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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2022

Open Access 01-12-2022 | Pigmentary Retinopathy | Research

Immunological consequences of compromised ocular immune privilege accelerate retinal degeneration in retinitis pigmentosa

Authors: K. Varsha Mohan, Alaknanda Mishra, Abaranjitha Muniyasamy, Prakriti Sinha, Parul Sahu, Ashwani Kesarwani, Kshama Jain, Perumal Nagarajan, Vinod Scaria, Manisha Agarwal, Naseem S. Akhter, Chanda Gupta, Pramod Upadhyay

Published in: Orphanet Journal of Rare Diseases | Issue 1/2022

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Abstract

Background

Retinitis pigmentosa (RP) is a hereditary retinal disease which leads to visual impairment. The onset and progression of RP has physiological consequences that affects the ocular environment. Some of the key non-genetic factors which hasten the retinal degeneration in RP include oxidative stress, hypoxia and ocular inflammation. In this study, we investigated the status of the ocular immune privilege during retinal degeneration and the effect of ocular immune changes on the peripheral immune system in RP. We assessed the peripheral blood mononuclear cell stimulation by retinal antigens and their immune response status in RP patients. Subsequently, we examined alterations in ocular immune privilege machineries which may contribute to ocular inflammation and disease progression in rd1 mouse model.

Results

In RP patients, we observed a suppressed anti-inflammatory response to self-retinal antigens, thereby indicating a deviated response to self-antigens. The ocular milieu in rd1 mouse model indicated a significant decrease in immune suppressive ligands and cytokine TGF-B1, and higher pro-inflammatory ocular protein levels. Further, blood–retinal-barrier breakdown due to decrease in the expression of tight junction proteins was observed. The retinal breach potentiated pro-inflammatory peripheral immune activation against retinal antigens and caused infiltration of the peripheral immune cells into the ocular tissue.

