Northwestern Medicine investigators have uncovered a missing link behind the harmful effects of autoantibodies linked to blood clots, pregnancy complications and other inflammatory conditions, according to a new study published in the Proceedings of the National Academy of Sciences.
The findings offer new details on how the immune system can turn against the body’s own protective mechanisms, said Ming Zhao, PhD, associate professor of Medicine in the Division of Cardiology and senior author of the study.
“There are diverse autoimmune diseases associated with certain types of phospholipids in the cell membrane. One of these, called anti-phosphatidylethanolamine (aPE), was first reported in the late 1980s, but since then, there have been few data or pieces of evidence that explain the mechanism of the disease,” Zhao said.
In the study, the investigators focused on autoantibodies that work against phosphatidylethanolamine (PE), a common phospholipid found in cell membranes. These anti-PE (aPE) antibodies have long been associated with thrombosis and obstetric disorders, but their exact mechanism of action remained unclear.
Unlike other well‑characterized autoimmune antibodies, aPE antibodies appeared to require an unknown “cofactor” to exert damaging effects.
Using a combination of biochemical purification techniques and functional experiments, the investigators identified that missing cofactor as C4b‑binding protein (C4BP), a critical regulator of the immune complement system, which is part of the body’s first line of defense.
The complement system helps eliminate pathogens, but it must be tightly controlled to prevent damage to healthy tissue. C4BP plays a central role in this control by acting as a natural brake on complement activation, Zhao said.
“This process is associated with innate immunity, which is called the complement system. Within the complement system, there are key regulators, because you don’t want your immunity to go haywire under disease conditions,” Zhao said.
Next, the team discovered that when aPE antibodies bind to C4BP, they interfere with its protective function, effectively removing the brakes from the complement system, promoting inflammation and tissue damage — processes known to contribute to clot formation and pregnancy‑related complications.
In a model of renal ischemia‑reperfusion injury — a condition characterized by intense complement‑driven inflammation — mice treated with aPE antibodies exhibited significantly greater tissue damage.
“If you interfere with one of the key regulators of immunity, that tends to shift the system toward an overreactive immune response,” Zhao said. The damage was reduced when the mice were treated with an antibody that blocks C5, a downstream component of the complement system, however.
Together, the findings open the door to improved diagnostic tools that incorporate C4BP into testing platforms, potentially allowing for more accurate identification of patients at risk for thrombosis, pregnancy complications or other inflammatory issues linked to aPE antibodies.
“Before the discovery, it had been difficult for clinicians to make a diagnosis and to find the right treatment,” Zhao said. “Our discovery makes it possible to recognize the pathogenic mechanism of the disease.”
Drugs that target the pathway — some of which are already in clinical use for other conditions — could offer a viable treatment option for patients affected by aPE‑related disease.
“The next step is to identify exactly where these antibodies are targeting within this protein complex and how that affects its function at the molecular level,” Zhao said.
The discovery would not have been possible without interdisciplinary collaboration, Zhao said.
“This is a highly interdisciplinary, collaborative effort. It involves experts from Northwestern and other institutions, from practicing clinicians and immunologists to biochemists and protein scientists,” he said.
Songwang Hou, PhD, research assistant professor of Medicine in the Division of Cardiology, was first author of the study. Additional co-authors included Paul F. Lindholm, MD, professor of Pathology, Jungwha Lee, PhD, MPH, professor of Preventive Medicine, Rosalind Ramsey-Goldman, MD, the Gallagher Research Professor of Rheumatology, and Joshua M. Thurman, MD, professor of Medicine at the University of Colorado.
The study was supported by National Institutes of Health grant 5R21AI171491.
