Sickle cell disease can lead to a severe complication known as acute chest syndrome (ACS), but the underlying mechanisms are not well understood. A new study by Mass General Brigham investigators identified an ancient immune pathway that is activated in patients with ACS and serves as a key driver of the disease. Blocking this pathway with clinically approved drugs alleviated disease severity in preclinical models. The results are published in Science Translational Medicine .
"Despite ACS being the leading cause of mortality in patients with sickle cell disease, we can currently only offer supportive care to our patients," said corresponding author Sean Stowell, MD, PhD, of the Department of Pathology at Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system. "Our study offers potential targets for therapeutic intervention for this devastating condition."
Sickle cell disease occurs due to an inherited mutation in hemoglobin that causes the destruction of red blood cells (RBCs), or hemolysis. This, in turn, can block blood vessels, injure the lungs, and eventually progress into ACS—a condition that includes shortness of breath, chest pain and wheezing that can quickly progress and turn fatal. Prior research has suggested that hemolysis can activate the complement system — a group of immune proteins that trigger a cascade of events to eliminate pathogens. However, it has been unclear how the complement system contributes to ACS and disease progression.
The research team analyzed blood samples from 27 patients with sickle cell disease and detected higher baseline levels of complement activation when compared to healthy controls. They also observed increased complement activation in patients experiencing ACS. Using a mouse model of sickle cell disease, the investigators found that the complement pathway helped cause the breakdown of red blood cells, indicating that factors other than mutated RBCs may be contributing to the symptoms of sickle cell disease.
They also found that the breakdown of red blood cells caused by complement activation created a cycle of even more activation, which led to ACS. By removing certain complement proteins or using existing drugs to block them, researchers were able to reduce the breakdown of red blood cells and prevent ACS in their studies with animal models.
The authors propose that randomized clinical trials could be conducted to see if complement inhibitors that target different parts of the pathway could be effective in patients with ACS.
Authorship: In addition to Stowell, Mass General Brigham authors include Connie M. Arthur, and Ryan P. Jajosky. Additional authors include Satheesh Chonat, Jayre A. Jones, Seema R. Patel, William M. Briones, Michelle L. Schoettler, Maya Maarouf, Lauren A. Jeffers, Olufolake Adisa, Fang Tan, Earl Fields, Morgan S. Sterling, Hans Verkerke, Sara H. Graciaa, Elisabetta M. Foppiani, Ross M. Fasano, Patricia E. Zerra, Yongzhi Qiu, Wilbur A. Lam, Solomon F. Ofori-Acquah, Michael Koval, Clinton H. Joiner, and David R. Archer.
Paper cited: Chonat S et al. "Complement is activated in patients with acute chest syndrome caused by sickle cell disease and represents a therapeutic target" Science Translational Medicine DOI: 10.1126/scitranslmed.adl4922
