Critical role discovered for the complement system in early macular degeneration

Main Category: Eye Health / Blindness
Also Included In: Seniors / Aging
Article Date: 20 Aug 2013 - 0:00 PDT Current ratings for:
Critical role discovered for the complement system in early macular degeneration

In a study published on line in the journal Human Molecular Genetics, Drs. Donita Garland, Rosario Fernandez-Godino, and Eric Pierce of the Ocular Genomics Institute at the Massachusetts Eye and Ear, Harvard Medical School, along with their colleagues, reported the unexpected finding that 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.

Macular degenerations, which occur in several forms, are important 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) affects older individuals; it is the leading cause of blindness for individuals over 65 years of age in developed countries, and its prevalence is 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 progression of early AMD for some patients, improved therapies to prevent vision loss from these disorders are needed.

This is the first report to demonstrate a role for the complement system in an inherited macular degeneration. Previous genetic studies have shown that variants in the genes 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 new results reported suggest 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.

The findings are important because they suggest that inherited macular degenerations share common features with AMD, such as a complement-mediated response to abnormal extracellular matrix. The results also suggest that alterations in the activity of the complement system are involved in the earliest stages of disease pathogenesis. This finding has important implications for the use of drugs that modulate the complement system for treating macular degenerations.

For these studies, the investigators used a mouse model of the inherited macular dystrophy Doyne Honeycomb Retinal Dystrophy/Malattia Leventinese (DHRD/ML) which is caused by the p.Arg345Trp mutation in the EFEMP1 gene. This mutation leads to extensive drusen in patients with DHRD/ML, and the gene targeted Efemp1R345W/R345W mice develop extensive basal deposits.

As a first step in their studies, Dr. Garland and colleagues used proteomic techniques to identify the proteins present in the basal deposits of the Efemp1R345W/R345W 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 investigators plan to continue their studies to help identify additional treatments to prevent vision loss from macular degenerations.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our eye health / blindness section for the latest news on this subject.

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.

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.

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; Hum. Mol. Genet. (2013) doi: 10.1093/hmg/ddt395 First published online: August 13, 2013

Massachusetts Eye and Ear Infirmary

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Body's defense system against infection shut down by potent mechanism in viruses

Main Category: Flu / Cold / SARS
Also Included In: Tropical Diseases;  Immune System / Vaccines
Article Date: 17 Aug 2013 - 0:00 PDT Current ratings for:
Body's defense system against infection shut down by potent mechanism in viruses

Researchers at the Salk Institute for Biological Studies have discovered a powerful mechanism by which viruses such as influenza, West Nile and Dengue evade the body's immune response and infect humans with these potentially deadly diseases. The findings may provide scientists with an attractive target for novel antiviral therapies.

Published in the August issue of the journal Cell Host and Microbe, the findings describe a novel mechanism that this group of so-called "enveloped viruses" uses to disarm the host's innate immune response. The mechanism the scientists uncovered is based on these viruses activating a class of molecules, known as TAM receptors, which are located on the outside of certain immune cells.

In the immune system, TAM receptors are used by cells, such as macrophages and dendritic cells, to clean up dead cells, and they are also central inhibitors of the body's innate immune response to bacteria, viruses and other pathogens.

The Salk scientists found that a substance called phosphatidylserine (PtdSer), which is found on the surface of enveloped viruses (viruses with an outer wrapping of a lipid membrane), binds to extracellular proteins and activates TAM receptors on immune cells. In dendritic cells, a type of immune cell that interacts with T and B cells to initiate the adaptive immune response, TAM receptor activation turns off a set of genes called interferons that play a key role in antiviral defense.

"Our findings suggest a unique way in which TAM receptors contribute to the establishment of viral infection by disabling the interferon response," says co-lead study author John A.T. Young, a professor in Salk's Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis. "As a consequence, the interferon-stimulated defense genes are not turned on, rendering the target cell more permissive for virus infection."