Conclusions

Our studies with RP patients and rd1 mouse model suggest that immunological consequences in RP is a contributing factor in the progression of retinal degeneration. The ocular inflammation in the RP alters the ocular immune privilege mechanisms and peripheral immune response. These aberrations in turn create an auto-reactive immune environment and accelerate retinal degeneration.
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Literature
1.
Grover S, Fishman GA, Anderson RJ, Alexander KR, Derlacki DJ. Rate of visual field loss in retinitis pigmentosa. Ophthalmology. 1997;104(3):460–5.PubMedCrossRef
2.
3.
Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. The Lancet. 2006;368(9549):1795–809.CrossRef
4.
McGee Sanftner LH, Abel H, Hauswirth WW, Flannery JG. Glial cell line derived neurotrophic factor delays photoreceptor degeneration in a transgenic rat model of retinitis pigmentosa. Mol Ther. 2001;4(6):622–9.PubMedCrossRef
5.
Yoshida N, Ikeda Y, Notomi S, Ishikawa K, Murakami Y, Hisatomi T, et al. Laboratory evidence of sustained chronic inflammatory reaction in retinitis pigmentosa. Ophthalmology. 2013;120(1):100–5.PubMedCrossRef
6.
Yoshida N, Ikeda Y, Notomi S, Ishikawa K, Murakami Y, Hisatomi T, et al. Clinical evidence of sustained chronic inflammatory reaction in retinitis pigmentosa. Ophthalmology. 2013;120(1):100–5.PubMedCrossRef
7.
Yoshida N, Ikeda Y, Notomi S, Ishikawa K, Murakami Y, Hisatomi T, et al. Relation between sustained chronic inflammatory reaction and oxidative damage in an animal model of retinitis pigmentosa. Investig Ophthalmol Visu Sci. 2013;54(15):658.
8.
9.
Whitcup SM, Nussenblatt RB, Lightman SL, Hollander DA. Inflammation in retinal disease. Int J Inflam. 2013;2013:724648.PubMedPubMedCentral
10.
Okita A, Murakami Y, Shimokawa S, Funatsu J, Fujiwara K, Nakatake S, et al. Changes of serum inflammatory molecules and their relationships with visual function in retinitis pigmentosa. Investig Ophthalmol Visu Sci. 2020;61(11):30.CrossRef
11.
Kumar M, Gupta RM, Nema HV. Role of autoimmunity in retinitis pigmentosa. Ann Ophthalmol. 1983;15(9):838–40.PubMed
12.
Iannaccone A, Radic MZ, editors. 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. Cham: Springer; 2019.
13.
Tonade D, Liu H, Kern TS. Photoreceptor cells produce inflammatory mediators that contribute to endothelial cell death in diabetes. Invest Ophthalmol Vis Sci. 2016;57(10):4264–71.PubMedPubMedCentralCrossRef
14.
Gregory MS, Repp AC, Holhbaum AM, Saff RR, Marshak-Rothstein A, Ksander BR. Membrane Fas ligand activates innate immunity and terminates ocular immune privilege. J Immunol. 2002;169(5):2727–35.PubMedCrossRef
15.
16.
Alekseev O, Adamus G, Iannaccone A. Inflammatory findings in autosomal recessive retinitis pigmentosa (ARRP) associated with EYS gene mutations. Investig Ophthalmol Vis Sci. 2021;62(8):3234.
17.
Epstein R, New D, Hollingsworth T, Meunier I, Lenchik N, Lu Q, et al. 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. Investig Ophthalmol Vis Sci. 2015;56(7):169.
18.
Salom D, Diaz-Llopis M, García-Delpech S, Udaondo P, Sancho-Tello M, Romero FJ. Aqueous humor levels of vascular endothelial growth factor in retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2008;49(8):3499–502.PubMedCrossRef
19.
20.
Forrester JV, Reid DM, Campbell AM. Autoimmunity and retinitis pigmentosa. Semin Ophthalmol. 1987;2(2):81–8.CrossRef
21.
Telias M, Denlinger B, Helft Z, Thornton C, Beckwith-Cohen B, Kramer RH. Retinoic acid induces hyperactivity, and blocking its receptor unmasks light responses and augments vision in retinal degeneration. Neuron. 2019;102(3):574-86.e5.PubMedPubMedCentralCrossRef
22.
Streilein JW. Ocular immune privilege: the eye takes a dim but practical view of immunity and inflammation. J Leukoc Biol. 2003;74(2):179–85.PubMedCrossRef
23.
Kyger M, Worley A, Adamus G. Autoimmune responses against photoreceptor antigens during retinal degeneration and their role in macrophage recruitment into retinas of RCS rats. J Neuroimmunol. 2013;254(1–2):91–100.PubMedCrossRef
24.
Garcia-Calderon PA, Engel P, Cols N, Heredia Garcia CD. Immune complexes in retinitis pigmentosa. Ophthalmic Paediatr Genet. 1984;4(3):199–202.PubMedCrossRef
25.
Heckenlively JR, Fawzi AA, Oversier J, Jordan BL, Aptsiauri N. Autoimmune retinopathy: patients with antirecoverin immunoreactivity and panretinal degeneration. Arch Ophthalmol. 2000;118(11):1525–33.PubMedCrossRef
26.
Shinomiya N, Kuratsuji T, Yata J. The role of T cells in immunoglobulin class switching of specific antibody production system in vitro in humans. Cell Immunol. 1989;118(2):239–49.PubMedCrossRef
27.
28.
McPherson SW, Heuss ND, Pierson MJ, Gregerson DS. Retinal antigen-specific regulatory T cells protect against spontaneous and induced autoimmunity and require local dendritic cells. J Neuroinflamm. 2014;11:205.CrossRef
29.
Mishra A, Das B, Nath M, Iyer S, Kesarwani A, Bhattacharjee J, et al. A novel immunodeficient NOD.SCID-rd1 mouse model of retinitis pigmentosa to investigate potential therapeutics and pathogenesis of retinal degeneration. Biol Open. 2017;6(4):449–62.PubMedPubMedCentral
