Primary sclerosing cholangitis (PSC) causes scars in the bile duct. It’s a grisly, painful disease. Slowly and relentlessly, it progresses to liver failure, infections, and tumors. The pathophysiology is largely unknown. Liver transplantation is the only cure. Now there is hope in a recent breakthrough in understanding the disease. A new study establishes that mucosal-associated T (MAIT) cells have an important role in the pathophysiology of PSC that can have implications for treatment.
Bile ducts carry the digestive fluid bile from the liver to the small intestine. The inflammation of PSC causes scarring within the bile ducts, making them hard and narrow, gradually causing serious liver damage. Most people with PSC also have inflammatory bowel disease, such as ulcerative colitis or Crohn’s disease. Liver transplant is usually curative, but the disease may recur in the transplanted liver in a small number of patients.
The gut microbiome has been implicated in the pathophysiology of PSC. “MAIT cells are very prevalent in the liver, and they directly interact with microbial metabolites,” explains lead investigator Dr. Espen Melum, of the Norwegian PSC Research Center, Oslo University Hospital, in a statement.
“When it was recently reported that PSC patients had a distinct set of bacteria in bile, we wanted to explore whether bile contains major histocompatibility complex class I-related gene protein (MR1) restricted antigens that can be processed by cholangiocytes and presented to MAIT cells to initiate or modulate the immune response in inflammatory bile disease,” continues Melum, also with the Institute of Clinical Medicine and Hybrid Technology Hub-Centre of Excellence at the University of Oslo.
Researchers screened bile from 28 patients collected at the time of liver transplantation. They found that MAIT cells were activated by antigens in eight of the 28 samples, suggesting a role in regulating the immune response against bile-derived pathogens. The activation was partly MR1-dependent in five of the eight bile samples, implying the involvement of the MR1-T-cell receptor pathway.
The investigators also tested bile from seven patients with other chronic liver diseases to see if the presence of MAIT antigens in bile was specific to patients with PSC. Two of the seven bile samples activated MAIT antigens, but the activation was less intense and not MR1 restricted.
To determine if the MAIT cell–activating antigens were of microbial origin, all 35 bile samples in the study were screened by genetic sequencing. Microbial DNA was detected in 15 of the samples, and all the samples with bacterial colonization were from PSC patients. Of the eight MAIT cell–activating bile samples, microbial DNA was detected in five. and those five were the samples that activated MAIT cells in an MR1-dependent manner. Bacteria known to potently activate MAIT cells through T-cell receptor–mediated activation were identified in these samples.The scientists emphasized, however, that some of the bacteria found in the samples may have been altered with antibiotics.
“These data provide a mechanistic link between the immune system and the microbiome. Understanding biliary immunology is the key to developing new treatments for PSC. In this paper, we add a piece to this puzzle by demonstrating the presence of MAIT antigens in bile,” stated Melum.
These findings are presented in The American Journal of Pathology.