New Genetic Research Investigates the Link between Inflammation and Macular Degeneration

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Photograph of a retina with wet age-related macular degeneration

European researchers investigating the link between inflammation and age-related macular degeneration (AMD) have identified a protein, called FHL-1, that functions as a type of "regulator" to protect the eye from an attack by the immune system.

According to lead author Dr. Simon Clark, this important genetic research has identified a new target for therapeutic drugs that can "reset" the immune imbalance in the eye, thus possibly preventing, or delaying the progression of, AMD.

From the Journal of Immunology

The research, entitled Identification of Factor H–like Protein 1 [explained below] as the Predominant Complement Regulator in Bruch's Membrane: Implications for Age-Related Macular Degeneration has been published online ahead-of-print in the November 5, 2014 edition of The Journal of Immunology.

The journal publishes novel, peer-reviewed findings in all areas of experimental immunology, including inflammation and autoimmunity. Immunology is a branch of biomedical science that deals with components of the immune system, immunity from disease, and the immune response.

[Editor's note: Bruch's membrane (pronounced "brooks") is the innermost layer of the choroid, the part of the eye containing blood vessels that nourish the retina. When damaged by disease or the aging process, Bruch's membrane is responsible for many bleeding disorders of the retina, such as age-related macular degeneration (AMD).]

The authors are Simon J. Clark, Christoph Q. Schmidt, Anne M. White, Svetlana Hakobyan, B. Paul Morgan, and Paul N. Bishop, who represent the following European institutions: the University of Manchester; Central Manchester University Hospitals NHS Foundation Trust; Manchester Academic Health Science Center; Cardiff University, United Kingdom, and Ulm University, Germany

About Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is gradual, progressive, painless deterioration of the macula, the small sensitive area in the center of the retina that provides clear central vision. Damage to the macula impairs the central (or "detail") vision that helps with essential everyday activities such as reading, preparing meals, watching television, playing card and board games, and sewing.

AMD is the leading cause of vision loss for people aged 60 and older in the United States. According to the American Academy of Ophthalmology, 10-15 million individuals have AMD and about 10% of people who are affected have the "wet" type of AMD.

Wet (Neovascular) Macular Degeneration

In wet, or exudative, macular degeneration (AMD), the choroid (a part of the eye containing blood vessels that nourish the retina) begins to sprout abnormal new blood vessels that develop into a cluster under the macula, called choroidal neovascularization (neo = new; vascular = blood vessels).

The macula is the part of the retina that provides the clearest central vision. Because these new blood vessels are abnormal, they tend to break, bleed, and leak fluid under the macula, causing it to lift up and pull away from its base. This damages the fragile photoreceptor cells, which sense and receive light, resulting in a rapid and severe loss of central vision.

About Dry Macular Degeneration

The dry (also called atrophic) type of AMD affects approximately 80-90% of individuals with AMD. Its cause is unknown, it tends to progress more slowly than the wet type, and there is not – as of yet – an approved treatment or cure. "Atrophy" refers to the degeneration of cells in a portion of the body; in this case, the cell degeneration occurs in the retina.

In dry age-related macular degeneration, small white or yellowish deposits, called drusen, form on the retina, in the macula, causing it to deteriorate or degenerate over time.

Photograph of a retina with drusen

A retina with drusen

Drusen are the hallmark of dry AMD. These small yellow deposits beneath the retina, near Bruch's membrane, are a buildup of waste materials, composed of cholesterol, protein, and fats. Typically, when drusen first form, they do not cause vision loss. However, they are a risk factor for progressing to vision loss.

About the Research

Excerpted from New insight into common cause of blindness, via The University of Manchester News:

One of the most important risk-associated genes is called complement factor H (CFH). This encodes a protein called factor H (FH) that is responsible for protecting our eyes from attack by part of our immune system, called the complement system. FH achieves this by sticking to tissues, and when it is present in sufficient quantities, it prevents the complement system from causing any damage.

Researchers … have now discovered that the protein factor H is not the main regulator of immunity in the back of the eye; instead it is a different protein that is made from the same CFH gene. This is called factor H-like protein 1 (FHL-1).

Dr. Simon Clark, who led the research, said that "FHL-1 is a smaller version of FH; about a third of the size. However, it has all the necessary components to regulate the immune system and is still subject to the genetic alterations that affect AMD risk. Research has shown that the FHL-1, because it is smaller than FH, can get into structures of the back of the eye which cannot be reached by the larger FH."

He said that this research suggests that it is FHL-1 rather than FH which protects the back of the eye from immune attack and that insufficient FHL-1 in the back of the eye may result in inflammation that eventually results in vision loss from AMD. As such, this work has identified a new target for therapeutics aimed at readdressing immune imbalance in the eye, thereby preventing or slowing down AMD.

Inflammation and Macular Degeneration

From Risk Factors for Age-Related Macular Degeneration:

Age and the environmental factors together produce an increased number of free radicals in the macula. The macula is the small sensitive area in the center of the retina that provides clear central vision. Free radicals are unstable molecules that must be neutralized to keep them from causing damage. Mother Nature has provided anti-oxidants in food to neutralize these free radicals.

However, when we have too many free radicals and not enough anti-oxidants, damage is done. The first signs of damage in the macula are small whitish or yellowish spots called drusen, which the ophthalmologist can see usually before the individual is experiencing vision loss.

This initial damage triggers inflammation, which causes more damage, exacerbated by more free radicals. This results in more inflammation and the cycle continues, eventually scarring the macula and causing central vision loss.

More about the Study from the Journal of Immunology

From the article abstract:

The tight regulation of innate immunity on extracellular matrix (ECM) is a vital part of immune homeostasis throughout the human body, and disruption to this regulation in the eye is thought to contribute directly to the progression of age-related macular degeneration (AMD).

The plasma complement regulator factor H (FH) is thought to be the main regulator that protects ECM against damaging complement activation. However, in the present study we demonstrate that a truncated form of FH, called FH-like protein 1 (FHL-1), is the main regulatory protein in the layer of ECM under human retina, called Bruch's membrane. Bruch's membrane is a major site of AMD disease pathogenesis and where drusen, the hallmark lesions of AMD, form.

We show that FHL-1 can passively diffuse through Bruch's membrane, whereas the full sized, glycosylated, FH cannot… We also show that FHL-1 is retained in drusen, whereas FH coats the periphery of the lesions, perhaps inhibiting their clearance.

Our results identify a novel mechanism of complement regulation in the human eye, which highlights potential new avenues for therapeutic strategies.

Additional Information


Topics:
Medical Updates
Macular Degeneration
Gene Therapy
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