By M. Eric Gershwin, MD
University of California at Davis
Revised April 22, 2017
Defining the causes that lead to having PBC has been a priority of my work for over 30 years. Further, it is puzzling that a disease that targets only one cell population (i.e. the cholangiocyte) has autoantibodies (Antimitochondrial antibodies – AMA) that recognize a protein found in mitochondria which are identical in all our cells. We most recently provided evidence that is crucial to both these seminal questions.
1. In terms of disease susceptibility, PBC clearly fits the mold of a complex disease that is a condition in which multiple factors (hence the term multifactorial) contribute to causing its onset. Several observations suggest that genetics do play a role in PBC susceptibility albeit not in a strictly hereditary fashion.
First, PBC has a higher risk of being found among first-degree relatives of patients who have already been diagnosed, although a screening test for serum AMA should not be encouraged when one case is present in the family. Even though there is a family risk, it is very low.
Second, PBC will affect both subjects of only 2 out of 3 genetically identical twin pairs. Most likely, more than one gene is responsible for having PBC so neither parent is to be ‘blamed’.
Gene variants can be studied in a person’s DNA by studying polymorphisms (coined SNPs) which are the DNA changes that make each of us unique. There are over 10 million SNPs known in the human genome and most recently our group completed the largest study to investigate over 600,000 SNPs in 1500 subjects including patients with PBC and controls.
The results demonstrated that genes related with the immune response were strictly related to PBC. In particular, specific SNPs of HLA (which could be defined as the license plate of white blood cells) and of the interleukin 12 (IL12, which mediates the inflammation in the liver) were associated with PBC.
We should note that these genes were found only in a minority of patients with PBC and are not suitable for a genetic screening for PBC as advertised by some commercial companies for other complex diseases.
Recently there has been a major effort in a field called epigenetics. This is based on random events that modify our DNA over time and play a big role in immune function. Interestingly some of this work is based on some research, partially funded by the PBCers Organization.
Some of you may remember that about ten or so years ago I went everywhere to find twins with a history of PBC. We found that not all identical twins developed PBC. This suggested to us that genetics were important but so was environment and perhaps some of those environmental changes led to DNA modifications, so-called epigenetics. Most importantly, we started investigating several mice models of PBC and results are promising.
We now even have a mouse in which only female mice get PBC; the males are OK!! This has helped us identify immune pathways that theoretically can be blocked to help patient and I am so pleased to tell you that MANY PBC trials in patients are underway now all over the world to test new drugs and all based on our work with PBC mice.
2. One major step to explain the bile duct specificity of the immune-mediate injury in PBC was recently taken by Ana Lleo in our laboratory. Our study demonstrated that bile duct cells are the only cells in the human body which are capable to die through programmed death (i.e. apoptosis) and release the protein targeted by AMA in an intact form. Such protein is released as following chewing from all other cells and cannot be thus recognized by AMA. Conversely, the protein released by bile duct cells can be captured by specific immune cells called macrophages which could in turn initiate the inflammatory cascade that characterizes the PBC liver.
This has also led to some new drug testing and especially drugs that may prevent inflammatory cells from finding the liver and therefore reducing the inflammation.
My lab has been on the trail of a cure for PBC since 1985 and we will not stop until it is completed.