A research team based at the Faculty of Biology, Medicine and Health, University of Manchester, and the Manchester Royal Eye Hospital, NHS Foundation Trust, has reported that increased mast cell infiltration in the retina are early events in AMD pathogenesis and potentially represents a unifying mechanistic link between well-known genetic associations in AMD and recruitment of immune cells. According to researchers, “the most striking finding from our proteomics study was that sub-macular stromal tissue punches from donors with Chr1 (chromosome 1) risk or Chr10 (chromosome 10) risk but without macroscopic AMD changes both contained increased levels of mast cell–specific proteases, including tryptase, chymase, and CPA3, compared with those from eyes with low genetic risk at these loci”. Consequently, this study suggests that mast cell infiltration of the choroid may provide early events in AMD pathogenesis.
It has been well known that the genetic risk of AMD is attributed to two loci, one at chromosome 1q32, around the CFH (complement factor H) gene, and the other at chromosome 10q26 (Chr10q26), around the ARMS2 and HTRA1 genes. One single-nucleotide polymorphism (SNP) is associated with chromosome 1 risk, and this change corresponds to a coding variant (Y402H) in the CFH gene, and present in ∼36% of Europeans. These homozygous individuals have a 7.4-fold increased risk of developing AMD. In addition, one SNP is associated with chromosome 10 risk, and present in 22% of individuals of European ancestry, and those who are homozygous for this change have a 10-fold increase in risk of late AMD. The current study investigated the association between genetic risk of AMD and biochemical and cellular changes in the Bruch’s membrane/inner choroid.
In particular, quantitative proteomics techniques are enormously valuable for elucidating disease mechanisms. In this study, the researchers aimed to determine whether genetic risk at chromosome 1 or chromosome 10 altered the proteome of the tissue as compared with tissue from donors without the common risk haplotypes at these loci. The chromosome 1 and chromosome 10 risk groups appeared to share common changes, compared with the low-risk group, particularly increased levels of mast cell–specific proteases, including tryptase, chymase, and carboxypeptidase A3. Commenting from the work, one of the authors, Dr. Richard D. Unwin at the University of Manchester, stated that: “what is really exciting about this work is that we are studying tissue from people before they have signs of the disease. This gives us a look into the very earliest stages, and gives us hope that we can intervene to stop the disease developing and ultimately prevent loss of vision”. In addition, and in follow-up to the work, Geraldine Hoad, a programme manager at the UK Macular Society’s, said: “this is an exciting development and we look forward to seeing further research in this area. We know lots of current treatments for wet AMD don’t work for everyone and for those with dry AMD there is no treatment at all. Finding something that works for everyone would be an important piece of the puzzle and make a huge difference to the lives of those affected. While this particular study is in its early stages. it’s great to see the benefit of our investment in the Manchester Eye Tissue Repository, which is proving a vital resource for lots of research in this area.”