For the past twenty years, our research has focused on the mechanisms by which tissue injury occurs when the immune system is misdirected to attack itself. When foreign substances or particles termed antigens (Ags) enter the bloodstream, they are targeted by antibodies (Abs). The combination of Ag and Ab is called an immune complex (IC). IC in turn trigger the activation of the complement cascade that can destroy targeted microbes. 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 laboratory's discovery that red blood cells (E) intercept complement coated IC (IC-C3b) in the bloodstream and safely transport them to the liver has been widely accepted as the fudamental immunologic mechanism and is described in detail in most Immunology books.

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. This part of the Ab is referred to as the variable (V) domain due to variations in the amino acid sequence between different Abs required to react with millions of different types of Ags. The remaining portion is called the constant (C) region in which amino acid sequence is relatively invariant. 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.

Selected Publications

 

• Yokoyama, I., and F.J. Waxman. 1993. Clonal variations in complement activation and deposition of C3b and C4b on model monoclonal immune complexes. Immunology. 80:167-176.
  
  
• Gibson, N and F.J. Waxman. 1994. Relationship between immune complex binding and release and the quantitive expression of the complement receptor, type 1 (CR1, CD35) on human erythrocytes. Clinical Immunol. and Immunopath. 70:104-113.
  
  
• White, K.W. M.B. Frank and F.J. Waxman. 1996. Effect of immunoglobulin variable domain structure on C3b and C4b deposition. Molecular Immunology. 33:759-768.
  
  
• White, K.W. and F.J. Waxman. 1997. Ig N-glycan orientation can influence interactions with the complement system. Journal of Immunology. 158:426-435.
  
  
• Gonzalez, M.L. and F.J. Waxman. 2000. Glomerular deposition of immune complexes made with IgG2a monoclonal antibodies. Journal of Immunology. 164:1071-1077.