ALERT: This system is being upgraded on Tuesday December 12. It will not be available for use for several hours that day while the upgrade is in progress. Deposits to DukeSpace will be disabled on Monday December 11, so no new items are to be added to the repository while the upgrade is in progress. Everything should be back to normal by the end of day, December 12.

Show simple item record

Circulating Autoantibodies in Age-Related Macular Degeneration Recognize Human Macular Tissue Antigens Implicated in Autophagy, Immunomodulation, and Protection from Oxidative Stress and Apoptosis. Iannaccone, Alessandro Giorgianni, Francesco New, David D Hollingsworth, TJ Umfress, Allison Alhatem, Albert H Neeli, Indira Lenchik, Nataliya I Jennings, Barbara J Calzada, Jorge I Satterfield, Suzanne Mathews, Dennis Diaz, Rocio I Harris, Tamara Johnson, Karen C Charles, Steve Kritchevsky, Stephen B Gerling, Ivan C Beranova-Giorgianni, Sarka Radic, Marko Z Health ABC study
dc.coverage.spatial United States 2016-12-18T17:30:26Z 2015
dc.identifier PONE-D-15-38073
dc.description.abstract 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.
dc.language eng
dc.publisher Public Library of Science (PLoS)
dc.relation.ispartof PLoS One
dc.relation.isversionof 10.1371/journal.pone.0145323
dc.subject Apoptosis
dc.subject Autoantibodies
dc.subject Autoantigens
dc.subject Autophagy
dc.subject Blotting, Western
dc.subject Chromatography, Liquid
dc.subject Confidence Intervals
dc.subject Electrophoresis, Gel, Two-Dimensional
dc.subject Enzyme-Linked Immunosorbent Assay
dc.subject Humans
dc.subject Immunomodulation
dc.subject Macular Degeneration
dc.subject Odds Ratio
dc.subject Oxidative Stress
dc.subject Tandem Mass Spectrometry
dc.title Circulating Autoantibodies in Age-Related Macular Degeneration Recognize Human Macular Tissue Antigens Implicated in Autophagy, Immunomodulation, and Protection from Oxidative Stress and Apoptosis.
dc.type Journal article Iannaccone, Alessandro|0726621
pubs.begin-page e0145323
pubs.issue 12
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Ophthalmology
pubs.organisational-group Ophthalmology, Vitreoretinal Diseases & Surgery
pubs.organisational-group School of Medicine
pubs.publication-status Published online
pubs.volume 10
dc.identifier.eissn 1932-6203
duke.contributor.orcid Iannaccone, Alessandro|0000-0001-5737-8424

Files in this item


This item appears in the following Collection(s)

Show simple item record