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Yan Li, Dawn Smith, Qing Li, Nader Sheibani, Suber Huang, Timothy Kern, Ram H. Nagaraj, Feng Lin; Antibody-Mediated Retinal Pericyte Injury: Implications for Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(9):5520-5526. doi: 10.1167/iovs.12-10010.
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To test the hypothesis that autoantibodies against retinal pericytes could develop in diabetic retinopathy, and that these autoantibodies could induce retinal pericyte dysfunction/death via complement.
Human primary retinal pericytes cultured in media containing normal (5 mM) or high (30 mM) glucose concentrations were incubated with normal human sera in the presence of a retinal pericyte-reactive antibody, then their viability was assessed by a BCECF-based cytotoxicity assay, and their function was assessed by a T-cell proliferation assay. The pericytes were also analyzed by RT-PCR and flow cytometry to detect CD38, an established diabetes-associated cell surface autoantigen. The potential of the anti-CD38 antibodies in inducing pericyte cellular injury was evaluated using the same cytotoxicity assays. In addition, autoantibody-mediated cytotoxicity in mouse retinal pericytes sensitized by sera from mice with developing diabetic retinopathy or control normal mice were also studied.
Retinal pericyte–reactive antibodies induced cellular damage by activating complement in the serum. The antibody-injured pericytes had reduced efficacy in inhibiting T cells. Hyperglycemic culture conditions rendered pericytes more susceptible to antibody-mediated attack. CD38 was expressed in retinal pericytes, and upregulated by TNF-α and IFN-γ, and anti-CD38 antibodies induced pericyte cytotoxicity. Retinal pericytes sensitized with sera from chronic diabetic mice suffered significantly augmented cytotoxicity compared with those sensitized with sera from the control mice.
The autoantibody-initiated complement activation could be a mechanism underlying the loss of function, and eventually, death of retinal pericytes in diabetic patients, suggesting that inhibiting complement activation could be a novel therapeutic approach.
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