Association of Proliferative Diabetic Retinopathy in the Elderly with the Blood Complement System

A common complication of diabetes mellitus, mainly type 2, is diabetic retinopathy, among which the most unfavorable form for complete loss of vision is considered to be proliferative diabetic retinopathy. The participation of the complement system in the development of proliferative diabetic retinopathy is mainly devoted to experimental work on a limited number of blood complement components and without assessing their risk in the pathogenesis of the disease. The purpose of the study was to determine the association of components of the blood serum complement system with the development of proliferative diabetic retinopathy in the elderly. In clinical conditions, 115 patients 60–74 years old suffering from proliferative diabetic retinopathy and 48 patients of the same age with the absence of this ophthalmopathology were examined. The components of the blood complement system were studied by enzyme immunoassay and hemolytic method. The relative risk of the influence of the complement components was calculated according to the generally accepted method. There was a statistically significant increase in the blood serum of patients with proliferative diabetic retinopathy of most components of the complement system, with the exception of the C₁ ing. and C₅ components. The content of the C_3a component increased especially to 127.6 ± 4.7 ng / ml versus 30.4 ± 3.5 ng/ml in the control, the C_5a component to 5.6 ± 0.5 ng/ml versus 2.4 ± 0.3 ng/ml, and factor H to 228.7 ± 4.9 versus 106.3 ± 3.8 mng / ml, respectively. The highest value of the relative risk among the studied components is inherent in the C_3a component of the blood complement with a reliable confidence interval of 4,451–5,103. The development of proliferative diabetic retinopathy in the elderly is associated with an increased content of C_3a, C_5a components and factor H in the blood serum, which can be used to develop targeted therapy for this disease.

1. Solomon S.D., Chew E., Duh E.J., Sobrin L., Sun J.K., Vanderbeek B.L., Wykoff C.C., Gardner T.W. Diabetic Retinopathy: A Position Statement by the American Diabetes Association. Diabetes Care. 2017;40(3):412–418. DOI: 10.2337/dc16-2641

2. Duh E.J., Sun J.K., Stitt A.W. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight. 2017;2(14):e93751. DOI: 10.1172/jci.insight.93751

3. Tarr J.M., Kaul K., Wolanska K., Kohner E.M., Chibber R. Retinopathy in diabetes. Adv Exp Med Biol. 2012;771:88–106. DOI: 10.1007/978-1-4614-5441-0_10

4. Rubsam A., Parikh S., Fort P.E. Role of Inflammation in Diabetic Retinopathy. Int J Mol Sci. 2018;19(4):942. DOI: 10.3390/ijms19040942

5. Clark S.J., Bishop P.N. The eye as a complement dysregulation hotspot. Semin Immunopathol. 2018;40(1):65–74. DOI: 10.1007/s00281-017-0649-6

6. Chen M., Xu H. Parainflammation, chronic inflammation, and age related macular degeneration. J Leukoc Biol. 2015;98(5):713–725. DOI: 10.1189/jlb.3RI0615-239R

7. Mukai R., Okunuki Y., Husain D., Kim C.B., Lambris J.D., Connor K.M. The Complement System Is Critical in Maintaining Retinal Integrity during Aging. Front Aging Neurosci. 2018;10:15. DOI: 10.3389/fnagi.2018.00015

8. Konyaev D.A. The relationship between the interleukin profile and the blood oxidative system in elderly patients with late stage age related macular degeneration. Scientific results of biomedical research = Nauchnye rezul’taty biomedicinskih issledovanij. 2020;6(1):118–125 (In Russ.). DOI: 10.18413/2658-6533-2020-6-1-0-10

9. Holers V.M. Complement and its receptors: new insights into human disease. Annu Rev Immunol. 2014;32:433–459. DOI: 10.1146/annurev-immunol-032713-120154

10. Sircar M., Rosales I.A., Selig M.K., Xu D., Zsengeller Z.K., Stillman I.E., Libermann T.A., Karumanchi S.A., Thadhani R.I. Complement 7 Is Up Regulated in Human Early Diabetic Kidney Disease. Am J Pathol. 2018;188(10):2147–2154. DOI: 10.1016/j.ajpath.2018.06.018

11. Cao S., Wang J.C., Gao J., Wong M., To E., White V.A., Cui J.Z., Matsubara J.A. CFH Y402H polymorphism and the complement activation product C5a: effects on NF κB activation and inflammasome gene regulation. Br J Ophthalmol. 2016;100(5):713–718. DOI: 10.1136/bjophthalmol 2015 307213

12. ETDRS, 1991. Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy. ETDRS report No 9. Ophthalmology. 1991;98:766–785.

13. Kim K., Kim E.S., Kim D.O., Yu S.Y. Progressive retinal neurodegeneration and microvascular change in diabetic retinopathy: longitudinal study using OCT angiography. Acta Diabetol. 2019;56(12):1275–1282. DOI: 10.1007/s00592-019-01395-6

14. Bora P.S., Sohn J.H., Cruz J.M., Jha P., Nishihori H., Wang Y., Kaliappan S., Kaplan H.J., Bora N.S. Role of complement and complement membrane attack complex in laser induced choroidal neovascularization. J Immunol. 2005;174(1):491–497. DOI: 10.4049/jimmunol.174.1.491

15. Inafuku S., Klokman G., Connor K.M. The Alternative Complement System Mediates Cell Death in Retinal Ischemia Reperfusion Injury. Front Mol Neurosci. 2018;11:278. DOI: 10.3389/fnmol.2018.00278

16. Shahulhameed S., Vishwakarma S., Chhablani J., Tyagi M., Pappuru R.R., Jakati S., Chakrabarti S., Kaur I. A Systematic Investigation on Complement Pathway Activation in Diabetic Retinopathy. Front Immunol. 2020;11:154. DOI: 10.3389/fimmu.2020.00154

17. Mandava N., Tirado Gonzales V., Geiger M.D., Patnaik J.L. Complement Activation in the Vitreous of Patients with Proliferative Diabetic Retinopathy. Invest Ophthalmol Vis Sci. 2020;61(11):39. DOI: 10.1167/iovs.61.11.39

18. Smith J.M., Mandava N, Tirado Gonzalez V., Garcia Santisteban R., Geiger M.D., Patnaik J.L. Correlation of Complement Activation in Aqueous and Vitreous in Patients With Proliferative Diabetic Retinopathy. Transl Vis Sci Technol. 2022; 11(4):13. DOI: 10.1167/tvst.11.4.13