autoimmune disease Archives - Sanford Burnham Prebys
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How our immune system controls gut microbes

AuthorMiles Martin
Date

April 6, 2022

And how this relationship could help fight autoimmune diseases

Sanford Burnham Prebys researchers including Carl Ware, PhD, and John Šedý, PhD have discovered an immunological process in the gut that could help improve treatment for autoimmune and gastrointestinal diseases. The study, published March 22 in Cell Reports, found that this process regulates the activation of white blood cells in the intestines, which ultimately helps the body control the composition of the gut microbiome. 

“The immune system is like a gardener for our gut bacteria, gently monitoring and responding to their populations and keeping an eye out for unwanted pathogens” says Ware, who directs the Infectious and Inflammatory Diseases Center at Sanford Burnham Prebys. “This ultimately helps the immune system control these microbes.”

This “gardening” relies on a molecule called BTLA, one of several checkpoint proteins used by the body to control the immune system. 

“This is a signaling system we’ve known about for decades, but this is a totally new function for it that we’ve never seen before,” says Šedý, a Sanford Burnham Prebys research assistant professor, who co-led the study with Ware. “I helped discover this system two decades ago, so it’s exciting that we’re still making new discoveries about its function.”  

To explore the role of BTLA in the gut, the team zeroed in on specialized lymph nodes in the intestines called Peyer’s patches, which are full of white blood cells that help monitor and respond to pathogens and other microbes in the gut.

“Gut bacteria are in constant competition, and the populations of specific species can fluctuate,” says Ware. “In a healthy microbiome, there’s a balance, and disrupting that balance can contribute to autoimmune diseases, gastrointestinal disorders and even some brain disorders.”

The team found that BTLA is critical for maintaining this balance because it triggers white blood cells to release antibodies that control the populations of different gut bacteria.

“It’s a finely calibrated system that we’re still only just beginning to understand in detail,” adds Ware.

Immune checkpoints like BTLA are already used in immunotherapy for some cancers, and these results make the researchers confident that this system can be leveraged to treat diseases in the gut, especially those that are also autoimmune disorders, such as Crohn’s disease or ulcerative colitis. 

“The immune system is unimaginably complex, and understanding it gives us the ability to manipulate it, and that can help us treat diseases,” says Šedý. “This discovery is a step forward in that larger narrative.” 

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5 lessons I’ve learned from rheumatoid arthritis and why I’m grateful to scientists who can change my world

AuthorMonica May
Date

June 26, 2019

Angela Durazo was a rising star triathlete—racking up age-group wins and corporate sponsorships. Then a diagnosis with rheumatoid arthritis, an autoimmune disorder caused by the immune system attacking healthy tissue, turned her life upside down. Here, she shares her story—including her new journey as a race car driver—and explains why research taking place at Institutes such as Sanford Burnham Prebys is critical to developing medicines that could help her and the 350 million people worldwide who live with the condition. 

I never thought of myself as an athlete. I was a cheerleader in high school and then participated in basketball for fun, but I wasn’t invested in the sports. Then some years and trials and tribulations later, seeking to find strength within myself, I accepted an invitation to cheer on a friend and I witnessed a triathlon. 

Instantly something spoke to me. The grit, determination, discipline. I was immediately enamored. I needed to do one, but I didn’t know if I could do it. All I knew was I had to try. And so I did. And it was in triathlon, where I truly found myself. Until a diagnosis rocked my world. 

Before I was diagnosed—a journey in itself—I’d never heard of rheumatoid arthritis (RA). No one in my family had it. No one in my life had it. However, I would soon come to find what living with this disease meant. I wouldn’t wish it on my worst enemy. 

First, I noticed stiffness in my hands when I woke up. I thought I might have slept on them wrong. But it kept happening night after night after night. Then it started affecting my workouts. During my runs, I started feeling like I had sandbags strapped around my legs. Unspeakable, unrelenting pain in my arm started. It felt—and still feels during a flare up—like someone is scraping my bone with a hot knife.  

