Complement and complement regulatory proteins in diabetes

In this chapter we have summarized the body of evidence that supports a role for the complement system and complement regulatory proteins in the pathogenesis of diabetic complications, with specific emphasis on the novel phenomenon of glycation-inactivation of CD59. Progress in this area has been remarkable considering that (1) ethical and practical issues preclude conducting in-depth mechanistic studies in humans, especially for chronic conditions such as the complications of diabetes that take years to develop and (2) non-clinical research is hampered due to the absence of animal models of diabetes that fully recapitulates diabetic vascular disease in the intensity and distribution seen in humans. Similar to other tightly regulated biological systems, phenotypic endpoints derived from complement activationdepend on the delicate balance between complement activators and inhibitors. In the specificcase of complement and its regulators, this “delicate balance” paradigm is well exemplifiedby the human disease Paroxysmal nocturnal hemoglobinuria (PNH), an acquired complement-mediated hemolytic anemia in which blood cells lack glucosylphosphatidylinositol (GPI)-anchored proteins including CD59 (Takeda et al., Cell 73:703-711, 1993; Parker et al., Stem Cells 14:396-411, 1996). Under “normal” conditions, the basal “tick-over” activation of complement is sufficient to induce only mild degree of hemolysis. In contrast, when stressors like infections amplify complement activation, excessive membrane attack complex (MAC) formation on unprotected red blood cells and platelets lacking CD59 results in “paroxysmal” crises of hemolysis, platelet activation and potentially lethal thrombotic episodes (Hill et al., Blood 121:4985-4996, 2013; Hillmen et al., N Engl J Med 355:1233-1243, 2006; Risitano et al., Immunobiology 217:1080-1087, 2012). The emerging clinical evidence summarized in this article indicates that comparable mechanisms could be operative in the pathogenesis of diabetes complications: on the one hand, biological responses to chronic hyperglycemia like formation of advanced glycated end-products (AGEs) and fructosamine adducts in proteins as well as auto-antibodies against oxidized and/or glycated proteins could activate complement while, on the other hand, glycation-inactivation of CD59 increases the susceptibility of tissues to complement (MAC) mediated damage.