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Home | Pregnancy Timeline | News Alerts |News Archive Aug 19, 2013

 

Research suggesst that alterations in the activity of the immune system are involved in the earliest stages of macular degeneration. This has important implications for the use of drugs in treating macular degeneration.






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Critical role of immune system in early macular degeneration

Macular degenerations occurs in several forms, all are causes of vision loss. Juvenile or early-onset macular degeneration includes several inherited disorders that can affect children and young adults.

In contrast, age-related macular degeneration (AMD) is the leading cause of blindness for individuals over 65 years of age in developed countries, and its increasing worldwide. Both inherited macular degeneration and AMD lead to the loss of central vision. While therapies exist for some forms of late AMD, and nutritional supplements can slow the progress of early AMD for some patients, improved therapies are needed.

However, on line this week in the journal Human Molecular Genetics, an unexpected finding is reported by Drs. Donita Garland, Rosario Fernandez-Godino, and Eric Pierce of the Ocular Genomics Institute at the Massachusetts Eye and Ear, Harvard Medical School. In mice genetically engineered to have an inherited form of macular degeneration, turning off the animals’ complement system—a part of the immune system—prevented the disease.

The findings are important because they suggest that inherited macular degenerations share common features with AMD. The results also suggest that alterations in the activity of the complement system are involved in the earliest stages of disease creation. This finding has important implications for using drugs to modify the complement system in treating macular degenerations.


This is the first report to demonstrate a role for the complement system in an inherited macular degeneration.

Previous genetic studies have shown that gene variants that encode several complement system components are important risk factors for AMD.

Based on this, drugs that inhibit specific complement system activities are being tested clinically as treatments for AMD. However, it is not entirely clear how alterations in complement system components lead to AMD.


The research suggests that complement activation by abnormalities in the extracellular matrix or the scaffold secreted by retinal cells plays an important role in the formation of basal deposits, one of the earliest stages of macular degeneration. Basal deposits are precursors of drusen, which appear as spots in the retina on clinical examination, and are accumulations of proteins and lipids outside the retinal cells; their presence is the first clinical indication of a risk of developing macular degeneration.

For these studies, the investigators created a mouse model of the inherited macular dystrophy Doyne Honeycomb Retinal Dystrophy/Malattia Leventinese (DHRD/ML) which is caused by the mutation in the EFEMP1 gene. This mutation leads to extensive drusen in patients with DHRD/ML, and the gene targeted mice develop extensive basal deposits.

As a first step in their studies, Dr. Garland's group identified the proteins present in the basal deposits of the mice. Like they do in people, these deposits form between the retinal pigment epithelial cells and their basement membrane, which is called Bruch’s membrane and is composed of extracellular matrix. These studies showed that the basal deposits are composed of normal extracellular matrix components that are present in abnormal amounts. This is logical because the EFEMP1 protein is secreted by retinal cells and is thought to be required for maturation of elastin fibers, which are part of Bruch’s membrane.

The proteomic analyses also suggest that the altered extracellular matrix stimulates a local immune response, including activation of the complement system. The complement system is part of our innate immune system, and helps fend off infections, but under certain circumstances can also lead to cell and tissue damage.

The Mass. Eye and Ear team applied the power of mouse genetics to study the role of complement in basal deposit formation, and generated Efemp1R345W/R345W:C3-/- double mutant mice, which have the disease-causing mutation in Efemp1 and also lack the key complement component C3. Without C3, the complement system cannot be activated. In contrast to their single mutant Efemp1-R345W cousins, the double mutant Efemp1R345W/R345W:C3-/- mice did not develop basal deposits, demonstrating that the complement system is required for formation of basal deposits.

The investigators plan to continue their studies to help identify additional treatments to prevent vision loss from macular degenerations.

Abstract
Macular degenerations, inherited and age-related, are important causes of vision loss. Human genetic studies have suggested perturbation of the complement system is important in the pathogenesis of age-related macular degeneration. The mechanisms underlying the involvement of the complement system are not understood, although complement and inflammation have been implicated in drusen formation. Drusen are an early clinical hallmark of inherited and age-related forms of macular degeneration. We studied one of the earliest stages of macular degeneration which precedes and leads to the formation of drusen, ie the formation of basal deposits. The studies were done using a mouse model of the inherited macular dystrophy Doyne Honeycomb Retinal Dystrophy/Malattia Leventinese (DHRD/ML) which is caused by a p.Arg345Trp mutation in EFEMP1. The hallmark of DHRD/ML is the formation of drusen at an early age, and gene targeted Efemp1R345 W/R345 W mice develop extensive basal deposits. Proteomic analyses of Bruch's membrane/choroid and Bruch's membrane in the Efemp1R345 W/R345 W mice indicate that the basal deposits are composed of normal extracellular matrix components present in abnormal amounts. The proteomic analyses also identified significant changes in proteins with immune-related function, including complement components, in the diseased tissue samples. Genetic ablation of the complement response via generation of Efemp1R345 W/R345 W:C3−/- double mutant mice inhibited the formation of basal deposits. The results demonstrate a critical role for the complement system in basal deposit formation, and suggest that complement-mediated recognition of abnormal extracellular matrix may participate in basal deposit formation in DHRD/ML and perhaps other macular degenerations.

© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

About Massachusetts Eye and Ear
Mass. Eye and Ear clinicians and scientists are driven by a mission to find cures for blindness, deafness and diseases of the head and neck. After uniting with Schepens Eye Research Institute in 2011, Mass. Eye and Ear in Boston became the world's largest vision and hearing research center, offering hope and healing to patients everywhere through discovery and innovation. Mass. Eye and Ear is a Harvard Medical School teaching hospital and trains future medical leaders in ophthalmology and otolaryngology, through residency as well as clinical and research fellowships. Internationally acclaimed since its founding in 1824, Mass. Eye and Ear employs full-time, board-certified physicians who offer high-quality and affordable specialty care that ranges from the routine to the very complex. U.S. News & World Report’s “Best Hospitals Survey” has consistently ranked the Mass. Eye and Ear Departments of Otolaryngology and Ophthalmology as among the top hospitals in the nation. Mass. Eye and Ear is home to the Ocular Genomics Institute which aims to translate the promise of personalized genomic medicine into clinical care for ophthalmic disorders. For more information about life-changing care and research, or to learn how you can help, please visit MassEyeAndEar.org and oculargenomics.meei.harvard.edu.

Reference:
Title: Mouse genetics and proteomic analyses demonstrate a critical role for complement in a model of DHRD/ML, an inherited macular degeneration

Authors: Donita L. Garland, Rosario Fernandez-Godino, Inderjeet Kaur, Kaye D. Speicher, James M. Harnly, John D. Lambris, David W. Speicher, Eric A. Pierce

Journal: Human Molecular Genetics

Abstract:
http://hmg.oxfordjournals.org/cgi/content/abstract/ddt395?ijkey=h47r9e0ZIXSQ182&keytype=ref

PDF:
http://hmg.oxfordjournals.org/cgi/reprint/ddt395?ijkey=h47r9e0ZIXSQ182&keytype=ref

Grant support:
This work was supported by grants from the Rosanne Silbermann Foundation, Research to Prevent Blindness, and the Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School.

Original press release: http://www.masseyeandear.org/news/press_releases/recent/Critical_Role_for_
Complement_System_in_Early_Macular_Degeneration/