30.
Han J, Dinculescu A, Dai X, Du W, Smith WC, Pang J. Review: the history and role of naturally occurring mouse models with Pde6b mutations. Mol Vis. 2013;19:2579–89.PubMedPubMedCentral
31.
Rajendram R, Saraswathy S, Rao NA. Photoreceptor mitochondrial oxidative stress in early experimental autoimmune uveoretinitis. Br J Ophthalmol. 2007;91(4):531–7.PubMedCrossRef
32.
33.
Ishida S, Usui T, Yamashiro K, Kaji Y, Ahmed E, Carrasquillo KG, et al. VEGF164 is proinflammatory in the diabetic retina. Invest Ophthalmol Vis Sci. 2003;44(5):2155–62.PubMedCrossRef
34.
Venters HD, Dantzer R, Kelley KW. A new concept in neurodegeneration: TNFalpha is a silencer of survival signals. Trends Neurosci. 2000;23(4):175–80.PubMedCrossRef
35.
Jiang X, McClellan SA, Barrett RP, Berger EA, Zhang Y, Hazlett LD. VIP and growth factors in the infected cornea. Invest Ophthalmol Vis Sci. 2011;52(9):6154–61.PubMedPubMedCentralCrossRef
36.
Streilein JW, Okamoto S, Sano Y, Taylor AW. Neural control of ocular immune privilege. Ann N Y Acad Sci. 2000;917:297–306.PubMedCrossRef
37.
Taylor AW, Ng TF. Negative regulators that mediate ocular immune privilege. J Leukoc Biol. 2018;103:1179–87.CrossRef
38.
39.
Kaur C, Foulds WS, Ling EA. Blood-retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog Retin Eye Res. 2008;27(6):622–47.PubMedCrossRef
40.
Leal EC, Martins J, Voabil P, Liberal J, Chiavaroli C, Bauer J, et al. Calcium dobesilate inhibits the alterations in tight junction proteins and leukocyte adhesion to retinal endothelial cells induced by diabetes. Diabetes. 2010;59(10):2637–45.PubMedPubMedCentralCrossRef
41.
Navaratna D, McGuire PG, Menicucci G, Das A. Proteolytic degradation of VE-cadherin alters the blood-retinal barrier in diabetes. Diabetes. 2007;56(9):2380–7.PubMedCrossRef
42.
Georgiadis A, Tschernutter M, Bainbridge JW, Balaggan KS, Mowat F, West EL, et al. The tight junction associated signalling proteins ZO-1 and ZONAB regulate retinal pigment epithelium homeostasis in mice. PLoS ONE. 2010;5(12):e15730.PubMedPubMedCentralCrossRef
43.
Aveleira CA, Lin CM, Abcouwer SF, Ambrosio AF, Antonetti DA. TNF-alpha signals through PKCzeta/NF-kappaB to alter the tight junction complex and increase retinal endothelial cell permeability. Diabetes. 2010;59(11):2872–82.PubMedPubMedCentralCrossRef
44.
Campbell M, Humphries M, Kennan A, Kenna P, Humphries P, Brankin B. Aberrant retinal tight junction and adherens junction protein expression in an animal model of autosomal dominant Retinitis pigmentosa: the Rho(−/−) mouse. Exp Eye Res. 2006;83(3):484–92.PubMedCrossRef
45.
46.
Gattegna R, Bleicher I, Iannaccone A. Emerging Phenotypic Characteristics and Identification of Novel Mutations in Autosomal Recessive Retinitis Pigmentosa (ARRP) Associated with the EYS Gene. Investig Ophthalmol Visu Sci. 2019;60(9):4508.
47.
Lueck K, Carr AF, Stampoulis D, Gerke V, Rescher U, Greenwood J, et al. Regulation of retinal pigment epithelial cell phenotype by Annexin A8. Sci Rep. 2017;7(1):4638.PubMedPubMedCentralCrossRef
48.
Sun D. Retinal pigment epithelial cells activate uveitogenic T cells when they express high levels of MHC class II molecules, but inhibit T cell activation when they express restricted levels. J Neuroimmunol. 2003;144(1–2):1–8.PubMedCrossRef
49.
50.
Noda K, Nakao S, Zandi S, Sun D, Hayes KC, Hafezi-Moghadam A. Retinopathy in a novel model of metabolic syndrome and type 2 diabetes: new insight on the inflammatory paradigm. FASEB J. 2014;28(5):2038–46.PubMedPubMedCentralCrossRef
51.
Salom D, Diaz-Llopis M, Quijada A, García-Delpech S, Udaondo P, Romero FJ, et al. Aqueous humor levels of hepatocyte growth factor in retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2010;51(6):3157–61.PubMedCrossRef
52.
Brinkman CJ, Pinckers AJ, Broekhuyse RM. Immune reactivity to different retinal antigens in patients suffering from retinitis pigmentosa. Invest Ophthalmol Vis Sci. 1980;19(7):743–50.PubMed
53.
Elner VM, Elner SG, Standiford TJ, Lukacs NW, Strieter RM, Kunkel SL. Interleukin-7 (IL-7) induces retinal pigment epithelial cell MCP-1 and IL-8. Exp Eye Res. 1996;63(3):297–303.PubMedCrossRef
54.
55.
56.
Streilein JW. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol. 2003;3(11):879–89.PubMedCrossRef
57.
58.
Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8(6):e1000412.PubMedPubMedCentralCrossRef
59.
van Wyk M, Schneider S, Kleinlogel S. Variable phenotypic expressivity in inbred retinal degeneration mouse lines: a comparative study of C3H/HeOu and FVB/N rd1 mice. Mol Vis. 2015;21:811–27.PubMedPubMedCentral
Metadata
Title
Immunological consequences of compromised ocular immune privilege accelerate retinal degeneration in retinitis pigmentosa
Authors
K. Varsha Mohan
Alaknanda Mishra
Abaranjitha Muniyasamy
Prakriti Sinha
Parul Sahu
Ashwani Kesarwani
Kshama Jain
Perumal Nagarajan
Vinod Scaria
Manisha Agarwal
Naseem S. Akhter
Chanda Gupta
Pramod Upadhyay
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2022
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-022-02528-x

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