This is a previously unknown mechanism for enveloped viruses, which are very common, to inhibit the body's normal antiviral response. Since PtdSer exposure seems to be a general feature of enveloped viruses, the researchers say many different viruses may use the mechanism to counteract the cellular antiviral response in cells with TAM receptors.

Understanding this mechanism allows researchers to work on developing broad-spectrum antiviral drugs that prevent viruses from shutting down the interferon response in cells by blocking TAM receptor activation. In their study, the Salk scientists tested a small-molecule drug called BMS-777607, initially developed for anti-cancer therapy, that does just that.

"With this small molecule, viruses can't activate TAM receptors, so they can't shut down the interferon response," says co-lead author Greg Lemke, a professor in Salk's Molecular Neurobiology Laboratory and the Françoise Gilot-Salk Chair, in whose laboratory TAM receptors were discovered.

With other scientists around the country, the Salk researchers are testing a variety of small molecule drugs in series of different viruses, including West Nile, Dengue, influenza, Ebola, Marburg, and hepatitis B. These drugs work, in large part, by blocking the virus' ability to activate TAM receptors, thereby leaving the interferon-mediated antiviral response intact.

"This is a completely novel approach," says Young, who holds the Nomis Foundation Chair at Salk. "It is a way of exploiting a normal piece of the cellular machinery in the immune system to block virus infections." And, if it works, it may prove to be an effective treatment to clear enveloped viruses during the acute phase of infection and perhaps also in chronic virus infections.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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Other researchers on the study were co-first authors Suchita Bhattacharyya and Anna Zag?rska, as well as Erin D. Lew and John Naughton, from the Salk Institute; Bimmi Shrestha and Michael S. Diamond of Washington University; and Carla V. Rothlin of Yale University.

The study was supported by the National Institutes of Health, the Nomis and Auen Foundations, the James B. Pendleton Charitable Trust, a Salk Institute innovation grant, the Human Frontiers Science Program, and the Leukemia and Lymphoma Society.

Enveloped Viruses Disable Innate Immune Responses in Dendritic Cells by Direct Activation of TAM Receptors

Cell Host & Microbe, Volume 14, Issue 2, 136-147, 14 August 2013; 10.1016/j.chom.2013.07.005

Salk Institute

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New understanding of how Ebola virus suppresses the human immune system

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Signal uncovered that prevents the immune system from spinning out of control

Main Category: Immune System / Vaccines
Also Included In: Allergy
Article Date: 25 Jul 2013 - 0:00 PDT Current ratings for:
Signal uncovered that prevents the immune system from spinning out of control

A team led by a University of Arizona researcher has discovered a previously unknown mechanism that prevents the immune system from going into overdrive, shedding light not only on how our body controls its response to pathogens but on conditions such as autoimmune diseases, allergies and chronic inflammation as well.

The group found a protein previously believed to only play a role in blood clotting acts as a negative feedback signal, telling defense cells to calm down, thereby preventing an immune reaction from spiraling out of control. The results, which could lead to new therapeutics for a variety of disorders caused by a faulty immune response, are published in the scientific journal Immunity.

When pathogens such as viruses or bacteria invade our body, the immune system reacts by producing a flurry of chemical signals, known as chemokines that act as a bugle call recruiting specialized defender cells to the scene, such as macrophages, which devour the intruders. This first line of defense is known as inflammation.

"Inflammation is a necessary defense mechanism - you can't live without it," said Sourav Ghosh, assistant professor in the department of cellular and molecular medicine at the UA College of Medicine and lead author of the study. "On the flip side, if you can't regulate the inflammation, it can damage the body."

To be effective against pathogens, yet prevent collateral damage from the body's own defenses, the immune system has to maintain just the right level of inflammation, explained Ghosh, who is also a member of the University of Arizona Cancer Center and theUA's BIO5 Institute.

"It needs to be not too high and not too low," he said. "The question had always been, how does the immune system maintain that balance? Our discovery explains this."

