Scientists at The University of Manchester have made important advances in understanding why our immune system can attack our own tissues resulting in eye and kidney diseases. It is hoped the research will pave the way for the development of new treatments for the eye condition age-related macular degeneration (AMD) and the kidney condition atypical Haemolytic Uremic Syndrome (aHUS).
Both AMD, which affects around 50 million people worldwide, and aHUS, a rare kidney disease that affects children, are associated with incorrectly controlled immune systems. A protein called complement factor H (CFH) is responsible for regulating part of our immune system called the complement cascade. Genetic alterations in CFH have been shown to increase a person’s risk of developing either AMD or aHUS, but rarely both. Why this is the case has never been explained until now.
Researchers from the Wellcome Trust Centre for Cell Matrix Research and the Ophthalmology and Vision Research Group in The University of Manchester’s Institute of Human Development have been expanding on their previous work that demonstrated a single common genetic alteration in CFH prevents it from fully protecting the back of the human eye. The research teams of Professor Tony Day and Professor Paul Bishop found that a common genetically altered form of CFH associated with AMD couldn’t bind properly to a layer under the retina called Bruch’s membrane. Having a reduced amount of CFH in this part of the eye leads to low-level inflammation and tissue damage, eventually resulting in AMD.
However, this mutation that changes CFH function in the eye has no affect on the protein’s ability to regulate the immune system in the kidney. A cluster of genetic mutations in a completely different part of CFH are associated with the kidney disease aHUS, but these have no affect on the eyes.
In their most recent study, which was funded by the Medical Research, the Manchester researchers have identified why these mutations in CFH result in diseases in very specific tissues. Professor Day explains: ‘For the first time we’ve been able to identify why these protein mutations are so tissue specific. We’re hoping our discovery will open the door to the development of tissue specific treatments to help the millions of people diagnosed with AMD every year.’
The research team looked at the two parts of CFH affected by the mutations. Both regions are capable of recognising host tissues, through interacting with sugars called glycosaminoglycans (GAGs). Successfully recognising these GAGs lets CFH build up a protective layer on the surface of our tissues that prevents our own immune system from attacking them.
It had always been believed that the region with mutations associated with aHUS was the most important for host recognition and for years people have been researching how to readdress immune dysregulation based on this belief. However, the recent discovery of a single common genetic alteration in the other part of CFH that is associated with eye disease raised the possibility that this previous opinion was not fully accurate. The University of Manchester

Stroke, heart attacks and numerous other common disorders result in a massive destruction of cells and tissues called necrosis. It’s a violent event: As each cell dies, its membrane ruptures, releasing substances that trigger inflammation, which in turn can cause more cellular necrosis. A new Weizmann Institute study may help develop targeted therapies for controlling the tissue destruction resulting from inflammation and necrosis.
The study, conducted in the laboratory of Prof. David Wallach of the Biological Chemistry Department, focused on a group of signalling enzymes, including caspase 8, which was discovered by Wallach nearly two decades ago. Earlier studies by scientists in the United States, China and Europe had shown that this group of proteins induces ‘programmed,’ or deliberate, necrosis intended to kill off damaged or infected cells. This revelation had generated the hope that by blocking the induction of necrotic cell death by these proteins, it might be possible to prevent excessive tissue damage in various diseases.
But in the new study, Wallach’s team sounds a warning. The researchers have revealed that under conditions favouring inflammation – that is, in the presence of certain bacterial components or other irritants – the same group of signalling enzymes can trigger an entirely different process in certain cells. It can activate a previously unknown cascade of biochemical reactions that causes inflammation more directly, without inducing necrosis, by stimulating the production of hormone-like regulatory proteins called cytokines. The research, mainly based on experiments in transgenic mice lacking caspase 8 in certain immune cells, was spearheaded by postdoctoral fellow Dr. Tae-Bong Kang. Team members Seung-Hoon Yang, Dr. Beata Toth and Dr. Andrew Kovalenko made important contributions to the study.
These findings suggest that prior to developing targeted necrosis-controlling therapies, researchers need to learn more about the signals transmitted by caspase 8 and its molecular partners: Since this signalling can lead to several entirely different outcomes, the scientists need to determine when exactly it results directly in necrosis and when it does not. Clarifying this matter is of enormous importance: Tissue necrosis occurs in a variety of disorders affecting billions of people, from the above-mentioned stroke and heart attack to viral infections and alcoholism-related degeneration of the liver. Weizmann Institute

The World Health Organisation (WHO) has urged countries with possible cases of novel coronavirus to share information. The move comes after Saudi Arabia said the development of diagnostic tests had been delayed by patent rights on the NCoV virus by commercial laboratories.
Twenty-two deaths and 44 cases have been reported worldwide since 2012, the WHO says. NCoV is from the same family of viruses as the one that caused Severe Acute Respiratory Syndrome (Sars). An outbreak of Sars in 2003 killed about 770 people. However, NCoV and Sars are distinct from each other, the WHO says.
The virus first emerged in Saudi Arabia, which is where most cases have since arisen. Saudi Deputy Health Minister Ziad Memish raised his concerns at the World Health Assembly in Geneva.
‘We are still struggling with diagnostics and the reason is that the virus was patented by scientists and is not allowed to be used for investigations by other scientists,’ he said. ‘I think strongly that the delay in the development of … diagnostic procedures is related to the patenting of the virus.’
WHO chief Margaret Chan expressed dismay at the information.
‘Why would your scientists send specimens out to other laboratories on [sic] a bilateral manner and allow other people to take intellectual property rights on a new disease?’ she asked.
‘Any new disease is full of uncertainty.’
She is urging the WHO’s 194 member states to only share ‘viruses and specimens with WHO collaborating centres… not in a bilateral manner.’
She added: ‘I will follow it up. I will look at the legal implications together with the Kingdom of Saudi Arabia. No IP (intellectual property) should stand in the way of you, the countries of the world, to protect your people.’ BBC

