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July 28, 2022

Same cell, different problem: Learning how iHPCs lead to complications in autoimmune disease, malaria

A macrophage is an immune cell that’s like a vacuum, zooming around your body and cleaning up things like old cells and bacteria. But occasionally, macrophages get confused and start eating healthy red blood cells. This can lead to serious complications in diseases like lupus, systemic idiopathic juvenile arthritis (SIJA) and even malaria.

In 2019, a BRI team led by Jessica Hamerman, PhD, and Holly Akilesh, PhD, made a key breakthrough, discovering a specific type of macrophage that eats healthy red blood cells. They coined these cells “inflammatory hemophagocytes” (iHPCs). They also learned that these cells not only cause macrophage activation syndrome (MAS), a life-threatening complication of lupus and SJIA — they can also cause severe malarial anemia (SMA), a leading cause of death for kids with malaria.

Now, Hamerman Lab scientists including PhD candidate Natalie Thulin, Susana Orozco, PhD, and Susan Canny, MD, PhD, are exploring these cells in different settings. They aim to better understand how the cells develop and ultimately hope to find ways to stop them from causing severe health issues.

“iHPCs are a really interesting cell type. They are found in a number of inflammatory diseases and their activity is implicated in driving disease. Yet, we don’t fully understand what cues initiate and drive their development,” Natalie says. “If we can learn more about them it could eventually lead to better treatments and care for these serious complications.”

Why do iHPCs develop?

At the height of the pandemic, Natalie started conducting research in the Hamerman Lab as part of her doctoral studies. Determined to get her project up and running while maintaining social distance, she and Dr. Orozco worked together via Zoom — getting Natalie setup in the lab and honing her skills in an analysis approach called flow cytometry. Soon, she was closely examining iHPCs.

“We see these cells developing and responding as if there was an infection, but there is no infection,” Natalie says. “I’m trying to understand why that happens. Why are they eating healthy cells and what damage are they causing?”

Natalie’s research is examining the development of iHPCs and disease progression in a disease model of MAS. This model causes MAS by manipulating an immune sensor called TLR7, which normally helps fight off viruses by detecting them and starting infection-fighting inflammation. In the MAS disease model, there is over production of TLR7 and it triggers inflammation when there is no virus — causing too much inflammation and ultimately leading to iHPC development and MAS. Natalie is working to understand why this happens. She’s starting by looking at a gene called Irf5, has been linked to MAS and the development of iHPCs.

So far, in her MAS disease model, she’s found that less Irf5 gene expression reduces the number of iHPCs that develop and prevents the development of MAS.

Next, she plans to do an experiment that isolates cells before they become iHPCs. She’ll examine if factors like inflammatory cytokines (a type of protein) or byproducts of red blood cells encourage or stop them from becoming iHPCs.

Do iHPCs lead to complications of malaria?

Dr. Orozco studies iHPCs in malaria, a disease caused by infection with Plasmodium parasites, which impacts millions of people worldwide. She’s working to understand if iHPCs are among the factors that can lead to SMA

“Improving treatments and better understanding how and why SMA happens is very important because it can be deadly,” Dr. Orozco says. “With malaria, it often impacts pregnant women and young children. When children under 5 get SMA, their likelihood of surviving is low.”

Dr. Orozco aims to better understand how and why iHPCs develop in lab models of malaria and if similar cells exist in human disease. She’s also investigating if these cells exist for a reason and help the immune system in some way — or if they just contribute to disease.

“We might be able to slow down overactive immune responses or create a targeted therapy to treat or prevent SMA, but first we need to understand exactly how and why it happens,” she says.

Improving care for kids with juvenile arthritis

Dr. Canny, a pediatric rheumatologist at Seattle Children’s, sees a handful of patients with MAS each year. Her goal is to determine how to diagnose MAS faster and to find treatments with fewer side effects. That’s why she splits her time between patient care and research in the Hamerman Lab at BRI.

Right now, she’s investigating several research questions including trying to understand whether iHPCs circulate through the body. Researchers have found them in the liver and bone marrow in samples from patients with MAS, but they’re not entirely sure how these cells move through the body and whether they can be detected in the blood. In lab models, her team has mapped how they circulate in the blood. Now she’s working to see if what they observed in lab models is true in people too.

She’s also investigating a process called TLR signaling. In lab models, this process proved to be very important in driving iHPCs to develop and ultimately cause disease. Now, she’s trying to see if this process holds true in human samples.

“Having a detailed understanding of how and why iHPCs develop could potentially help us diagnose MAS earlier and treat it sooner,” she says. “Being able to identify new and more targeted therapies without side effects like broad immunosuppression, eye problems, and significant weight gain is really important. That’s what drives me.”

Working together to find answers

Each month, these scientists and Dr. Hamerman come together to discuss ideas, new findings and more across their various projects.

“It’s fascinating to see where our work converges and diverges because sometimes we’re finding the exact same things and sometimes our findings are completely different,” Natalie says.

Natalie has enjoyed working with Dr. Orozco to share lab research findings and hone her skills with advanced research tools. Working with Dr. Canny has helped her zero in on questions most relevant to human disease.

“My work really focuses on these really basic mechanisms,” Natalie says. “Often, I’ll show [Dr. Canny] my work and she’ll say ‘focus on this — this is really important because this is something I see in patients.’”

This type of collaboration is what BRI is all about.

“We brainstorm together, we ask for input if we’re stuck on something,” Dr. Canny says. “We have this great collaboration of ideas and resources, we always ask each other ‘have you looked at this paper, have you thought about this?’ This team approach is really helping us move the science forward.”

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