September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Circulating autoantibodies in age-related macular degeneration (AMD) recognize human macular tissue antigens implicated in immunomodulation, protection from oxidative stress and apoptosis, and autophagy
Author Affiliations & Notes
  • Alessandro Iannaccone
    Ophthalmology/Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Marko Z. Radic
    Microbiology, Immunology and Biochemistry, Univ Tennessee Health Sci Ctr, Memphis, Tennessee, United States
  • Sarka Beranova-Giorgianni
    Pharmaceutical Sciences, Univ Tennessee Health Sci Ctr, Memphis, Tennessee, United States
  • Nataliya Lenchik
    Internal Medicine/Endocrinology, Univ Tennessee Health Sci Ctr, Memphis, Tennessee, United States
  • TJ Hollingsworth
    Ophthalmology/Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Ivan Gerling
    Internal Medicine/Endocrinology, Univ Tennessee Health Sci Ctr, Memphis, Tennessee, United States
  • Francesco Giorgianni
    Pharmaceutical Sciences, Univ Tennessee Health Sci Ctr, Memphis, Tennessee, United States
  • Footnotes
    Commercial Relationships   Alessandro Iannaccone, None; Marko Radic, None; Sarka Beranova-Giorgianni, None; Nataliya Lenchik, None; TJ Hollingsworth, None; Ivan Gerling, None; Francesco Giorgianni, None
  • Footnotes
    Support  Supported by NEI/NIH grant 1R01EY022706 and Research to Prevent Blindness, Inc. New York, NY (Physician Scientist Award to AI and unrestricted grant to UTHSC Ophthalmology/Hamilton Eye Institute), a UTHSC College of Pharmacy Seed Grant (FG), and from an NIH grant S10RR16679 and UTHSC College of Pharmacy for LTQ mass spectrometer. Human donor tissue was provided by the Mid-South Eye Bank and the National Disease Research Institute (NDRI).
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 6560. doi:
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      Alessandro Iannaccone, Marko Z. Radic, Sarka Beranova-Giorgianni, Nataliya Lenchik, TJ Hollingsworth, Ivan Gerling, Francesco Giorgianni; Circulating autoantibodies in age-related macular degeneration (AMD) recognize human macular tissue antigens implicated in immunomodulation, protection from oxidative stress and apoptosis, and autophagy. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6560.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To report on two new antigens recognized by serum auto-antibodies (AAbs) found in the serum of 131 AMD participants (compared to 245 unaffected subjects), to present evidence that these biomarkers discriminate well AMD from control sera, and to illustrate a mechanistic hypothesis for how the specific AAbs identified in our studies may play a role in AMD pathogenesis.

Methods : Protein lysates obtained from human macular full-thickness retina/ retinal pigment epithelium (RPE)/Bruch’s membrane/choroid punches were immunoprecipitated with a representative selection of AMD sera positive (n=28, 18 with advanced and 10 with early to mid-stage AMD) to WB testing to identify antigens targeted by AAbs using 2D gel electrophoresis (GE) and mass spectrometry (MS). MS methods have been previously reported (Lenchik et al. ARVO 2013, Abs. 4103). Two candidate antigens were confirmed by immunoprecipitation-WB (IP-WB) and by direct ELISA against recombinant proteins on 18 AMD and 16 control sera.

Results : Novel targets recognized by serum AAbs from AMD participants were shown to be Annexin A5 (ANXA5) and Protein S100-A9 (S100A9). Anti-ANXA5 autoreactivity was 0.44±0.03 in AMD samples and 0.24±0.01 in controls (p=0.0000001), and anti-S100A9 autoreactivity was 0.52±0.06 in AMD samples and 0.26±0.02 in controls (p=0.001). In 2x2 table analyses, ELISA reactivity against ANXA5 ≥0.3 [χ2=30.68, p=0.00003 by Fisher exact test; odds ratio (OR) = 48.00 (5.89–391.21, 95%CI)] and against anti-S100A9 ≥0.3 [χ2=6.51, p=0.026 by Fisher exact test; OR=5.42 (1.14–25.83, 95%CI)] was associated with much higher likelihood of having AMD. All these autoantigens share implications in immunomodulation, protection from oxidative stress and apoptosis, and in particular autophagy.

Conclusions : With the identification of anti-ANXA5 and anti-S100A9 AAbs, we have now characterized an array of six autoimmune biomarkers in AMD which include CD5L/AIM [New et al. IOVS 2014; 55: E-Abstract 65] and three heath shock proteins (HSPs), HSPA8 and HSPA9, two members of the HSP70 family, and HSPB4/CRYAA [Iannaccone et al. PLOS One 2015, in press]. We propose that these AAbs could contribute to AMD biogenesis and progression particularly (yet not only) by compromising autophagy and leading to activation of the inflammasome.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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