All organisms, even plants, have some kind of immune system at their disposal that acts as an army fighting against the onslaught of microbes, viruses, parasites and other pathogens in the environment. Vertebrates have evolved the most sophisticated arsenal of "soldiers" and "weapons," relying on two powerful lines of defense: a non-specific, or innate, immune response and the specific, or adaptive, immune response.

In the non-specific response, the immune system throws a first wave of countermeasures at the intruders, consisting of - among other things - aggressive chemicals, destructive enzymes and kamikaze-like neutrophils, specialized white blood cells that destroy the attackers by devouring them, killing themselves in the process.

"First you don't know who the enemy is, so you fire everywhere with your eyes closed," Ghosh explained. "But once you know the enemy, you need to shut off this first response firing and bring in the special ops so to speak."

The special ops come in the form of the specific immunity, capable of targeting pathogens very precisely, taking out the enemy in a sniper-like fashion, while sparing friendly microbes and cells belonging to the body. Most importantly, this portion of the immune system contains cells that remember every attacker trying to conquer an organism throughout its lifetime, allowing the immune system to summon the most effective, specialized task force to counter a pathogen it recognizes from a previous battle.

"The innate immune response is necessary to activate the adaptive response," Ghosh said. "But once activated, there has to be a mechanism that prevents the adaptive response from going into overdrive. From previous studies, we knew there had to be some kind of signal that does this, but we didn't know the nature of that signal. Now we do."

Two kinds of immune cells turned out to be the key players in mediating the immune response: the dendritic cells, so called because of the tree-like branches they grow during their development ("dendron" means "tree" in Greek), which belong to the first wave of defense; and the T-cells, so named because they mature in the thymus gland of the second, which are part of the second wave, the specific immune response.

"The dendritic cells activate the T-cells," Ghosh explained. "Only when they're activated, not when they're resting, do the T-cells produce this protein that we knew only from the blood clotting process, called Protein S."

The T-cells display Protein S on their surface, where it makes contact with a receptor the dendritic cells carry on their surface. This triggers a signal telling the dendritic cell to stop switching on T-cells, causing the immune response to slow down.

"We thought about which cells could be the source of that signal," said Carla Rothlin of the School of Medicine at Yale University, who led the study together with Ghosh. "You don't want to put the brakes on from the very beginning, or otherwise the immune response would never amount to anything. But you want to slow it down once it starts going too fast."

"We figured that once the specific response is underway, you don't really need the unspecific response anymore, so the T-cells appeared to be the best candidates for the source of this signal."

To test their hypothesis, the researchers studied the immune response in mice in which the gene coding for Protein S had been deactivated selectively in their T-cells, rendering them unable to communicate with the dendritic cells.

As expected, these mice were unable to regulate their immune response, resulting in higher levels of inflammation compared to their normal counterparts.

To assess the relevance of their findings to humans, Ghosh and his co-workers then studied blood from patients with inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. Consistent with their previous results, patients suffering from increased inflammation had lower levels of Protein S in their blood stream compared to healthy volunteers.

The findings could help scientists and clinicians develop better treatments for inflammatory diseases, for example by designing drugs that substitute for insufficient Protein S. According to Ghosh, patients with inflammatory bowel disease are 20 times more likely to develop colon cancer, further underlining the significance of this study.

Study co-author Dr. Jonathan Leighton reported anecdotal evidence from the clinical practice that is in line with the dual roles Protein S is believed to play.

"Patients with inflammatory bowel disease can develop blood clots if they have active disease," said Leighton, a UA alumnus who holds the Chair of the Division of Gastroenterology at Mayo Clinic in Scottsdale, Ariz. "From a clinical standpoint, we think that three factors predispose to inflammation in inflammatory bowel disease - genetic, environmental and the immune system. This research is exciting because it focuses on the immune system. No one has found a consistent inflammatory pathway that explains all the clinical manifestations, and it may be that different pathways are affected in different patients. We don't understand how it all relates quite yet, but this study is a step toward a better understanding that will ultimately help us treat patients more effectively."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our immune system / vaccines section for the latest news on this subject.

