Turning the Tide in Lupus Research

Jane Buckner, MD, and Jeffrey Carlin, MD

As people who are affected by lupus know, it is one of the most puzzling and complex autoimmune diseases, say Benaroya Research Institut­­­e scientists and Virginia Mason clinical researchers. Diagnosis is difficult because it can affect all the systems of the body. Current treatments haven’t effectively treated the many symptoms of lupus and they have significant side effects.

“The manifestations of the disease are so varied, there are no two people alike,” says Jeffrey Carlin, MD, head of BRI clinical research for lupus and member of the Virginia Mason rheumatology section. “But good things are on the horizon for people with lupus. Scientists are discovering much more about the disease and how it works. New drugs, currently in development, will target the immune system more specifically, making them more effective, with fewer side effects.”

BRI’s approach to research takes all the complex elements of autoimmune diseases into consideration. “We not only go broadly, but we go deeply,” says BRI President Jane Buckner, MD. “We study genetics, we develop in-depth knowledge of the immune response, we discover how the immune system operates in people with lupus compared to those without disease and we translate our knowledge to clinical trials. Our patients provide feedback that goes back to the laboratory and that improves the treatments. That’s how we do science — in a deep, extensive continuous improvement loop.”

Dr. Buckner is a rheumatologist who sees people with lupus at Virginia Mason every week. “It’s a very difficult disease, and we’re dedicated to improving the care of our patients and ultimately curing lupus,” she emphasizes. “The answer will be in finding diverse ways to rebalance a person’s immune system so it doesn’t cause lupus.”

How Lupus Occurs

Typically, the immune system fights off infections and bacteria to keep the body healthy, but in autoimmune diseases, the immune system makes a mistake and attacks the body’s own cells and tissues. In lupus, the body attacks parts of dying cells throughout the entire body that would normally be quickly cleared away. This triggers the adaptive cells in the immune system to turn on and produce antibodies that can produce inflammation in blood vessels, skin, membranes, brain, nerves and kidney.

Other autoantibodies attach themselves to blood cells producing low red cell counts, white cell counts and platelet counts. People can suffer from fatigue, fever, joint pain, a butterfly-shaped rash on the face, skin lesions, shortness of breath, chest pain, headaches, confusion, memory loss, blood clots and bleeding problems. Symptoms vary from person to person, can flare off and on and can range from mild to life-threatening.

Though the cause of lupus is unknown, scientists have discovered three different factors that play a role in triggering lupus. These are genetic risks that predispose people to lupus; hormones — the disease is nine times more common in women; and environmental factors such as a virus, smoking, UV light and drugs.

How the Immune System Works

The immune system has two arms that respond when an infection such as a virus occurs. The “innate” immune system is the part that responds first and is always present and ready to fight an infection. This part sounds the alarm so the first responders -— much like the firefighters — come on the scene. The firefighters then pull a major fire alarm that communicates to other cells that they need to respond. These alarms are the cytokines, and they alert the “adaptive” part of the immune system to take action. The adaptive part of the immune system eliminates the infection. In this system, the B cells produce antibodies that bind to the virus to clear it from the body, but they can’t do it without the help of the T cells. The T cells help orchestrate the B cells, telling them what to do and shutting down the immune response when the virus is gone.

Genetics Play A Major Role

“Genes are an important part of lupus,” says Karen Cerosaletti, PhD, principal investigator, who has researched genetics for 20 years at BRI and who has focused on lupus. “If you have a sibling with lupus, you are 20 times more likely to have the disease compared with the general population,” she notes. “Genes affect every part of the immune system in lupus. Genes tell us the pathways that are important in lupus that we could target for treatment. Genes that are found in lupus may also be involved in other autoimmune diseases, and we can apply what we learn in lupus to other diseases.”

Karen Cerosaletti, PhD

In Dr. Cerosaletti’s recent research, she found that the BANK1 lupus gene increases the number of B cells in your body. When these B cells go amiss, they can make antibodies that recognize dying cells, starting the cycle of immune destruction causing lupus. “This gene predisposes your body to lupus, and this pathway could be a target for treatment,” she stresses.

A recent study at BRI in collaboration with Seattle Children’s Research Institute has shown how a variation in the gene IFIH1 increases the risk of lupus, while also protecting people from viruses. “This type of information helps us to understand why these genes are so common, and also helps us create more targeted treatments for lupus,” says Dr. Buckner, a leader of the study.