A JDRF-funded study out of Switzerland has shown that a single gene called SIRT1 may be involved in the development of type 1 diabetes (T1D) and other autoimmune diseases. The study represents the first demonstration of a mono-genetic defect leading to the onset of T1D.

The research began when Marc Donath, M.D., endocrinologist and researcher at the University Hospital Basel in Switzerland, discovered an interesting pattern of autoimmune disease within the family of one of his patients, a 26-year-old male who had recently been diagnosed with T1D. The patient showed an uncommonly strong family history of T1D; his sister, father, and paternal cousin had also been diagnosed earlier in their lives. Additionally, another family member had developed ulcerative colitis, also an autoimmune disease.

‘This pattern of inheritance was indicative of dominant genetic mutation, and we therefore decided to attempt to identify it,’ Dr. Donath said.

Four years of analysis using three different genotyping and sequencing techniques pointed to a mutation on the SIRT1 gene as the common indicator of autoimmune disease within the family. The SIRT1 gene plays a role in regulating metabolism and protecting against age-related disease. To gain more understanding of how this genetic change in SIRT1 leads to T1D, Dr. Donath and his team performed additional studies with animal models of T1D. When the mutant SIRT1 gene found in the families was expressed in beta cells, those beta cells generated more mediators that were destructive to them. Furthermore, knocking out the normal SIRT1 gene in mice resulted in their becoming more susceptible to diabetes with greatly increased islet destruction. Dr. Donath speculates that the beta cell impairment and death due to the SIRT1 mutation subsequently activates the immune system toward T1D.

‘The identification of a gene leading to type 1 diabetes could allow us to understand the mechanism responsible for the disease and may open up new treatment options,’ Dr. Donath explained.

Patricia Kilian, Ph.D., director of the Beta Cell Regeneration Program at JDRF, concurred, and said that the development is exciting for many reasons: ‘While the change in the genetic makeup within this family with type 1 diabetes is rare, the discovery of the role of the SIRT1 pathway in affecting beta cells could help scientists find ways to enhance beta cell survival and function in more common forms of the disease. This study also reinforces increasing evidence that abnormal beta cell function has a role in the development of type 1 diabetes, and that blocking or reversing early stages of beta cell dysfunction may help prevent or significantly delay the disease’s onset. Drug companies are already in the process of developing SIRT1 activators, which could eventually speed our ability to translate these new research findings into meaningful therapies for patients.’ JDRF

For the majority of cancer patients, it’s not the primary tumour that is deadly, but the spread or ‘metastasis’ of cancer cells from the primary tumour to secondary locations throughout the body that is the problem. That’s why a major focus of contemporary cancer research is how to stop or fight metastasis.
Previous lab studies suggest that metastasising cancer cells undergo a major molecular change when they leave the primary tumour – a process called epithelial-to-mesenchymal transition (EMT). As the cells travel from one site to another, they pick up new characteristics. More importantly, they develop a resistance to chemotherapy that is effective on the primary tumour. But confirmation of the EMT process has only taken place in test tubes or in animals.
In a new study Georgia Tech scientists have direct evidence that EMT takes place in humans, at least in ovarian cancer patients. The findings suggest that doctors should treat patients with a combination of drugs: those that kill cancer cells in primary tumours and drugs that target the unique characteristics of cancer cells spreading through the body.
The researchers looked at matching ovarian and abdominal cancerous tissues in seven patients. Pathologically, the cells looked exactly the same, implying that they simply fell off the primary tumour and spread to the secondary site with no changes. But on the molecular level, the cells were very different. Those in the metastatic site displayed genetic signatures consistent with EMT. The scientists didn’t see the process take place, but they know it happened.
‘It’s like noticing that a piece of cake has gone missing from your kitchen and you turn to see your daughter with chocolate on her face,’ said John McDonald, director of Georgia Tech’s Integrated Cancer Research Center and lead investigator on the project. ‘You didn’t see her eat the cake, but the evidence is overwhelming. The gene expression patterns of the metastatic cancers displayed gene expression profiles that unambiguously identified them as having gone through EMT.’
The EMT process is an essential component of embryonic development and allows for reduced cell adhesiveness and increased cell movement.
According to Benedict Benigno, collaborating physician on the paper, CEO of the Ovarian Cancer Institute and director of gynecological oncology at Atlanta’s Northside Hospital, ‘These results clearly indicate that metastasising ovarian cancer cells are very different from those comprising the primary tumour and will likely require new types of chemotherapy if we are going to improve the outcome of these patients.’ Georgia Tech