Jasmine Nguyen

Introduction. Age-related macular degeneration (AMD) is the leading cause of visual deficit in older populations in the developed world.¹   There are two different types of AMD: a wet type and a dry type. The wet type is characterized by exudate with choroidal neovascularization while the dry type is characterized by the deposits of drusen within the retinal pigment epithelium (RPE).² Both genetic and environmental factors play a role in the risk of developing AMD, however genetic factors play a larger role.³   Specifically smoking, higher dietary fat, and obesity play a larger role in the risk of developing AMD, while the Y402H variant of the CFH gene has also been supported to lead to a higher risk of AMD.^1,3   Complement factor H (CFH) is involved in the inactivation of the alternate complement pathway.¹ This high risk variant leads to chronic inflammation by inhibiting MP elimination during inflammation resolution that leads to vulnerability to uncontrolled complement activation.⁴   Furthermore this variant cannot inhibit the terminal complement pathway efficiently leading to more membrane attack complex in the choroid.⁵ Methods. Mice with either the wild genotype or the Y402H genotype were fed either a normal diet or a high fat, cholesterol enriched (HFC) diet and aged.¹   In a separate experiment, mice with Cfh+/+, Cfh+/-, or Cfh -/- were either fed a normal diet or a HFC diet.² The height of sub- RPE deposit was measured in each variation as well as RPE height itself.^1,2   The presence of multinucleated cells was also measured to measure RPE damage.² Results. It was found that the tallest deposits were found in mice with the Cfh +/- genotype fed a HFC diet and in mice with the Y402H genotypic variant.^1,2 It is hypothesized that because Cfh -/- lacks the key activators of the complement cascade, it did not develop the pathology typical of AMD.¹ Furthermore, in Cfh +/- mice, there is a much higher recruitment of mononuclear phagocytes (MNP), establishing a complement-mediated effector response in sub-RPE deposits present in comparison to Cfh -/- HFC mice.¹   Conclusions. A deficiency in CFH or the high risk variant Y402H genotype is found to lead to a decrease in inactivation of the alternate complement pathway leading to a state of chronic inflammation due to decreased inactivation of the alternate complement cascade pathway that leads to the pathology characteristic of AMD when fed a HFC diet.^1,5

1. Landowski M, Kelly U, Klingeborn M, et al. Human complement factor H Y402H polymorphism causes an age- related macular degeneration phenotype and lipoprotein dysregulation in mice. Proc Natl Acad Sci U S A 2019;116(9):3703-3711. doi: 10.1073/pnas.1814014116 [doi].
2. Toomey CB, Kelly U, Saban DR, Bowes Rickman C. Regulation of age-related macular degeneration-like pathology by complement factor H. Proc Natl Acad Sci U S A. 2015;112(23):3040. doi:10.1073/pnas.1424391112 [doi].
3. Sobrin L, Seddon JM. Nature and nurture- genes and environment- predict onset and progression of macular degeneration. Progress in Retinal and Eye Research. 2014;40:1-15. doi:10.1016/j.preteyeres.2013.12.004.
4. Calippe B, Augustin S, Beguier F, et al. Complement Factor H Inhibits CD47-Mediated Resolution of Inflammation. Immunity. 2017;46(2):261-272. doi:10.1016/j.immuni.2017.01.006.
5. Whitmore SS, Sohn EH, Chirco KR, et al. Complement activation and choriocapillaris loss in early AMD: Implications for pathophysiology and therapy. Progress in Retinal and Eye Research. 2015;45:1-6 doi:10.1016/j.preteyeres.2014.11.005.