The study was funded by the National Institutes of Health (NIH) grants R01 AI077058, R01 AI089824, CA95060 and T32 AI007019); the Crohn's and Colitis Foundation; the American Heart Association; the American Asthma Foundation; the Lupus Research Institute; a CONICET Postdoctoral Fellowship and a Gershon-Trudeau Postdoctoral Fellowship.

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Mixing ISO-14001, Environment, and OHSAS-18001 Safety and health, Right into a Unified System

Mixing the ISO-14001 Environment Management and OHSAS-18001 Safety and health Management standards right into a single, unified system, can provide substantial advantages over applying scalping strategies individually. Costs could be reduced having a single, combined group of documentation, reduced training costs, along with a lower registration audit cost. This is actually the most practical and least time intensive road to registration.

ISO-14001 and OHSAS-18001 are two of the most common and many asked for ISO management systems outdoors from the ISO-9001 (or even the more industry specific AS-9100, ISO/TS-16949, and ISO-13485) Quality Management System. Increasingly more forward thinking information mill asking for their providers come with an effective Environment Management system in-place. This is particularly important when confronted with companies whose public image is essential for them. Many European information mill flowing lower their environment management needs for their sub-tier providers too. When you are registered towards the ISO type quality system, adding registration towards the Environment and Safety and health standards isn't difficult whatsoever. You have the knowledge of how scalping strategies work and just how they're given, enhanced and maintained. Which means that applying both can't only help you save considerable money over applying individually, but it will likewise enhance your company's bottom lime once the savings of controlling these critical facets of business begins to start working. Applying both of these management systems greatly reduces your company's contact with legal cases too. Let us examine all these systems and discuss how effective implementation can help you save money and control risks.

ISO-14001 may be the Worldwide Environment Management standard. This is actually the second most implemented ISO system. By 2012, nearly one fourth of the million companies have grown to be ISO licensed. The ISO 14001 standard doesn't dictate environment performance needs. Rather, it works as a framework to help organizations in developing their very own environment management systems. ISO 14001 could be integrated along with other management functions and assists companies in meeting their environment and economic goals. ISO 14001, like ISO-9001 is extremely scalable, therefore it might be put on any size or kind of organization, service or product, in almost any sector of activity, so whether you've three or 5,000 employees, manufacture hazardous chemicals, or only produce intellectual property, you are able to approve your company to ISO-14001.

OHSAS-18001 is really a virtual mirror of ISO-14001 other than it focuses its management efforts around the company's safety and health issues instead of its environment issues. Because of this applying both isn't a lot more difficult than applying just one. A lot of the effort in applying these is training the employees how you can effectively rely on them. ISO accreditation agencies and registrars recognize this to allow them to provide a reduced registration audit when you are performing both systems concurrently - over a 30% reduction.

Additionally to enhanced procedures efficiencies, applying these standards can lead to a large discount in insurance charges. Both insurance, as you have substantially less contact with legal cases, and workers comp insurance, since you address, monitor and manage your company's safety and health issues, could be reduced - sometimes having to pay back the price of implementation is really a single year, based on your company's size, exposure along with other relevant issues.

Learning and applying the ISO-14001 Environment Management and OHSAS-18001 Safety and health Management standards, whilst not hard for a previously qualified ISO-9001 Quality System manager, simply requires trading time to get learning both of these standards as well as in how you can mix them. Many methods and techniques could be combined. For example, you simply need one corrective action procedure, one management review meeting, and a bouquet of documents which will cover the needs of both standards. One method to ease this time around consuming process is to apply qualified and trained consultants. Should you want to follow this path, make sure your consultants are not only seen trained on the ISO-14001 and OHSAS-18001 standards, but additionally regarding how to mix them right into a single combined system. ANAB accredited registrars are actually offering Lead Auditor practicing combined management systems.

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