Environmental basis of primary biliary cholangitis.

Abstract

Autoimmunity is a consequence of both genetic and environmental factors, occurring in genetically susceptible hosts with environmental triggers. While genome-wide association studies have revealed a number of susceptible genes contributing to etiology, the environmental triggers remain poorly understood. Primary biliary cholangitis, formally known as primary biliary cirrhosis, is considered a model autoimmune disease for which our group has extensively evaluated environmental factors involved in its etiology. Bacterial infection and xenobiotics have been proposed as candidate environmental factors that may explain tolerance breakdown and production of primary biliary cholangitis-specific antimitochondrial autoantibodies. Large-scale case-control studies have consistently detected an association of primary biliary cholangitis with urinary tract infections caused by Escherichia coli, as E. coli PDC-E2 is molecularly similar to human PDC-E2, the immunodominant target of AMAs. Another bacterium of interest is Novosphingobium aromaticivorans, a ubiquitous xenobiotic-metabolizing bacterium that produces lipoylated proteins, which are highly reactive with sera from primary biliary cholangitis patients. Regarding xenobiotics, case-control studies have suggested that frequent use of nail polish is associated with an increased susceptibility to primary biliary cholangitis. We found that 2-octynamide, the conjugate derived from 2-octynoic acid present in cosmetics, lipsticks, and some chewing gums, was unique in both its quantitative structure-activity relationship analysis and reactivity with primary biliary cholangitis sera. 2-nonyamide is another xenobiotic that also has the optimal chemical structure for xenobiotic modification of the PDC-E2 epitope, as demonstrated by the enhanced epitope recognition with AMA-positive PBC sera. Moreover, we found that C57BL/6 mice immunized with 2-octynoic acid-BSA possess many of the features characteristic to primary biliary cholangitis. Impact statement Autoimmunity is believed to develop in genetically susceptible hosts with triggers from the environment. Researchers have recently demonstrated that bacteria and xenobiotics commonly present in our environment are potential triggers of tolerance breakdown against autoantigens and autoimmunity, particularly in primary biliary cholangitis (PBC). The link between xenobiotics and PBC has been further confirmed with the establishment of PBC model mice by immunizing mice with xenobiotics.

• Authors: Atsushi Tanaka, Patrick Sc Leung, M Eric Gershwin
• Journal: Experimental biology and medicine (Maywood, N.J.) (Exp Biol Med (Maywood)) Vol. 243 Issue 2 Pg. 184-189 (01 2018) ISSN: 1535-3699 [Electronic] England
• PMID: 29307284 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Review)

Chemical References

• Cosmetics
• Xenobiotics

Topics

• Animals
• Cosmetics (toxicity)
• Disease Models, Animal
• Environmental Exposure
• Escherichia coli (growth & development, metabolism)
• Genome-Wide Association Study
• Gram-Negative Bacterial Infections (complications)
• Humans
• Liver Cirrhosis, Biliary (etiology, pathology, physiopathology)
• Mice, Inbred C57BL
• Sphingomonadaceae (growth & development, metabolism)
• Urinary Tract Infections (complications)
• Xenobiotics (toxicity)