Viacheslav Kriachkov:

I am a research officer at WEHI, working in the Epigenetics and Development division. I first met Zhen when he gave a division seminar on DNA mutations in September last year. I was interested in getting his expertise on proteins that cause mutations in our DNA.

To better comprehend human disease, there are two types of DNA mutations that we must understand: germline and somatic. Germline mutations are inherited from our parents while somatic mutations occur after we are born. Somatic mutations can occur in any cell except for the sperm and egg cells and therefore can’t be passed onto children. We know that these ‘acquired’ alterations can lead to cancer and other diseases.

Autoimmune diseases, like rheumatoid arthritis and multiple sclerosis, arise when our immune cells start attacking healthy organs and tissues. While some inherited genetic mutations are known to lead to a higher risk of developing autoimmune diseases, we think that some acquired mutations can also lead to the development of these diseases.

I was planning to apply for the Jenny Tatchell Awards for Blue Sky Research and asked if Zhen wanted to get involved. These awards fund high risk, high reward new ideas and innovative approaches from WEHI’s early career researchers –it’s wonderful to have this kind of support for our big ideas.

We plan to identify the parts of our genome that are most sensitive to acquiring mutations and learn if these could be linked to autoimmune disease development.

To do this, we’re looking into B cells These are white blood cells that are an integral part of our adaptive immune system, which recognises and remembers germs and fights them better next time. The main function of B cells is to produce antibodies against foreign pathogens, and in the process they can express an enzyme (known as AICDA) that mutates DNA. We think this could make B cells particularly sensitive to mutations.

This project has many moving parts and we’re planning to do several experiments with human B cells. Currently, I’m preparing the B cells for experimentation and designing libraries and protocols for them. Zhen will be even more involved when we try to capture and identify mutations.

Zhen Xu:

I’m proud that two research officers from different teams –Viacheslav from epigenetics and myself from the Blood Cells and Blood Cancer division – can come together and collaborate on a shared interest of DNA, proteins, autoimmune diseases and cancer.

Our project is increasingly important as there are over 80autoimmune disorders known to date that can affect multiple organs and tissues in our body. Our incomplete understanding of the immune system makes it extremely difficult to unravel the mechanisms of autoimmune diseases.

Once Viacheslav has developed the bank of B cells we will look closely at a B cell-specific protein that plays an essential role in the adaptive immune system, known as AID.

When AID doesn’t work correctly it can cause acquired genetic mutations that can lead to cancer. One of these is a type of blood cancer called diffuse large B cell lymphoma. In around half of all patients with this cancer, there are signs of the protein AID making mistakes.

This finding implies that it’s not only genetic mutations we’re born with that can cause autoimmune diseases, but also those we pick up during life. This is especially important to study because B cells that have the AID protein are prone to acquiring these mutations.

The mutations we’re looking for in this study and their related DNA areas can help us figure out how self-reactive cells, which mistakenly attack the body’s healthy cells, avoid immune checkpoints. These checkpoints make sure our immune cells don’t overreact and cause autoimmune disease. They can also be exploited by cancer cells to evade immune surveillance.

This information will help other researchers study self-reactive B cells from patients, allowing them to test this idea more. Ultimately, our study will give us important clues about how AID mutations in B cells might lead to autoimmune diseases.

Investigating how acquired mutations could explain a missing piece of autoimmune genetics from a cancer biology lens is a new concept, one that not many people have studied. We hope to gain insights and data that could help better diagnose and treat patients with autoimmune diseases in the future.

We’re incredibly grateful for Jenny Tatchell’s support and flattered our research was chosen. It truly allows us to dive deep into our project and design a complex experiment that otherwise may have been overlooked.

It also gives us confidence and confirmation that our idea is a good one, and we can make a difference to those with autoimmune diseases.