Finding Ways to Break the Lupus Cycle

“The signals that turn on the fire alarm in lupus are small proteins called cytokines,” says Jessica Hamerman, PhD, BRI principal investigator. Made by cells of the “innate” part of the immune system, cytokines are usually made in fast bursts to direct the B cells to make antibodies to fight an infection. “In lupus, the cytokines don’t get turned off and they amplify the response and feed the fire,” she explains. “When the B cells make antibodies that bind to the dying cells, it causes innate cells to make even more cytokines. The cells are activated again and again by the cytokine alarm, creating a vicious cycle.”

Dr. Hamerman researches how particular cells of the innate part of the immune system, called plasmacytoid dendritic cells, produce cytokines when they see dying cells, to signal the fire alarm. In lupus, important cytokines are called type 1 interferons. “It’s hard to block the type 1 interferons once they’re released from plasmacytoid dendritic cells, so we study how these cells interpret the signals from dying cells to make these cytokines. Then maybe we can interfere in the signal so they don’t make the interferons or make less of them. That would take the oxygen out of the fire or break the cycle.”

In studying all of the signaling steps in plasmacytoid dendritic cells, Dr. Hamerman and her team discovered a novel protein that controls the production of type 1 interferon and could be a target for therapies. “We’ve studied the protein in model systems and now in human samples from the BRI biorepository with exciting results,” she says. Dr. Hamerman’s study on cytokines just happened to connect to lupus — a disease that affected her grandmother.

Discovering New Pathways for Treatment

BRI Principal Investigators Adam Lacy-Hulbert, PhD, and Mridu Acharya, PhD, study how cells make the bad decision to attack the body’s own cells. Dr. Lacy-Hulbert studies cells of the innate immune system called dendritic cells, which organize communications. “We research how dendritic cells make the decision to react to foreign materials or the body’s own cells and how they communicate it to the immune cells,” he says.

Dr. Acharya studied with Dr. Lacy-Hulbert and applied the knowledge to B cells in lupus. They are taking the information they are learning in model systems and applying it in human samples. “The B cells of people with lupus are hyperactive, causing inflammation and damage to tissues,” says Dr. Acharya. “We have discovered a new molecular pathway in lupus that includes certain proteins that normally work together to prevent B cells from targeting a person’s own cells, but it doesn’t function properly when people develop lupus. We want to understand why these proteins fail in lupus and potential treatments to get them working properly again.”

Dr. Acharya will use the BRI biorepositories to study this in people with lupus and healthy people to see the differences. She recently was among the ten researchers who received a Novel Research Grant from the Lupus Research Alliance to pursue this line of inquiry.

Stopping Activation of Lupus

T cells can help B cells become activated and make antibodies. To understand the role of T cells in lupus, BRI scientists in the laboratory of Principal Investigator Bill Kwok, PhD, can identify the specific targets of these T cells using a novel technology developed at BRI called tetramers.

Tetramers capture the specific T cells that recognize dying cells in the blood of patients with lupus. Scientists can then describe the distinctive features of these T cells to find out how they go amiss. Preliminary results show that lupus specific T cells grow and divide, making more disease-specific T cells in a subset of patients with lupus. Dr. Kwok’s lab is further investigating the role of these T cells in the disease process.

Testing New Therapies Through Clinical Trials

BRI and Virginia Mason are also on the forefront of testing new drugs for lupus. “Within the year, we should have several new clinical trials for patients that will test new drugs targeting the pathways of lupus,” says Dr. Carlin. “We are also a part of the Lupus Clinical Investigators Network.” This group works to facilitate the clinical study of new and existing therapies to treat, cure and ultimately prevent lupus. This provides more clinical trials for Virginia Mason patients with lupus to hopefully expand treatment options.

“Through our lupus biorepository, where we collect volunteers’ blood samples and medical histories, we can also learn more about the variance of lupus in different people,” says Dr. Carlin. “Some may be more affected genetically, or in B cells or T cells. If we know that, we can tailor medicine to each person.”

BRI has a Clinical Research Registry people can join to be informed of clinical trials that may be appropriate for them.

People with lupus and family members without lupus can also join the biorepository to help with medical research.

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