This week we profile a recent publication in Science from Dr. Jessica Hamerman (pictured, right)
and Holly Akilesh (pictured, left) at Benaroya Research Institute at Virginia Mason.
Can you provide a brief overview of your lab’s current research focus?
We’re focused on understanding how the innate immune response is regulated during infection, inflammation, and autoimmune disease. We are interested in understanding how mature myeloid cells initiate the inflammatory response, and how inflammation influences how these cells develop, with an emphasis on macrophages and dendritic cells. Our work will not only shed light on how the inflammatory response is regulated during infection, but will also inform us on how to manipulate the innate immune system to achieve more efficient elimination of pathogens, yet limit inflammatory and autoimmune diseases.
What is the significance of the findings in this publication?
Our research team discovered a unique type of cell linked with a life-threatening complication of viral and autoimmune diseases. Macrophage activation syndrome, or MAS, is an inflammatory condition that leads to anemia. In addition to anemia, people with MAS suffer persistent fevers, headaches, large lymph nodes and, in severe cases, organ dysfunction or death.
The cells we discovered are macrophages we called “inflammatory hemophagocytes” (iHPCs), because they are only seen during inflammation and they eat red blood cells causing anemia. Our team was able to show that the iHPCs develop under the influence of two specific proteins, TLR7 and TLR9, that recognize infection and are associated with autoimmune disease. We also found that iHPCs develop during malaria infection, another situation with severe anemia, drawing a parallel between MAS and severe malarial anemia, the second leading cause of death in children with malaria. Not only do we see iHPCs develop and eat red blood cells in both MAS and malaria, but the same signaling pathways drive these cells in both diseases.
Our discovery demonstrates that if we can interfere with the development of these iHPCs, we’ll be able to treat MAS, severe malarial anemia as well as other dangerous forms of inflammation-associated anemia. So, our discovery could lead to new treatments for MAS in patients with systemic juvenile idiopathic arthritis (SJIA), Kawasaki disease and lupus, as well as in children with severe malaria.
This work was a large collaborative effort between many scientists, led in my group by Holly Akilesh, PhD. We also had other collaborators at BRI, at the University of Washington in Immunology and Rheumatology as well as at the Feinstein Institute for Medical Research in New York.
What are the next steps for this research?
Next steps will involve collaborations with pediatric rheumatologists here in Seattle and elsewhere in the US to look for iHPCs in the blood of people with autoimmune disease related anemia. We are also examining iHPCs in blood from children in Africa with malaria. We are also continuing to study the signaling pathways driving iHPC development to allow us to identify additional therapeutic targets to interfere with iHPC development and function.
This research was funded by:
This work was supported by NIH T32 AR007108 and an American Association of Immunology Fellowship, NSF Graduate Research Fellowship DGE-0718124, NIH T32 AI007044-39, NIH T32 AI106677, NIH R21 CA195256, DOD BCRP W81XWH-08-1-0570, Lupus Research Alliance, NIH R01 DK09369, NIH R01 AI118803, NIH R01 AI081948, NIH R01 AI113325, and NIH R21 AI138067, and NIH R21 ES024437.