Advertisement

Increased Protein Citrullination as a Trigger for Resident Immune System Activation, Intraretinal Inflammation, and Promotion of Anti-retinal Autoimmunity: Intersecting Paths in Retinal Degenerations of Potential Therapeutic Relevance

  • Alessandro IannacconeEmail author
  • Marko Z. Radic
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1185)

Abstract

We present evidence that protein citrullination, a proinflammatory and immune system-activating posttranslational modification (PTM) of arginine residues mediated by peptidyl arginine deiminases (PADs), is elevated in mouse models of retinal degenerations. Together with the fact that the animal models that we investigated (and their human counterparts) exhibit also anti-retinal autoantibodies, we propose that retinal citrullination is an immunogenic trigger that activates the immune system both locally and systemically, contributing to disease pathogenesis. Consistent with this possibility, we show that PAD compromise reduces the severity of Mertk-related retinal degeneration. Thus, PAD inhibition may be as a potential treatment strategy for retinal degenerations.

Keywords

Citrullination Posttranslational protein modification Peptidyl arginine deiminase Immune system Autoimmunity Retinitis pigmentosa Age-related macular degeneration MERTK Disease pathogenesis Disease progression Treatment 

Notes

Acknowledgments

We thank Dr. TJ Hollingsworth, PhD, UTHSC Neuroscience Imaging Facility, for technical assistance with the histology sections of the double KO mice. This work was supported by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY, to the Duke Eye Center.

References

  1. Adamus G, Brown L, Schiffman J et al (2011) Diversity in autoimmunity against retinal, neuronal, and axonal antigens in acquired neuro-retinopathy. J Ophthalmic Inflamm Infect 1:111–121CrossRefGoogle Scholar
  2. Adamus G, Wang S, Kyger M et al (2012) Systemic immunotherapy delays photoreceptor cell loss and prevents vascular pathology in Royal College of Surgeons rats. Mol Vis 18:2323–2337PubMedPubMedCentralGoogle Scholar
  3. Bhattacharya SK (2009) Retinal deimination in aging and disease. IUBMB Life 61:504–509CrossRefGoogle Scholar
  4. Bhattacharya SK, Sinicrope B, Rayborn ME et al (2008) Age-related reduction in retinal deimination levels in the F344BN rat. Aging Cell 7:441–444CrossRefGoogle Scholar
  5. Bonilha VL, Shadrach KG, Rayborn ME et al (2013) Retinal deimination and PAD2 levels in retinas from donors with age-related macular degeneration (AMD). Exp Eye Res 111:71–78CrossRefGoogle Scholar
  6. Carboni G, Forma G, Bond AD et al (2012) Bilateral paraneoplastic optic neuropathy and unilateral retinal compromise in association with prostate cancer: a differential diagnostic challenge in a patient with unexplained visual loss. Doc Ophthalmol 125:63CrossRefGoogle Scholar
  7. Conlon TJ, Deng WT, Erger K et al (2013) Preclinical potency and safety studies of an AAV2-mediated gene therapy vector for the treatment of MERTK associated retinitis pigmentosa. Hum Gene Ther Clin Dev 24:23–28CrossRefGoogle Scholar
  8. Epstein RS, New DD, Hollingsworth TJ et al (2015) Defective mer-tyrosine kinase (mer-TK) function is associated with anti-arrestin and anti- interphotoreceptor retinoid-binding protein (IRBP) autoantibodies (AAbs) in Mer, Axl, Tyro3−/− (TAM) mice and in autosomal recessive retinitis pigmentosa (arRP) patients with a null MERTK mutation. Invest Ophthalmol Vis Sci 56:E-Abstract 169Google Scholar
  9. Ghazi NG, Abboud EB, Nowilaty SR et al (2016) Treatment of retinitis pigmentosa due to MERTK mutations by ocular subretinal injection of adeno-associated virus gene vector: results of a phase I trial. Hum Genet 135:327–343CrossRefGoogle Scholar
  10. Heckenlively JR, Solish AM, Chant SM et al (1985) Autoimmunity in hereditary retinal degenerations. II. Clinical studies: antiretinal antibodies and fluorescein angiogram findings. Br J Ophthalmol 69:758–764CrossRefGoogle Scholar
  11. Heckenlively JR, Aptsiauri N, Nusinowitz S et al (1996) Investigations of antiretinal antibodies in pigmentary retinopathy and other retinal degenerations. Trans Am Ophthalmol Soc 94:179–200PubMedPubMedCentralGoogle Scholar
  12. Heckenlively JR, Jordan BL, Aptsiauri N (1999) Association of antiretinal antibodies and cystoid macular edema in patients with retinitis pigmentosa. Am J Ophthalmol 127:565–573CrossRefGoogle Scholar
  13. Hollingsworth TJ, Radic MZ, Beranova-Giorgianni S et al (2018) Murine retinal citrullination declines with age and is mainly dependent on peptidyl arginine deiminase 4 (PAD4). Invest Ophthalmol Vis Sci 59:3808–3815CrossRefGoogle Scholar
  14. Iannaccone A, Vingolo EM, Tanzilli P et al (1994) Long-term results of a pilot study on thymopentin in the treatment of retintitis pigmentosa: pathophysiological considerations [Italian]. In: The IV National Congress of the Italian Association for Ocular Pharmacology (AISFO). MediConsult, CataniaGoogle Scholar
  15. Iannaccone A, Giorgianni F, New DD 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:e0145323CrossRefGoogle Scholar
  16. Iannaccone A, Hollingsworth TJ, Koirala D et al (2017) Retinal pigment epithelium and microglia express the CD5 antigen-like protein, a novel autoantigen in age-related macular degeneration. Exp Eye Res 155:64–74CrossRefGoogle Scholar
  17. Jones JE, Causey CP, Knuckley B et al (2009) Protein arginine deiminase 4 (PAD4): current understanding and future therapeutic potential. Curr Opin Drug Discov Devel 12:616–627PubMedPubMedCentralGoogle Scholar
  18. Kyger M, Worley A, Adamus G (2013) Autoimmune responses against photoreceptor antigens during retinal degeneration and their role in macrophage recruitment into retinas of RCS rats. J Neuroimmunol 254:91–100CrossRefGoogle Scholar
  19. New DD, Hollingsworth TJ, Giorgianni F et al (2015) The Cu/Zn+ superoxide dismutase knockout mouse (Sod1−/−), a model of age-related macular degeneration (AMD), exhibits anti-retinal autoantibodies (AAbs) and marked signs of intraretinal inflammation prior to onset of an AMD-like phenotype. Invest Ophthalmol Vis Sci 56:E-Abstract 3986Google Scholar
  20. Radhakrishnan SS, Laing AE, Adamus G et al (2009) Clinical characteristics of patients with auto-immune retinopathies (AIR) and neuropathies (AIN): differential diagnosis with retinitis pigmentosa (RP). Invest Ophthalmol Vis Sci 50:E-Abstract 975Google Scholar
  21. RetNet – Retinal Information Network. http://www.sph.uth.tmc.edu/Retnet/
  22. Rispoli E, Vingolo EM, Iannaccone A (1991) Thymopentin in retinitis pigmentosa. Evaluation of its possible therapeutical effects after 18 months of treatment, preliminary results. New Trends Ophthalmol 6:235–241Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Duke Eye Center, Duke University School of MedicineDurhamUSA
  2. 2.Department of Microbiology, Immunology and BiochemistryUniversity of Tennessee Health Science CenterMemphisUSA

Personalised recommendations