The role of complement system and other inflammatory factors in the development of age-related macular degeneration

Cover Page

Cite item

Full Text

Abstract

The article is a review of literature on the role of complement system and inflammatory factors in the development of age-related macular degeneration. The review uses materials of domestic and foreign researchers. The clinical characteristics of age-related macular degeneration are presented, the role of genetic factors, complement factors, biomarkers of inflammation and alternative pathway of complement activation in the pathogenesis and risk of age-related macular degeneration is determined. Age-related macular degeneration is a chronic progressive multifactorial disease that affects macular area of the retina and is the main cause of loss of central vision in patients of older age group. The most important genetic factors are chromosome 1 (1q32) including complement factor H and complement factor H related genes and chromosome 10 (10q31). Variants associated with a moderate effect on developmental risk were identified in C3, complement factor I and complement factor B genes. In the pathogenesis of age-related macular degeneration, the key role is played by the damaged regulation of the alternative complement pathway. Single nucleotide polymorphisms in complement genes that affect the risk of development of age-related macular degeneration are predominantly involved in the alternative pathway of activation of the complement system. In pathomorphological studies, the initial localization of the pathological process of this pathology was established to be a complex of retinal pigment epithelium, Bruch’s membrane, and choriocapillaries followed by loss of photoreceptor function. The review of studies of systemic inflammatory biomarkers, cytokines, vascular endothelial growth factors in peripheral blood, blood serum, aqueous humour at various stages and forms of age-related macular degeneration is presented.

