The role of complement system, especially membrane attack complex (MAC) - the final product of complement activation, in wet-type age-related macular degeneration (AMD) has been established by Dr. Bora's group. In this study, we first investigated the interactions among MAC, chemokine (C-C motif) ligand 2 (CCL2) and vascular endothelial growth factor (VEGF) that occur in vivo during the development of choroidal neovascularization (CNV), which is the hall-mark of wet-type AMD. Our results demonstrated that during laser-induced CNV in C57BL/6 mice, MAC, CCL2 and VEGF are formed and/or expressed in the following order: MAC → CCL2 → VEGF. Neutralization experiments demonstrated that MAC is an upstream mediator and the effect of MAC on the development of laser-induced CNV can be attributed to its direct effect on VEGF as well as its effect on VEGF that is mediated by CCL2. Next, we studied the levels of MAC and its regulator - CD59, as well as the activity of three complement activation pathways, in the serum of patients with wet-type AMD and age-matched controls. We observed that the levels of MAC were significantly elevated while the levels of CD59 were decreased in the serum of patients with wet-type AMD. Complement pathway activity assay demonstrated that complement system is activated via the alternative pathway, but not the classical or lectin pathways, in the patients with wet-type AMD. Collectively, the results derived from our study would lead to a better understanding of the immuno-pathogenesis of wet-type AMD and are required for the development of effective therapy and/or diagnostic tools.
|Advisor:||Bora, Nalini S.|
|Commitee:||Bora, Nalini S., Bora, Puran S., Chang, Jason Y., Gilbert, Kathleen M., Soderberg, Lee SF|
|School:||University of Arkansas for Medical Sciences|
|Department:||Microbiology and Immunology|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 73/10(E), Dissertation Abstracts International|
|Keywords:||Macular degeneration, Membrane attack complex|
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