Unable to keep up with training due to the pain and fatigue, I retired from triathlon after seven years. Little did I know the journey that would unfold next—taking me through dozens of doctors, two more career changes (I had a brief endeavor in acting in which I won a Best Actress Award for lead actress in an International feature film) and ultimately leading me to my life’s passion: race car driving. 

My experience continues to teach me so much. Now, nearly ten years after my diagnosis, I feel like I’ve finally crawled my way out of hell. To a healthy person, that may sound like an exaggeration. But to anyone who struggles with RA or any chronic diseases, they will know exactly what I mean.

Here are five lessons I have learned as a person reclaiming my life despite living with RA:

Trust yourself. I knew in my heart that something was deeply wrong. However, as a young, seemingly healthy athlete, doctors thought I was simply overtraining. One even floated the idea that I was a hypochondriac (I won’t repeat what I told that doctor.) Finally, after a year and a half of doctor visits, I stumbled across the term “rheumatoid arthritis” on the Internet. I convinced my doctor to test for RA and I finally had my answer. It couldn’t come soon enough: At this point my hands had begun to puff and distend (ulnar deviation). 

RA is a disability. When I started competing in paratriathlons, created for people with physical disability, some people questioned if I was really disabled. What these individuals didn’t understand is that—even though invisible from the outside—RA caused permanent damage to my mobility. In addition to the arthritis, it eroded my tendons and bursas (fluid-filled sacs that cushion the bone). Even when medicated, I couldn’t rely on my body. One day you can be fine and the next day you aren’t. One day I could run like a gazelle and the next day I feel like I have sandbags on my legs. My coach and those closest to me saw these effects firsthand. In fact, arthritis is a leading cause of work disability in the U.S., according to the Centers for Disease Control and Prevention (CDC).

Your disease does not define you. I still get chills when I think about the moment that I sat in a Formula race car for the first time. This was eight years after my diagnosis. I felt like I had found my spirit that had been missing since my retirement from triathlon. Race car driving is tough on my hands—Formula cars do not have power steering, amplified by G-forces generated by driving more than 160 miles per hour. I have to work twice as hard to keep my strength up. But frankly, I would work three times as hard if needed. I am not letting RA prevent me from pursuing my passion. 

Develop healthy coping skills. Between doctors saying that you won’t walk again and often having to prove your illness, paying attention to mental health is incredibly important for people with RA or any chronic disease. I struggled deeply with depression—and at one point alcohol—and I know many others who also struggle with unhealthy coping mechanisms. Find your support group. Go to therapy. I went to intensive trauma therapy for well over a year to accept the loss of my old body and learn how to embrace this new body with RA. One piece of advice that my trauma specialist told me which transcends any health condition: “RA has already taken so much from you, do not let it take anymore. Turn your pain into power and fight.”

When medicines fail, research is hope. New drugs such as biologics are wonderful. I was incredibly hopeful when I first learned about them. But they only work for one-third of patients. For the other two-thirds of the RA population, we are left figuring it out on our own. And there is so much we don’t know—from what triggers the immune system’s attack to why certain people respond to treatments and others don’t. Get engaged in your research foundations. Attend events. Join Facebook groups. And don’t be afraid to ask questions. YOU are your biggest advocate.

I took this year off racing to heal my body with an experimental treatment, which is working. Now, I’m recalibrating and looking forward to next year’s adventure—IndyCar development—and taking some podiums! 

I believe whole heartedly that one-day we will have a cure for RA. Until then, I hope that others with RA know they aren’t alone, and that as long as autoimmune research advances at Institutes such as Sanford Burnham Prebys, we have hope for the future.

Read more about Angela Durazo at Today.com or watch her share her story.

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An evening with autoimmune disorder experts

AuthorMonica May
Date

June 26, 2019

On June 20, 2019, nearly 100 community members, including many people living with autoimmune disorders and their loved ones, joined us at our latest SBP Insights event. The discussion featured unique perspective from three experts—a scientist, a doctor and a patient—on a single topic: autoimmune disorders. 

More than 50 million Americans have an autoimmune disorder, such as Crohn’s disease, psoriasis or rheumatoid arthritis. These conditions are often painful, chronic and debilitating. For unknown reasons, more than 80 percent of these patients are women. 