About the authors

E A Abdulaeva

Kazan State Medical Academy

Author for correspondence.
Email: abd@inbox.ru
Kazan, Russia

References

  1. Clinical guidelines «Age-related macular degeneration». Russian public organization «Association of Ophthalmologists». 2017. http://cr.rosminzdrav.ru/#!/schema/91 (access date: 03.05.2018). (In Russ.)
  2. webpage on the Internet
  3. Budzinskaya M.V., Plyukhova A.A., Sorokin P.A. Anti-VEGF therapy resistance in neovascular age-related macular degeneration. Vestnik oftal’mologii. 2017; 133 (4): 103–107. (In Russ.)
  4. Panova I.E. Vozrastnaya makulyarnaya degeneratsiya: etiologiya, patogenez, diagnostika i lechenie. Uchebnoe posobie dlya vrachey-oftal’mologov. (Age-related macular degeneration: etiology, pathogenesis, diagnosis, treatment. A manual for ophthalmologists.) Ekaterinburg: Solaris. 2015; 16 p. (In Russ.)
  5. Lim L.S., Mitchell P., Seddon J.M. et al. Age-related macular degeneration. Lancet. 2012; 379 (9827): 1728–1738. doi: 10.1016/S0140-6736(12)60282-7.
  6. Schramm E.C., Clark S.J., Triebwasser M.P. et al. Genetic variants in the complement system predisposing to age-related macular degeneration: a review. Mol. Immunol. 2014; 61 (2): 118–125. doi: 10.1016/j.molimm.2014.06.032.
  7. Edwards A.O., Ritter R., Abel K.J. et al. Complement factor H polymorphism and age-related macular degeneration. Science. 2005; 308: 421–424. doi: 10.1126/science.1110189.
  8. Hageman G.S., Anderson D.H., Johnson L.V. et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc. Natl. Acad. Sci. USA. 2005; 102: 7227–7232. doi: 10.1073/pnas.0501536102.
  9. Haines J.L., Hauser M.A., Schmidt S. et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005; 308 (5720): 419–421. doi: 10.1126/science.1110359.
  10. Sofat R., Casas J.P., Webster A.R. et al. Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype. Int. J. Epidemiol. 2012; 41: 250–262. doi: 10.1093/ije/dyr204.
  11. Fritsche L.G., Chen W., Schu M. et al. Seven new loci associated with age-related macular degeneration. Nat. Genet. 2013; 45 (4): 433–439. doi: 10.1038/ng.2578.
  12. Fagerness J.A., Maller J.B., Neale B.M. et al. Variation near complement factor I is associated with risk of advanced AMD. Eur. J. Hum. Genet. 2009; 17 (1): 100–104. doi: 10.1038/ejhg.2008.140.
  13. Gold B., Merriam J.E., Zernant J. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat. Genet. 2006; 38 (4): 458–462. doi: 10.1038/ng1750.
  14. Yates J.R.W., Sepp T., Matharu B.K. et al. Complement C3 variant and the risk of age-related macular degeneration. N. Engl. J. Med. 2007; 357: 553–561. doi: 10.1056/NEJMoa072618.
  15. Helgason H., Sulem P., Duvvari M.R. et al. A rare nonsynonymous sequence vari- ant in C3 is associated with high risk of age-related macular degeneration. Nat. Genet. 2013; 45: 1371–1374. doi: 10.1038/ng.2740.
  16. Raychaudhuri S., Iartchouk O., Chin K. et al. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat. Genet. 2011; 43: 1232–1236. doi: 10.1038/ng.976.
  17. Seddon J.M., Yu Y., Miller E.C. et al. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat. Genet. 2013; 45: 1366–1370. doi: 10.1038/ng.2741.
  18. Zhan X., Larson D.E., Wang C. et al. Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. Nat. Genet. 2013; 45: 1375–1379. doi: 10.1038/ng.2758.
  19. Yu Y., Triebwasser M.P., Wong E.K. et al. Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration. Hum. Mol. Genet. 2014; 23 (19): 5283–5293. doi: 10.1093/HMG/ddu226.
  20. Smailhodzic D., Klaver C.C.W., Klevering B.J. et al. Risk alleles in CFH and ARMS2 are independently associated with systemic complement activation in age-related macular degeneration. Ophthalmology. 2012; 119 (2): 339–346. doi: 10.1016/j.ophtha.2011.07.056.
  21. Tortajada A., Montes T., Martínez-Barricarte R. et al. The disease-protective complement factor H allotypic variant Ile62 shows increased binding affinity for C3b and enhanced cofactor activity. Hum. Mol. Genet. 2009; 18: 3452–3461. doi: 10.1093/HMG/ddp289.
  22. Ansari M., McKeigue P.M., Skerka C. et al. Genetic influences on plasma CFH and CFHR1 concentrations and their role in suscep- tibility to age-related macular degeneration. Hum. Mol. Genet. 2013; 22: 4857–4869. doi: 10.1093/HMG/ddt336.
  23. Hageman G.S., Gehrs K., Lejnine S. et al. Clinical validation of a genetic model to estimate the risk of developing choroidal neovascular age-related macular degeneration. Hum. Genomics. 2011; 5: 420–440. doi: 10.1186/1479-7364-5-5-420.
  24. Buitendijk G.H.S., Rochtchina E., Myers C. et al. Prediction of age-related macular degeneration in the general population: the Three Continent AMD Consortium. Ophthalmology. 2013; 120 (12): 2644–2655. doi: 10.1016/j.ophtha.2013.07.053.
  25. Klos A., Wende E., Wareham K.J. et al. International Union of Pharmacology. LXXXVII. Complement peptide C5a, C4a, and C3a receptors. Pharmacol. Rev. 2013; 65: 500–543. doi: 10.1124/pr.111.005223.
  26. McHarg S., Clark S.J., Day A.J. et al. Age-related macular degeneration and the role of the complement system. Molecular. Immunology. 2015; 67 (1): 43–50. doi: 10.1016/j.molimm.2015.02.032.
  27. Chen M., Forrester J.V., Xu H. Synthesis of complement factor H by retinal pigment epithelial cells is down-regulated by oxidized photoreceptor outer segments. Exp. Eye Res. 2007; 84: 635–645. doi: 10.1016/j.exer.2006.11.015.
  28. Ripoche J., Day A.J., Harris T.J. et al. The complete amino acid sequence of human complement factor H. Biochem. J. 1988; 249: 593–602. doi: 10.1042/bj2490593.
  29. Clark S.J., Ridge L.A., Herbert A.P. et al. Tissue-specific host recognition by complement factor H is mediated by differential activities of its glycosaminoglycan-binding regions. J. Immunol. 2013; 190 (5): 2049–2057. doi: 10.4049/jimmunol.1201751.
  30. Langford-Smith A., Keenan T.D.L., Clark S. et al. The role of complement in age-related macular degeneration: heparan sulphate, a zip code for complement factor H? J. Innate. Immun. 2014; 6 (4): 407–416. doi: 10.1159/000356513.
