June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Sera from subjects with age-related macular degeneration (AMD) exhibit strong autoreactivity against human macular Heat Shock Proteins (HSPs)
Author Affiliations & Notes
  • Alessandro Iannaccone
    Ophthal/Hamilton Eye Inst, Univ Tennessee Health Sci Ctr, Memphis, TN
  • David New
    Ophthal/Hamilton Eye Inst, Univ Tennessee Health Sci Ctr, Memphis, TN
  • Francesco Giorgianni
    Pharmaceutical Sciences, Univ Tennessee Health Sci Ctr, Memphis, TN
  • Nataliya Lenchik
    Ophthal/Hamilton Eye Inst, Univ Tennessee Health Sci Ctr, Memphis, TN
    Medicine/Endocrinology, Univ Tennessee Health Sci Ctr, Memphis, TN
  • Sarka Beranova-Giorgianni
    Pharmaceutical Sciences, Univ Tennessee Health Sci Ctr, Memphis, TN
  • Ivan Gerling
    Medicine/Endocrinology, Univ Tennessee Health Sci Ctr, Memphis, TN
  • Marko Radic
    Microbiology, Immunology and Biochemistry, Univ Tennessee Health Sci Ctr, Memphis, TN
  • Footnotes
    Commercial Relationships Alessandro Iannaccone, None; David New, None; Francesco Giorgianni, None; Nataliya Lenchik, None; Sarka Beranova-Giorgianni, None; Ivan Gerling, None; Marko Radic, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 815. doi:https://doi.org/
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      Alessandro Iannaccone, David New, Francesco Giorgianni, Nataliya Lenchik, Sarka Beranova-Giorgianni, Ivan Gerling, Marko Radic; Sera from subjects with age-related macular degeneration (AMD) exhibit strong autoreactivity against human macular Heat Shock Proteins (HSPs). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):815. doi: https://doi.org/.

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

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Abstract

Purpose: To report on the identity of novel anti-HSP serum auto-antibodies (AAbs) found in the serum of 131 AMD participants [previously identified via comparison of Western blots (WB) vs. 245 unaffected subjects, (Lenchik et al. ARVO 2013, Abs. 4103; Iannaccone et al. ARVO 2012, Abs. 2272)] and to show preliminary evidence that these biomarkers discriminate robustly AMD sera from control sera.

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). Three candidate proteins were confirmed by immunoprecipitation-WB (IP-WB) and by direct ELISA against recombinant proteins on 18 AMD and 16 control sera.

Results: Targets recognized by serum AAbs from AMD participants were shown to be two members of the HSP70 family, HSPA8 and HSPA9, as well as HSPB4, best known as alpha-crystallin A, or CRYAA. Anti-HSPA8 reactivity was 2.19-fold higher in AMD than controls (p=0.00006, 2-sided t-test), anti-HSPA9 was 1.97 fold higher (p=0.000294), and anti-HSPB4/CRYAA was 1.74 fold higher (p=0.0004). In 2x2 table analyses, ELISA reactivity over specific cut-offs was associated with much higher likelihood of having AMD (χ2>32, p≤0.00088 by Fisher exact test, and odds ratios ≥28.0) for all AAbs.

Conclusions: HSPs are molecular chaperones that prevent the accumulation of cellular cytotoxic protein aggregates and are involved in response to, and upregulated by oxidative stress. If the capacity of HSPs to repair protein damages is overwhelmed, then proteins are mainly cleared in proteasomes or in lysosomes. Increased HSP levels, including CRYAA, have been observed in aging or stressed RPE cells and in the RPE of AMD donor eyes, which is evidence for oxidatively stressed tissue. Thus, anti-HSP AAbs appear to be robust serum biomarkers of AMD mechanistically related to the oxidative stress that characterizes AMD. Our data also raise the possibility that pharmacological modulation of HSPs or inhibition of these anti-HSP AAbs may also represent treatment targets for AMD.

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