The mammalian complement system is a critical host defense mechanism comprising more than 20 proteins and cellular receptors and more primitive versions of this system have been conserved through at least 600 million years of evolution. Our current efforts are directed to better understand how the Ab portion of the IC affects its interaction with the complement system. One portion of the Ab molecule is responsible for attaching to its target Ag. The C region is generally considered to be responsible for biological functions of the Ab such as complement activation. However, we have discoved that V domain sequence can affect complement activation within C region.
Abs are glycoproteins, containing sugars attached to protein.
Little is known about the physiologic role played by the Ab's sugar residues attached to the C region. We recenlty discovered that V domain residues can influence the orientation of the sugar residues attached to the C region of the Ab molecule. Interestingly, the molecular orientation of the Ab's sugars can, in turn, influence how well the Ab triggers the complement cascade. We are currently pinpointing the specific amino acid residues invlolved in modifying the orientation of the sugars and determining how Ab structure affects the localization of IC in organs such as the kidney that are vulnerable to injury by the immune system. We hope this research will permit us to discover ways to engineer Abs as more useful immunotherapeutics and to better understand the pathogenesis of diseases ranging from lupus to diabetes.