IMMUNOLOGY

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This is Huge – Study Suggests Immune System Could Play a Central Role in AMD

 

Age-related macular degeneration (AMD) damages the light-sensitive cells of the macula, the central part of the retina that allows us to see fine visual detail. As the disease progresses, patients encounter great difficulty reading, driving, or performing hobbies and tasks that require hand-eye coordination. Treatments exist to prevent severe vision loss in certain types of advanced AMD, but none prevent or cure the disease. Currently, 2 million Americans have advanced AMD and another 7 million have intermediate stages.

 

Recent studies have identified several genes with alterations that increase the risk of developing the disease. In addition, environmental risk factors have also been suggested as possible causes of the disease. One explanation may be that environmental exposures influence DNA methylation, which regulates gene expression. Changes in this process may result in the production of too much or too little of a gene’s protein, leading to cellular dysfunction and disease. Changes in DNA methylation have been implicated in cancer, lupus, multiple sclerosis, and many other diseases.

 

According to an article published in Cell Reports (2012;2:1151-1158), it was shown that changes in genes in the immune system function may cause AMD. The study identified decreased levels of DNA methylation, a chemical reaction that switches off genes, on the interleukin-17 receptor C gene (IL17RC). The lack of DNA methylation led to increased gene activity and, in turn, increased levels of IL17RC proteins in patients with AMD. IL17RC is a protein that promotes immune responses to infections, such as fungal attacks. According to the authors, the study also suggests IL17- and IL17RC-mediated immune responses can be crucial in causing AMD, and that by measuring IL17RC gene activity in at-risk patients, there is the possibility to identify an early method to detect AMD.”

 

To test whether changes in DNA methylation might play a role in AMD, the study evaluated three pairs of twins — one pair identical and two pairs fraternal — where only one of the siblings had AMD. Identical twins have the same genetic makeup while fraternal twins share about half of their DNA. Because of their similar genetic backgrounds, identical and fraternal twins can be helpful in studying the differences between the effects of genetics and the environment. When compared with the unaffected twins, methylation patterns were altered in 231 genes of affected twins. This finding is consistent with the hypothesis that environmental exposures may epigenetically regulate expression of many genes and lead to AMD.

 

Among the 231 genes, the study found that DNA methylation was absent in a region of the IL17RC gene in twins with AMD. The lack of methylation in the IL17RC gene led to increased gene activity and, in turn, increased levels of its protein in circulating blood. The study further validated these findings by comparing seven siblings with and without AMD as well as 202 AMD patients and 96 control subjects without the disease. These studies also found increased IL17RC levels in circulating blood and, most importantly, in the retina of patients with AMD but not controls.

 

Based on these results, the authors propose that chronic increased levels of the IL17RC protein in the retina likely promote inflammation and recruitment of immune cells that damage the retina and lead to AMD. The authors are planning to evaluate what environmental factors may be responsible for the regulation of IL17RC and how the epigenetic regulation leading to the chronic inflammation in AMD patients can be reversed by novel therapies. They will also evaluate the role of epigenetics in other eye diseases.

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