Circulating Autoantibodies in Age-Related Macular Degeneration Recognize Human Macular Tissue Antigens Implicated in Autophagy, Immunomodulation, and Protection from Oxidative Stress and Apoptosis.
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BACKGROUND: We investigated sera from elderly subjects with and without age-related macular degeneration (AMD) for presence of autoantibodies (AAbs) against human macular antigens and characterized their identity. METHODS: Sera were collected from participants in the Age-Related Maculopathy Ancillary (ARMA) Study, a cross-sectional investigation ancillary to the Health ABC Study, enriched with participants from the general population. The resulting sample (mean age: 79.2±3.9 years old) included subjects with early to advanced AMD (n = 131) and controls (n = 231). Sera were tested by Western blots for immunoreactive bands against human donor macular tissue homogenates. Immunoreactive bands were identified and graded, and odds ratios (OR) calculated. Based on these findings, sera were immunoprecipitated, and subjected to 2D gel electrophoresis (GE). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify the targets recognized by circulating AAbs seen on 2D-GE, followed by ELISAs with recombinant proteins to confirm LC-MS/MS results, and quantify autoreactivities. RESULTS: In AMD, 11 immunoreactive bands were significantly more frequent and 13 were significantly stronger than in controls. Nine of the more frequent bands also showed stronger reactivity. OR estimates ranged between 4.06 and 1.93, and all clearly excluded the null value. Following immunoprecipitation, 2D-GE and LC-MS/MS, five of the possible autoreactivity targets were conclusively identified: two members of the heat shock protein 70 (HSP70) family, HSPA8 and HSPA9; another member of the HSP family, HSPB4, also known as alpha-crystallin A chain (CRYAA); Annexin A5 (ANXA5); and Protein S100-A9, also known as calgranulin B that, when complexed with S100A8, forms calprotectin. ELISA testing with recombinant proteins confirmed, on average, significantly higher reactivities against all targets in AMD samples compared to controls. CONCLUSIONS: Consistent with other evidence supporting the role of inflammation and the immune system in AMD pathogenesis, AAbs were identified in AMD sera, including early-stage disease. Identified targets may be mechanistically linked to AMD pathogenesis because the identified proteins are implicated in autophagy, immunomodulation, and protection from oxidative stress and apoptosis. In particular, a role in autophagy activation is shared by all five autoantigens, raising the possibility that the detected AAbs may play a role in AMD via autophagy compromise and downstream activation of the inflammasome. Thus, we propose that the detected AAbs provide further insight into AMD pathogenesis and have the potential to contribute to disease biogenesis and progression.
Published Version (Please cite this version)
Iannaccone, Alessandro, Francesco Giorgianni, David D New, TJ Hollingsworth, Allison Umfress, Albert H Alhatem, Indira Neeli, Nataliya I Lenchik, et al. (2015). Circulating Autoantibodies in Age-Related Macular Degeneration Recognize Human Macular Tissue Antigens Implicated in Autophagy, Immunomodulation, and Protection from Oxidative Stress and Apoptosis. PLoS One, 10(12). p. e0145323. 10.1371/journal.pone.0145323 Retrieved from https://hdl.handle.net/10161/13283.
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Alessandro Iannaccone, MD, MS, FARVO is Professor of Ophthalmology and Director of the Center for Retinal Degenerations and Ophthalmic Genetic Diseases, which was established in 2016. Prior to joining Duke University, Dr. Iannaccone was an Associate Professor of Ophthalmology at the Hamilton Eye Institute in Memphis, TN, where he served as the founding Director of the Retinal Degenerations & Ophthalmic Genetics Service and the Lions’ Visual Function Diagnostic Lab since 1997.
Dr. Iannaccone received his medical degree from the University La Sapienza, Rome, Italy, where he also completed his residency in Ophthalmology, followed by fellowships on retinal degenerations with Dr. Jacobson at the Scheie Eye Institute, University of Pennsylvania and on pediatric retinal and optic nerve diseases at the University of Tennessee Health Science Center, where he subsequently also obtained a Masters in Biostatistics and Epidemiology.
He specializes in inherited and degenerative diseases of the retina and macula, including age-related macular degeneration, ophthalmic genetic diseases, autoimmune and paraneoplastic retinopathies and optic neuropathies, and other acquired conditions such as drug-induced retinal toxicity.
In addition to his clinical expertise, Dr. Iannaccone has more than 20 years of experience with visual function testing via electrophysiological and psychophysical methods, and retinal imaging. He has been an invited lecturer on nearly 75 occasions, and he has written, presented, and published extensively in these areas, with over 110 peer-reviewed manuscripts, nearly 40 other publications, including numerous book chapters, and nearly 190 meeting presentations. In 2019, Dr. Iannaccone also co-edited the book entitled, “Handbook of Clinical Electrophysiology of Vision”, published by Springer Nature.
Over the years, Dr. Iannaccone has mentored nearly 70 students, residents, clinical and research fellows, and international visiting ophthalmologists. In addition to lecturing residents and fellows for many years on retinal degenerations and ophthalmic genetics, since 2020 he also directs the Duke Clinical Fellowship Program in Retinal Degenerations and Ophthalmic Genetics. He has served as a reviewer for many peer-reviewed journals for numerous years, and more recently he has also been invited to serve as an Editorial Board Member for the journals, Translational Vision Science and Technology and Genes.
Dr. Iannaccone has served as a Scientific Advisory Board member for the Foundation Fighting Blindness (FFB), the Choroideremia Research Foundation, and the Blue Cone Monochromacy Families Foundation, served also on the Advocacy and Outreach Committee of the Association for Research in Vision and Ophthalmology (ARVO), of which he is a longtime member and a Silver Fellow.
He is a member of several other professional societies, including the American Academy of Ophthalmology (AAO), the International Society for Genetic Eye Disease and Retinoblastoma (ISGEDR), the International Society for Clinical Electrophysiology of Vision (ISCEV) and the Italian Society of Ophthalmology (SOI). Dr. Iannaccone was also the Co-Founder of the FFB’s Mid-South Chapter of Memphis, on which he has also served as Chair of the Educational Committee and President, and has been a longtime member of the Memphis Downtown Lions Club. He remains involved with the FFB fundraising activities in North Carolina, and he is presently a member of the Lions Club International.
Dr. Iannaccone’s research has received uninterrupted funding since 1998 through numerous grants, contracts, and awards from federal agencies, private foundations, and industry, including a K23 Award, an R21 and an R01 from the National Eye Institute, a Career Development Award from Research to Prevent Blindness (RPB), and the prestigious RPB’s Physician Scientist Award. He also received the ARVO/Alcon Clinician-Scientist Research Award. He has been serving for over 15 years as Site PI for numerous multicenter clinical studies and trials focused primarily on inherited retinal and macular diseases. Lastly, he is a Key Opinion Leader (KOL) consultant for numerous companies involved in efforts to develop treatments and cures for inherited retinal and macular diseases.
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