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E. R. Longbottom, P. Coffey, J. Greenwood, S. E. Moss; Retinal Pigment Epithelial Cell Secretion of Complement Factor H. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2193.
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Age-related macular degeneration (AMD) is one of the most common causes of visual impairment in the developed world. In 2005, 4 papers 1-4 were published documenting a single nucleotide polymorphism (SNP) Y402H within exon 9 of the complement factor H (CFH) gene, which conferred an increased risk of AMD development. This has been further supported by subsequent studies in different populations 5 6 .The role of CFH is that of a regulator of the innate complement immune system. CFH provides protection for host tissue against inappropriate complement. The AMD linked SNP results in a single amino acid change of a tyrosine to a histidine, within a region of the CFH protein identified as being involved in binding to heparin 10 7 and C-reactive protein 8, interactions involved in CFH's protective role 9.The Y402H SNP in CFH is associated with 2.7 and 7.6 fold increased risk (heterozygous and homozygous respectively) of developing AMD. The hypothesis is that CFH plays a role in protection of host tissue during inflammatory events, and that the mutations within CFH gene compromise the level of protection. The resulting exposure to complement attack, leads to damage to the RPE cells that are essential in maintaining the function of photoreceptor cells.
Using RPE cell lines and primary cultured porcine RPE cells in transwell systems, we use protein precipitation followed by western blotting to quantify the levels of CFH secreted.We report on the synthesis, trafficking and regulation of secretion of both variants of CFH in RPE cell lines and primary RPE cell cultures. We have also examined the apical versus basolateral secretion of CFH in confluent cultures, and examined the effects of inflammatory mediators on CFH secretion.
Preliminary findings suggest that there is no polarised secretion of CFH from either RPE cell line or primary RPE cell cultures. However there may be a small effect on CFH secretion by INFγ from ARPE19 cells.
Further examination of the role of CFH in the RPE will help us to understand the role this molecule plays in AMD development and how the mutations within the gene and its regulation exergate an effect.1. Klein,R.J. et al.. Science 308, 385-389 (2005)2. Haines,J.L. et al. Science 308, 419-421 (2005)3. Hageman,G.S. et al. Proc. Natl. Acad. Sci. U. S. A 102, 7227-7232 (2005)4. Edwards,A.O. et al. Science 308, 421-424 (2005)5. Simonelli,F. et al. Br. J. Ophthalmol. 90, 1142-1145 (2006)6. Magnusson,K.P. et al. PLoS. Med. 3, e5 (2005)7. Blackmore,T.K. et al. J. Immunol. 160, 3342-3348 (1998)8. Giannakis,E. et al. Eur. J. Immunol. 33, 962-969 (2003)9. Rodriguez de,C.S., et al., Mol. Immunol. 41, 355-367 (2004).
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