Novosphingobium aromaticivorans: a potential initiator of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is characterized by a T-cell-mediated destruction of bile duct epithelial cells that line the small intrahepatic bile ducts. The targets of activated T-lymphocytes are the dihydrolipoamide acetyltransferase components of the 2 oxo acid dehydrogenases, enzyme complexes that are important in oxidative energy metabolism. Pyruvate dehydrogenase is the best known of these. Its dihydrolipoamide acetyltransferase component is referred to as PDC-E2. A major question in understanding the pathogenesis of PBC is why PBC patients lose their tolerance to antigens that are found in virtually every cell in the body. A possible cause is molecular mimicry between microbial agents and self-antigens. Infection with or exposure to a microorganism whose PDC-E2 bears close homology with human PDC-E2 could act as an immunological trigger that initiates the development of PBC. Emerging data suggest that there is a microorganism that may initiate the onset of PBC. Novosphingobium aromaticivorans is a gram negative strictly aerobic bacteria that is found worldwide in soil, water, and coastal plain sediments. Its PDC-E2-like proteins have a higher degree of homology with the immunodominant region of human PDC-E2 than any microorganism thus far studied (100-1,000 times greater than that of Escherichia coli). In addition, N. aromaticivorans can metabolize xenobiotics that are similar to the chemical compounds that react with sera from PBC patients. Some of these xenobiotics are immunologically related to lipoic acid, the cofactor that is at the active center of PDC-E2. Thus, N. aromaticivorans can theoretically break down self-tolerance in two ways: by molecular mimicry due to subclinical infection and by the metabolism of xenobiotics that are present in the environment. In an initial study, investigators found that antibodies against N. aromaticivorans were found in 77 of 77 PBC patients from Milan, Italy, who had antibodies to PDC-E2 and that the titers to N. aromaticivorans proteins were similar to those to human PDC-E2. The report in this issue of The American Journal of Gastroenterology confirms these earlier findings and demonstrates that exposure to N. aromaticivorans occurs in genetically different PBC patients from other regions. Thirteen of 14 Icelandic PBC patients who were AMA positive reacted against at least one of the 2 oxo acid dehydrogenase-E2 complexes. These observations provide additional evidence that exposure to N. aromaticivorans may trigger the development of PBC.