ug and Michael Lenardo was able to identify a total of 11 patients, and addressed the detailed molecular mechanisms: Absence of CD55 protein dampened a proper control of the complement system, an important component of innate immune defense, inducing proinflammatory cytokine signaling. Concomitantly, the researchers could show that loss of CD55 led to impaired production of IL-10, a key anti-inflammatory signaling molecule in the gut.
The combination of these effects lead to a severe clinical disease which may be life-threating: The over-functioning complement system collapses in the absence of regulatory IL-10 molecules. The observed bowel inflammation is an immediate consequence, enforced by the constant immune cell stimulation through the gut flora, where fine-tuned regulatory mechanisms are of particular relevance. Inflamed intestinal lymphatic vessels lead to loss of protein through blood plasma, a major disease manifestion of CD55 deficiency, accompanied by a risk of thrombosis.
After deciphering the molecular consequences of this particular genetic defect, the investigators aimed at identifying a potential targeted therapy for this condition, and were successful: A clinically approved drug that dampens complement activity could also be applied in case of absent CD55 protein.
“This disease is an ideal example for the importance of rare disease research,” says Kaan Boztug. “By investigating the molecular mechanisms underlying the disease, we are then able to strategically test for re-purposing approved medications for a personalized therapy. Furthermore, through investigating single genetic defects, we are able to unravel novel aspects of the biological function of the affected gene.”
The role of CD55 in maintaining bowel homeostasis was hitherto largely unexplored. Similarly, the molecular mechanisms underlying protein loss in the bowel – a process that plays a role in a wide array of diseases – were widely unknown. Here, the present study provided important insights that widen our understanding of the complex regulatory mechanisms of bowel homeostasis, which could eventually be relevant for other types of rare and common diseases.