  31. Blaum B.S., Hannan J.P., Herbert A.P. et al. Structural basis for sialic acid-mediated self-recognition by complement factor H. Nat. Chem. Biol. 2015; 11 (1): 77–82. doi: 10.1038/nchembio.1696.
  32. Mullins R.F., Dewald A.D., Streb L.M. et al. Elevated membrane attack complex in human choroid with high risk complement factor H genotypes. Exp. Eye Res. 2011; 93: 565–567. doi: 10.1016/j.exer.2011.06.015.
  33. Mullins R.F., Schoo D.P., Sohn E.H. et al. The membrane attack complex in aging human choriocapillaris: relationship to macular degeneration and choroidal thinning. Am. J. Pathol. 2014; 184: 3142–3153. DOI: 10,1016/j.ajpath.2014.07.017.
  34. Stanton C.M., Yates J.R., den Hollander A.I. et al. Complement factor D in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2011; 52: 8828–8834. doi: 10.1167/iovs.11.
  35. Silva A.S., Teixeira A.G., Bavia L. et al. Plasma levels of complement proteins from the alternative pathway in patients with age-related macular degeneration are independent of Complement Factor H Tyr(4)(0)(2)His polymorphism. Mol. Vis. 2012; 18: 2288–2299. PMID: 22969267.
  36. Singh A., Faber C., Falk M. et al. Altered expression of CD46 and CD59 on leukocytes in neovascular age-related macular degeneration. Am. J. Ophthalmol. 2012; 154 (1): 193–199.e2. doi: 10.1016/j.ajo.2012.01.036.
  37. Cipriani V., Matharu B.K., Khan J.C. et al. Genetic variation in complement regulators and susceptibility to age-related macular degeneration. Immunobiology. 2012; 217: 158–161. doi: 10.1016/j.imbio.2011.09.002.
  38. Cao S., Ko A., Partanen M. et al. Relationship between systemic cytokines and complement factor H Y402H polymorphism in patients with dry age-related macular degeneration. Am. J. Ophthalmol. 2013; 156: 1176–1183. doi: 10.1016/j.ajo.2013.08.003.
  39. Lee I.T., Liu S.W., Chi P.L. et al. TNF-alpha mediates PKCdelta/JNK1/2/c-Jun-dependent monocyte adhesion via ICAM-1 induction in human retinal pigment epithelial cells. PLoS One. 2015; 10 (2): e0117911. doi: 10.1371/journal. pone.0117911.
  40. Faber C., Jehs T., Juel H.B. et al. Early and exudative age-related macular degeneration is associated with increased plasma levels of soluble TNF receptor II. Acta. Ophthalmol. 2015; 93 (3): 242–247. doi: 10.1111/aos.12581.
  41. Chau K.Y., Sivaprasad S., Patel N. Plasma levels of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) in age-related macular degeneration. Eye (Lond.). 2008; 22 (6): 855–859. doi: 10.1038/sj.eye.6702722.
  42. Mooijaart S.P., Koeijvoets K.M., Sijbrands E.J. et al. Complement Factor H polymorphism Y402H associates with inflammation, visual acuity, and cardiovascular mortality in the elderly population at large. Exp. Gerontol. 2007; 42: 1116–1122. doi: 10.1016/j.exger.2007.08.001.
  43. Mo F.M., Proia A.D., Johnson W.H. et al. Interferon gamma-inducible protein-10 (IP-10) and eotaxin as biomarkers in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2010; 51: 4226–4236. DOI: 10,1167/iovs.09-3910.
  44. Hong T., Tan A.G., Mitchell P. et al. A review and meta-analysis of the association between C-reactive protein and age-related macular degeneration. Surv. Ophthalmol. 2011; 56: 184–194. doi: 10.1016/j.survophthal.2010.08.007.
  45. Mitta V.P., Christen W.G., Glynn R.J. et al. C-reactive protein and the incidence of macular degeneration: pooled analysis of 5 cohorts. JAMA Ophthalmol. 2013; 131: 507–513. doi: 10.1001/jamaophthalmol.2013.2303.
  46. Yip J.L., Khawaja A.P., Chan M.P. et al. Cross sectional and longitudinal associations between cardiovascular risk factors and age related macular degeneration in the EPIC-Norfolk eye study. PLoS One. 2015; 10: e0132565. doi: 10.1371/journal.pone.0132565.
  47. Yu Y., Ren X.R., Wen F. et al. T-helper-associated cytokines expression by peripheral blood mononuclear cells in patients with polypoidal choroidal vasculopathy and age-related macular degeneration. BMC Ophthalmology. 2016; 16: 80–87. doi: 10.1186/s12886-016-0251-z.
  48. Neroev V.V., Slepova O.S., Rjabina M.V. The change of vegf content in the tear fluid and blood serum of patients with the wet form of age macular degeneration treated by Lucentis. Rossiyskiy oftal’mologicheskiy zhurnal. 2013; 6 (3): 62–66. (In Russ.)
  49. Slepova O.S., Eremeeva E.A., Ryabina M.V. et al. Cytokines in lacrimal fluid and blood serum: early biomarkers of age-related macular degeneration. Meditsinskaya immunologiya. 2015; 17 (3): 245–252. (In Russ.)
  50. Cha D.M., Woo S.J., Kim H.J. et al. Comparative analysis of aqueous humor cytokine levels between patients with exudative age-related macular degeneration and normal controls. Invest. Ophthalmol. Vis. Sci. 2013; 54 (10): 7038–7044. doi: 10.1167/iovs.13-12730.
  51. Muether P.S., Neuhann I., Buhl C. et al. Intraocular growth factors and cytokines in patients with dry and neovascular age-related macular degeneration. Retina. 2013; 33 (9): 1809–1814. doi: 10.1097/IAE.0b013e318285cd9e.
  52. Agawa T., Usui Y., Wakabayashi Y. et al. Profile of intraocular immune mediators in patients with age-related macular degeneration and the effect of intravitreal bevacizumab injection. Retina. 2014; 34 (9): 1811–1818. doi: 10.1097/IAE.0000000000000157.
  53. Jonas J.B., Tao Y., Neumaier M. et al. Monocyte chemoattractant protein 1, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 in exudative age-related macular degeneration. Arch. Ophthalmol. 2010; 128 (10): 1281–1286. doi: 10.1001/archophthalmol.2010.227.
  54. Jonas J.B., Tao Y., Neumaier M. et al. Cytokine concentration in aqueous humour of eyes with exudative age-related macular degeneration. Acta Ophthalmol. 2012; 90 (5): 381–388. doi: 10.1111/j.1755-3768.2012.02414.x.
  55. Sakurada Y., Nakamura Y., Yoneyama S. et al. Aqueous humor cytokine levels in patients with polypoidal choroidal vasculopathy and neovascular age-related macular degeneration. Ophthalmic. Res. 2015; 53 (1): 2–7. doi: 10.1159/000365487.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