Scientists know these disorders occur when the immune system mistakenly attacks healthy tissue. But researchers still don’t understand why immunosuppressive treatments don’t work for everyone or know the initial trigger that causes the immune system to misfire. Answers to these fundamental questions could unlock insights that lead to new, effective medicines. 

“Before I was diagnosed, I thought doctors had it all sorted out. Now I know there is so much they don’t know,” says 17-year-old Madison Koslowski, who was diagnosed last year with juvenile idiopathic arthritis. She uses a wheelchair and cane for mobility while she works with her doctor to find a treatment that relieves her intense joint pain. “Right now, my friends are planning their future and figuring out where they will go to college. But for me, there are so many unknowns. I don’t know if I’m going to respond to the next medicine we try or if I will be really sick. I feel like my life is on pause. I have no idea when it will start again.”

17-year-old Madison Koslowski (right), who was diagnosed last year with juvenile idiopathic arthritis, poses with race-car driver Angela.
17-year-old Madison Koslowski (right), who was diagnosed last
year with juvenile idiopathic arthritis, poses with race-car
driver Angela.

Madison traveled from Los Angeles with her mother and a friend to hear race-car driver Angela Durazo speak about her journey with rheumatoid arthritis and learn what’s on the horizon for autoimmune treatments (read Angela’s story).

Following Angela’s presentation, Carl Ware, PhD, professor and director of the Infectious and Inflammatory Diseases Center at Sanford Burnham Prebys, took the stage and provided an overview of the science behind autoimmune disease. Ware also described his ongoing research collaboration with Eli Lilly, which recently led to a new Phase 1 clinical trial for autoimmune disorders. 

Hal Hoffman, MD, chief, division of allergy, immunology and rheumatology at UCSD and Rady Children’s Hospital, wrapped up the discussion with an overview of how he and his team are turning to rare immune disorders to understand the conditions as a whole. A Q&A followed the brief presentations. 

The discussion was moderated by Zaher Nahle, PhD, CEO of the Arthritis National Research Foundation.

Join us at our next SBP Insights discussion, which focuses on pancreatic cancer and takes place on November 21, 2019. Event details.

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Immune therapy enters Phase 1 clinical trial

AuthorMonica May
Date

November 15, 2018

Sanford Burnham Prebys Medical Discovery Institute (SBP) today announced that the first healthy subject has been dosed in a Phase 1 clinical trial evaluating LY3361237, a biologic that inhibits inflammation by activating an immune checkpoint receptor. LY3361237 arose from a research collaboration between Eli Lilly and Company (Lilly) and SBP formed in 2015 that seeks to discover and develop new immunological therapies. 

Diseases such as lupus, psoriasis and rheumatoid arthritis result from dysfunction of the immune system. Many of these conditions are characterized in part by immune checkpoint failure, resulting in the immune system attacking normal tissue. Previous studies have shown that activating checkpoint receptors can suppress inflammation and restore immune balance—indicating its therapeutic potential. More than 80 diseases are caused by the immune system attacking the body’s own organs, tissues and cells, according to the National Institutes of Health (NIH).  

“Today’s milestone is an important step forward for patients who suffer from autoimmune disease,” says Carl Ware, PhD, director of the Infectious and Inflammatory Diseases Center at SBP. “This advance also illustrates how the fundamental understanding of a biological process—in this case, the role of checkpoint receptors in immune function—can translate to the development of new medicines.”

“Immunological disorders—many of which disproportionately impact women—affect millions of people around the world and remain an area of great medical unmet need,” adds Ajay Nirula, MD, PhD, vice president of Immunology at Lilly. “Our collaboration with SBP is a powerful example of how uniting complementary areas of expertise—deep foundational scientific knowledge from SBP combined with expertise in protein engineering, immunobiology and clinical development from Lilly— can lead to a promising new candidate to treat autoimmune disorders.”

The study will evaluate the safety, tolerability and pharmacokinetics of LY3361237 in healthy subjects. Further information about the trial can be found on ClinicalTrials.gov using the Identifier NCT03695198.

