gms | German Medical Science

Background: The formation of drusen at the macula and the degeneration of RPE cells is characteristic for AMD and represents the most common cause of blindness in developed countries. The ARMS2 variant at 10q26 (A69S, rs10490924) is strongly associated with AMD. This polymorphism is linked to a mutation in the 3’ untranslated region in the ARMS2 gene, which introduces an instability motif into the transcribed mRNA. So far the biological function of ARMS2 is still unclear and whether ARMS2 deficiency contributes to the disease.

Methodes: ARMS2 was recombinantly expressed in Pichia pastoris and purified via chromatography. The protein was investigated for cell binding proerties by incubation with different cell surfaces using flow cytometry. For the identification of the biological function, the recombinant ARMS2 protein was incubated with normal human serum and interacting proteins were identified by comassie staining and mass spectometry. Furthermore endogenous ARMS2 protein expression, location and interaction with properdin was evaluated in human retinal sections derived from ARMS2 genotyped individuals.

Results: We identified specific binding of the ARMS2 protein to the surface of human apoptotic and necrotic RPE and T cells, but not to living cells including human erythrocytes. Bound to the cell surface, ARMS2 recruits the complement activator properdin from the serum to the cell surface. Bound to ARMS2, properdin acts as a platform for C3 convertases, which enhances opsonization of the cell surface with complement C3b. ARMS2 interaction with purified and endogenous properdin is confirmed by laser scanning microscopy, by biolayer interferometry and by ELISA. Furthermore ARMS2 colocalizes with properdin in retinal sections after co-staining with ARMS2 antiserum and a monoclonal properdin antibody. In summary, surface bound ARMS2 interacts with the complement activator properdin and accelerates the opsonization of dead cells for phagocytosis.