Antigenic mimicry of ubiquitin by the gut bacterium Bacteroides fragilis: a potential link with autoimmune disease

The bacterium Bacteroides fragilis is a member of the normal human gut microbiota and the only bacterium known to encode a homologue of eukaryotic ubiquitin. Ubiquitin is highly conserved across eukaryotes and is essential for normal eukaryotic cell function. The B. fragilis gene appears to have entered the bacterial genome by horizontal gene transfer from a eukaryotic source. It encodes a protein (BfUbb) with 63% identity to human ubiquitin which is exported from the bacterial cell. The aim of this study was i) to determine if there was antigenic cross-reactivity between B. fragilis ubiquitin and human ubiquitin and ii) to determine if humans produced antibodies to BfUbb. Molecular model comparisons of BfUbb and human ubiquitin predicted a high level (99.8% confidence) of structural similarity. Linear epitope mapping identified epitopes in BfUbb and human ubiquitin that cross-react. BfUbb also has epitope(s) that do not cross-react with human ubiquitin. The reaction of human serum (n= 474) to BfUbb and human ubiquitin from patients who had tested positive for suspected autoimmune diseases; negative for specific IgE; had an ulcerative colitis diagnosis and healthy volunteers was compared by ELISA. Some individuals had a higher level of antibodies to BfUbb than human ubiquitin while others had high levels of antibodies to both. Serum from patients referred for first-time testing to an Immunology Laboratory for autoimmune disease are more likely to have a high level of antibodies to BfUbb than healthy volunteers. Molecular mimicry of human ubiquitin by BfUbb could be a trigger for autoimmune disease.