

Abstract

Background: Autoimmune liver disease (AILD) encompasses 3 main distinct clinical diseases: autoimmune hepatitis, primary biliary cholangitis (formally known as cirrhosis, PBC) and primary sclerosing cholangitis (PSC). These conditions are an important, yet under-appreciated cause of patient morbidity and mortality with ongoing unmet needs for further research and clinical advances. Key Messages: There is observational evidence for genetic predisposition, with all 3 conditions being more common in first degree relatives. AILD is associated with the presence of auto-antibodies and higher risks of other non-hepatic auto-immune conditions. Genetic risk association studies have identified HLA and non-HLA risk loci for the development of disease, with some HLA loci providing prognostic information. This re-enforces the concept that genetic predisposition to autoimmunity is important, likely in the context of environmental exposures. Such environmental triggers are unclear but relevant risks include smoking, drug and xenobiotic exposure as well as the complexities of the microbiome. There is evidence for a loss of immune tolerance to self-antigens playing a part in the development of these conditions. In particular the IL-2 and IL-12 regulatory pathways have been implicated in pre-disposing to an unopposed inflammatory response within the liver. Main immunological themes revolve around loss of immune tolerance leading to T-cell mediated injury, imbalance in the regulation of immune cells and defective immune response to foreign antigens. For PBC and PSC, there is then the added complexity of the consequences of cholestasis on hepato-biliary injury, immune regulation and liver fibrosis. Conclusions: Whilst specific disease causes and triggers are still lacking, AILD arises on the background of collective genetic and environmental risk, leading to chronic and abnormal hepato-biliary immune responses. Effective and more rational therapy will ultimately be developed when the multiple pathways to liver injury are better understood.

Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues

“…2 million deaths per year (Byass, 2014;Marcellin and Kutala, 2018). CLD progression relies mainly on (Arndtz and Hirschfield, 2016;Thrift et al, 2017;Marcellin and Kutala, 2018;Younossi et al, 2018): (i) chronic infection by hepatotropic viruses like hepatitis B virus (HBV, the most common risk factor in Asia) and hepatitis C virus (HCV), both worldwide distributed; (ii) excess alcohol consumption (i.e., alcoholic liver disease or ALD) and iii) non-alcoholic fatty liver disease (NAFLD), both predominant in western countries; iv) autoimmune liver diseases, including primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH); v) hereditary diseases, including Wilson's disease, haemochromatosis and α1-anti-trypsin deficiency. The worldwide estimated incidence and prevalence of CLDs largely varies depending on the specific etiology, geographic area and likely other factors (sex, race, socioeconomic status) (Marcellin and Kutala, 2018).…”

Performance of a calculator for diagnosing the cause of liver damage

“…There is a subtype of DILI with autoimmune background. AIH will attract more attention because many serious issues related to it remain to be elucidated [17,18,19].…”

Lactation-Based Maternal Educational Immunity Crosses MHC Class I Barriers and Can Impart Th1 Immunity to Th2-Biased Recipients

“…However, with that caveat stated, the work suggests that prepregnancy immunization in the human population could provide a way to improve immunity to a disease that kills more than 4000 persons each day (46) and, furthermore, that wet nursing by a woman with a robust Th1 response could significantly enhance immunity in some vulnerable infants. What we have yet to learn is whether there are any negative consequences of maternal educational immunity, like the production of autoreactive T cells as a consequence of suckling a mother with a T cell-mediated autoimmune disease, such as type 1 diabetes (47) or primary biliary cholangitis (48). We also do not yet understand the role of maternal CD8 + cells or Tregs that home to the pup thymus and whether they participate in the development of tolerance to maternal Ags, as observed in those breastfed who later receive a transplant from their mothers (49).…”