Interested in keeping up with SBP’s latest discoveries, upcoming events and more? Subscribe to our monthly newsletter, Discoveries.

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Rheumatoid arthritis drug works by restoring balance to immune cells

AuthorJessica Moore
Date

September 29, 2016

In rheumatoid arthritis, the immune system’s patrollers—T cells—see the membrane that surrounds joints as a threat, and engage other immune cells to destroy it. Worse, those misguided T cells become hyperactive. Instead of dying when they should, they continue to fuel inflammation that breaks down the joint tissue.

Scientists led by Salvatore Albani, MD, PhD, an adjunct professor in the Immunity and Pathogenesis Program, have now found a way to return these manic, long-lived T cells to normal—and conveniently, in a drug called hydroxychloroquine, which is already approved to treat symptoms of rheumatoid arthritis. The new results are published in the European Journal of Immunology.

“Hydroxychloroquine is already being used to treat various autoimmune diseases including rheumatoid arthritis,” said Albani. “But, by revealing its mechanisms, we will now be able to develop a better drug for these disabling diseases.”

Rheumatoid arthritis is one of the most common autoimmune diseases, affecting 1.5 million adults in the U.S. Severe joint pain, swelling and stiffness make it challenging for patients to accomplish everyday tasks, and many are easily fatigued. Even with new treatments that have become available in recent years, only 20-40% of patients can keep symptoms at bay over the long term.

 

In the new study, Albani and his team wondered how overactive T cells survive in rheumatoid arthritis. They realized that the cells might require more energy and molecular building blocks than they could generate using standard metabolic pathways. An important cellular process called autophagy—the breakdown of large molecules and organelles for reuse, which is ramped up during starvation—was the first place they thought to look.

Just as they suspected, rates of autophagy were higher in the T cells of patients with rheumatoid arthritis, compared with healthy individuals. Applying hydroxychloroquine to those T cells restored their normal lifespans. The researchers also used a well-established mouse model of rheumatoid arthritis to show that hydroxychloroquine reduced joint swelling.

According to Albani, not all patients respond to hydroxychloroquine. “We think it may work best at early stages of the disease, when T cells are most important,” he said. “We plan to further explore that possibility, as well as ways to improve the outcomes of treating rheumatoid arthritis with autophagy inhibitors.”

The paper is available online here.

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Study reveals protein that dials immune responses up and down

AuthorJessica Moore
Date

May 25, 2016

Research led by scientists at the Sanford Burnham Prebys Medical Discovery Institute (SBP) has identified a new regulator of immune responses. The study, published recently in Immunity, sheds new light on why T cells fail to clear chronic infections and eliminate tumors. The findings open the door for a new approach to modulating T cell responses in many clinical settings, including infections, autoimmune diseases, and tumors that are unresponsive to currently available therapies. Continue reading “Study reveals protein that dials immune responses up and down”

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Scientists find optimal method for generating regulatory T cells to treat autoimmune disease

Authorjmoore
Date

March 11, 2016

While we normally think of T cells as recognizing invaders, their roles are more complex. For example, some T cells, called regulatory T cells (Tregs) suppress conventional T cells’ immune responses. Because conventional T cells can escape normal controls and drive autoimmune diseases such as rheumatoid arthritis and type 1 diabetes, as well as rejection of transplants, Tregs are increasingly viewed as a way to rein in autoimmune diseases. Continue reading “Scientists find optimal method for generating regulatory T cells to treat autoimmune disease”

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New insight on the development of T cells that promote autoimmune disease

Authorjmoore
Date

February 8, 2016

Generally, T cells, the policemen of the body, activate immune responses upon finding infected or diseased cells, but some T cells respond the same way to normal cells in the body. If unchecked, such T cells can cause autoimmune diseases such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. These self-reactive T cells are a recently discovered type of T cell, the TH17 cell. Preventing young T cells from becoming TH17 cells is of major interest as a means to treat autoimmune diseases. Continue reading “New insight on the development of T cells that promote autoimmune disease”