© 2018 Abdulaeva E.A.

Creative Commons License

This work is licensed
under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.




Согласие на обработку персональных данных с помощью сервиса «Яндекс.Метрика»

1. Я (далее – «Пользователь» или «Субъект персональных данных»), осуществляя использование сайта https://journals.rcsi.science/ (далее – «Сайт»), подтверждая свою полную дееспособность даю согласие на обработку персональных данных с использованием средств автоматизации Оператору - федеральному государственному бюджетному учреждению «Российский центр научной информации» (РЦНИ), далее – «Оператор», расположенному по адресу: 119991, г. Москва, Ленинский просп., д.32А, со следующими условиями.

2. Категории обрабатываемых данных: файлы «cookies» (куки-файлы). Файлы «cookie» – это небольшой текстовый файл, который веб-сервер может хранить в браузере Пользователя. Данные файлы веб-сервер загружает на устройство Пользователя при посещении им Сайта. При каждом следующем посещении Пользователем Сайта «cookie» файлы отправляются на Сайт Оператора. Данные файлы позволяют Сайту распознавать устройство Пользователя. Содержимое такого файла может как относиться, так и не относиться к персональным данным, в зависимости от того, содержит ли такой файл персональные данные или содержит обезличенные технические данные.

3. Цель обработки персональных данных: анализ пользовательской активности с помощью сервиса «Яндекс.Метрика».

4. Категории субъектов персональных данных: все Пользователи Сайта, которые дали согласие на обработку файлов «cookie».

5. Способы обработки: сбор, запись, систематизация, накопление, хранение, уточнение (обновление, изменение), извлечение, использование, передача (доступ, предоставление), блокирование, удаление, уничтожение персональных данных.

6. Срок обработки и хранения: до получения от Субъекта персональных данных требования о прекращении обработки/отзыва согласия.

7. Способ отзыва: заявление об отзыве в письменном виде путём его направления на адрес электронной почты Оператора: info@rcsi.science или путем письменного обращения по юридическому адресу: 119991, г. Москва, Ленинский просп., д.32А

8. Субъект персональных данных вправе запретить своему оборудованию прием этих данных или ограничить прием этих данных. При отказе от получения таких данных или при ограничении приема данных некоторые функции Сайта могут работать некорректно. Субъект персональных данных обязуется сам настроить свое оборудование таким способом, чтобы оно обеспечивало адекватный его желаниям режим работы и уровень защиты данных файлов «cookie», Оператор не предоставляет технологических и правовых консультаций на темы подобного характера.

9. Порядок уничтожения персональных данных при достижении цели их обработки или при наступлении иных законных оснований определяется Оператором в соответствии с законодательством Российской Федерации.

10. Я согласен/согласна квалифицировать в качестве своей простой электронной подписи под настоящим Согласием и под Политикой обработки персональных данных выполнение мною следующего действия на сайте: https://journals.rcsi.science/ нажатие мною на интерфейсе с текстом: «Сайт использует сервис «Яндекс.Метрика» (который использует файлы «cookie») на элемент с текстом «Принять и продолжить».