The immune system is an incredible feat of biology that works around the clock to protect us from disease. The human immune system has multiple strategies to deal with many different types of invaders. Unfortunately, this powerful protection system can sometimes get confused, work too hard and end up damaging our own cells. When this happens, a person gets diagnosed with what is called an autoimmune disease. Autoimmune diseases are a serious public health problem: the 100+ different autoimmune diseases affect over 20 million Americans (~80% of those people identify as women, and many autoimmune diseases are linked to socioeconomic conditions that lead to higher levels of stress)1,2.
A graphic illustrating the various parts of the body that can be affected by autoimmune disease. This image was licensed from Adobe.
Given the focus of our department on dissecting the mechanisms of and developing therapies for human disease, it may come as no surprise that we are home to a faculty member whose work is focused on autoimmune diseases: Dr. Paul Thompson, Director of the Program in Chemical Biology and Professor of Biochemistry & Molecular Biotechnology. Following up on his findings in the lab, Dr. Thompson has co-founded two pharmaceutical companies: Danger Bio, which seeks treatments for a variety of autoimmune disorders including lupus; and Padlock Therapeutics, which is committed to developing treatments for Rheumatoid Arthritis (RA) 3. RA is one of the most common autoimmune diseases, directly affecting approximately 14 million people around the world (lupus affects approximately 5 million people globally)4. Finding therapeutic solutions to RA could drastically improve the lives of millions of people.
What goes wrong in Rheumatoid Arthritis?
In RA, the immune system mistakenly attacks the cells of the patient (AKA the host)5. In RA patients, the immune system confuses antigens from the host (AKA autoantigens) for foreign antigens that signal the presence of an invader. Activated immune cells follow the trail of these mis-identified autoantigens to different parts of the body, where they begin to attack and kill the cells they find there. In RA, these are usually the cells that surround and protect our joints. As the immune cells attack, the joint becomes inflamed and can lead to pain, swelling and eventual bone erosion and joint deformity6. The inflammatory signals generated at the joints can also spread throughout the body and damage other tissues including the heart and blood vessels. These symptoms have a meaningful impact on the quality of life of the millions of patients with RA – in fact, major depressive disorder is anywhere from two to four times more common in patients with RA7.
A representation comparing hands that are unaffected (left) and affected (right) by rheumatoid arthritis. In the left unaffected hand, the protective joint tissue between bones is intact. In the right affected hand, the protective joint tissue is damaged, leading to bone misalignment and impaired hand function. Image licensed from Adobe.
But how do the immune cells get confused? And how can we either help them stop mis-identifying self-antigens or help dampen their inflammatory effects?
These are some of the questions Dr. Paul Thompson and his lab members are trying to answer. The research of our award-winning medicinal chemist focuses on a change that cells make to some of their proteins called citrullination. This small change to a protein can be likened to putting on brightly colored lipstick: it is a small change to a small area, but it has a big impact on how you are seen by those around you. Protein citrullination has important functions throughout the body8, but RA patients tend to have citrulline added to more of their proteins than the average person. In fact, the standard diagnostic test for RA is checking a patient’s blood for autoantibodies that recognize citrulline. This test can even diagnose patients before the onset of symptoms, suggesting an increase in protein citrullination is likely an important part of disease progression. This led scientists like Dr. Thompson to ask whether blocking or decreasing levels of citrullination could be part of a treatment for RA.
An illustration of components of the immune system contributing to RA and other autoimmune diseases. Three cells are shown at the left, alongside citrullinated proteins (reddish with blue tags) that are in the process of being recognized by autoantibodies (green). This then stimulates immune cells (beige, purple and yellow cells) to cause inflammation and tissue degradation. Illustration by Leonora Martínez Núñez, PhD.
How can we decrease harmful levels of citrulline?
The most effective way to decrease the amount of citrullinated proteins floating around is to block the activity of the enzymes that actually turn the molecules in proteins into citrulline. The family of Protein Arginine Deiminases or PADs (a chemical reaction called deimination of the amino acid Arginine is what makes citrulline, as shown below) are the enzymes responsible for adding citrulline to other proteins. Dr. Thompson’s lab has focused on designing drugs that block the activity of PADs.
To date, Dr. Thompson and his team have developed drugs that can block the activity of the entire PAD family all at once, and drugs that can individually target specific PAD family members. Using his chemistry background, Dr. Thompson leads his research team in the use of kinetic and structural analyses to guide the design of these inhibitors. For example, determining the structure of a specific PAD enzyme led to the discovery that PAD2 must bind calcium in a sequential manner to become active.
The chemical reaction that creates citrulline superimposed over the combined ribbon and space-filling structure of a PAD enzyme. Illustration by Leonora Martínez Núñez, PhD.
Using this information, the lab successfully designed several different compounds that affect PAD activity in cells in a dish and protect mice from developing RA symptoms9. These findings led Dr. Thompson to start a company called Padlock Therapeutics to continue identifying and testing PAD inhibitors. Acquired by Bristol-Myers Squibb in 201610, the science Padlock Therapeutics developed is currently progressing towards the clinic.
PAD inhibitors might do more than just treat RA.
Focusing drug design on the PADs to decrease protein citrullination is a particularly exciting strategy, since increased protein citrullination is actually found in more autoimmune diseases than RA. Lupus, multiple sclerosis, colitis, type I diabetes and psoriasis have also been linked to abnormal protein citrullination11. Dr. Thompson believes that PADs might be the key to treating multiple autoimmune diseases, as well as diseases like ALS and cancer.
Dr. Paul Thompson in his research lab. Photo courtesy of UMass Chan Medical School.
Dr. Thompson’s work is just one example of how fundamental biochemical research can potentially transform the clinic. This is exactly the focus and mission of our department: to advance our scientific knowledge and translate it to new therapeutic strategies. Click here to learn more about Dr. Thompson’s lab, and click here if you want to read about more transformative research happening in our department. If you’re interested in financially supporting Dr. Thompson’s work developing therapeutics for autoimmune diseases, click here.
