Correlation of Complement Activation in Aqueous and Vitreous in Patients With Proliferative Diabetic Retinopathy

Overview

Journal Transl Vis Sci Technol

Specialties Biomedical Engineering
Ophthalmology

Date 2022 Apr 14

PMID 35420644

Authors

Jesse M Smith

Nikhil Mandava

Vanessa Tirado-Gonzalez

Rodrigo Garcia-Santisteban

Matthew D Geiger

Jennifer L Patnaik

Ashley Frazer-Abel

Anne M Lynch

Naresh Mandava

V Michael Holers

Brandie D Wagner

Idaira Sanchez-Santos

Daniela Meizner

Hugo Quiroz-Mercado

Alan G Palestine

Affiliations

Soon will be listed here.

Abstract

Purpose: A growing body of evidence suggests complement dysregulation is present in the vitreous of patients with diabetic eye disease. Further translational study could be simplified if aqueous-as opposed to vitreous-were used to sample the intraocular complement environment. Here, we analyze aqueous samples and assess whether a correlation exists between aqueous and vitreous complement levels.

Methods: We collected aqueous, vitreous, and plasma samples from patients with and without proliferative diabetic retinopathy (PDR) undergoing vitrectomy. We assessed correlation between complement levels in aqueous and vitreous samples after using a normalizing ratio to correct for vascular leakage. Spearman correlation coefficients were used to assess the correlation between complement levels in the aqueous and vitreous.

Results: Aqueous samples were obtained from 17 cases with PDR and 28 controls. In all patients, aqueous Ba, C3a, and albumin levels were strongly correlated with vitreous levels (Spearman correlation coefficient of 0.8 for Ba and C3a and 0.7 for albumin; all P values < 0.0001). In PDR eyes only, aqueous and vitreous C3a levels were significantly correlated (Spearman correlation coefficient 0.7; P = 0.002), whereas in control eyes, both Ba and C3a (Spearman correlation coefficients of 0.7; P < 0.0001) were significantly correlated.

Conclusions: A strong correlation exists between aqueous and vitreous complement levels in diabetic eye disease.

Translational Relevance: The results establish that accurate sampling of the intraocular complement can be done by analyzing aqueous specimens, allowing for the rapid and safe measurement of experimental complement targets and treatment response.

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References

Adamis A, Berman A . Immunological mechanisms in the pathogenesis of diabetic retinopathy. Semin Immunopathol. 2008; 30(2):65-84. DOI: 10.1007/s00281-008-0111-x. View

Zhang J, Gerhardinger C, Lorenzi M . Early complement activation and decreased levels of glycosylphosphatidylinositol-anchored complement inhibitors in human and experimental diabetic retinopathy. Diabetes. 2002; 51(12):3499-504. DOI: 10.2337/diabetes.51.12.3499. View

Moriarty A, Spalton D, Moriarty B, Shilling J, Ffytche T, Bulsara M . Studies of the blood-aqueous barrier in diabetes mellitus. Am J Ophthalmol. 1994; 117(6):768-71. DOI: 10.1016/s0002-9394(14)70320-4. View

Jha P, Bora P, Bora N . The role of complement system in ocular diseases including uveitis and macular degeneration. Mol Immunol. 2007; 44(16):3901-8. PMC: 2045508. DOI: 10.1016/j.molimm.2007.06.145. View

Demeler U, SAUTTER H . [Iris angiography studies in patients with diabetes mellitus]. Adv Ophthalmol. 1978; 36:233-44. View

Rubsam A, Parikh S, Fort P . Role of Inflammation in Diabetic Retinopathy. Int J Mol Sci. 2018; 19(4). PMC: 5979417. DOI: 10.3390/ijms19040942. View

Clark S, Bishop P . The eye as a complement dysregulation hotspot. Semin Immunopathol. 2017; 40(1):65-74. PMC: 5794836. DOI: 10.1007/s00281-017-0649-6. View

Park D, Connor K, Lambris J . The Challenges and Promise of Complement Therapeutics for Ocular Diseases. Front Immunol. 2019; 10:1007. PMC: 6529562. DOI: 10.3389/fimmu.2019.01007. View

ALGVERE P, Kornacki B . Fluorescein angiography of the iris. A correlation of microangiopathy in the iris and retina. Acta Ophthalmol (Copenh). 1978; 56(5):803-16. DOI: 10.1111/j.1755-3768.1978.tb06645.x. View

10.

Jha P, Sohn J, Xu Q, Wang Y, Kaplan H, Bora P . Suppression of complement regulatory proteins (CRPs) exacerbates experimental autoimmune anterior uveitis (EAAU). J Immunol. 2006; 176(12):7221-31. DOI: 10.4049/jimmunol.176.12.7221. View

11.

Tarr J, Kaul K, Wolanska K, Kohner E, Chibber R . Retinopathy in diabetes. Adv Exp Med Biol. 2013; 771:88-106. DOI: 10.1007/978-1-4614-5441-0_10. View

12.

Jha P, Sohn J, Xu Q, Nishihori H, Wang Y, Nishihori S . The complement system plays a critical role in the development of experimental autoimmune anterior uveitis. Invest Ophthalmol Vis Sci. 2006; 47(3):1030-8. PMC: 1975680. DOI: 10.1167/iovs.05-1062. View

13.

Hubens W, Beckers H, Gorgels T, Webers C . Increased ratios of complement factors C3a to C3 in aqueous humor and serum mark glaucoma progression. Exp Eye Res. 2021; 204:108460. DOI: 10.1016/j.exer.2021.108460. View

14.

Janeway Jr C, Medzhitov R . Innate immune recognition. Annu Rev Immunol. 2002; 20:197-216. DOI: 10.1146/annurev.immunol.20.083001.084359. View

15.

Mandava N, Tirado-Gonzalez V, Geiger M, Patnaik J, Frazer-Abel A, Lynch A . Complement Activation in the Vitreous of Patients With Proliferative Diabetic Retinopathy. Invest Ophthalmol Vis Sci. 2020; 61(11):39. PMC: 7520707. DOI: 10.1167/iovs.61.11.39. View

16.

Qin X, Goldfine A, Krumrei N, Grubissich L, Acosta J, Chorev M . Glycation inactivation of the complement regulatory protein CD59: a possible role in the pathogenesis of the vascular complications of human diabetes. Diabetes. 2004; 53(10):2653-61. DOI: 10.2337/diabetes.53.10.2653. View

17.

GOLDMANN H, WITMER R . [Antibodies in the aqueous humor]. Ophthalmologica. 1954; 127(4-5):323-30. DOI: 10.1159/000301976. View

18.

Manoharan N, Patnaik J, Olson J . INCREASED COMPLEMENT LEVELS IN HUMAN VITREOUS ASPIRATES OF PROLIFERATIVE DIABETIC RETINOPATHY AND RETINAL DETACHMENT EYES. Retina. 2018; 39(11):2212-2218. DOI: 10.1097/IAE.0000000000002288. View

19.

Muramatsu D, Wakabayashi Y, Usui Y, Okunuki Y, Kezuka T, Goto H . Correlation of complement fragment C5a with inflammatory cytokines in the vitreous of patients with proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 2012; 251(1):15-7. DOI: 10.1007/s00417-012-2024-6. View

20.

Lynch A, Mandava N, Patnaik J, Frazer-Abel A, Wagner B, Palestine A . Systemic activation of the complement system in patients with advanced age-related macular degeneration. Eur J Ophthalmol. 2019; 30(5):1061-1068. DOI: 10.1177/1120672119857896. View