How gene mutation triggers the immune system

Scientists discovered how a gene mutation affects T cell function to promote immune disorders and then tested a treatment based on the discovery-successfully fixing donated immune cells from a 16-year-old boy with an abnormally low level of white blood cells called lymphopenia. The discovery centers on mutation of the gene Gimap5, which is important to the healthy formation and function of CD4+ T cells, one of the immune system's super soldiers against infection and disease.

The protein associated with the Gimap5 gene (also Gimap5), is important because it regulates a protein that inactivates an enzyme called GSK3, researchers said. If GSK3 isn't inactivated it causes DNA damage in T cells that are expanding, causing the cells not to survive or function properly. In mice and human blood cells, the researchers tested drugs that inhibit GSK3, improving immune system function in mice and restoring normal T cell function in the human cells.

GSK3 inhibitors are used to treat other diseases like Alzheimer's, mood disorders and diabetes mellitus. GSK3 inhibitors will improve T cell survival and function and may prevent or correct immune-related disorders in people with Gimap5 loss-of-function mutations.Therapeutically targeting this pathway may be relevant for treating people with Gimap5 mutations linked to autoimmunity in Type 1 diabetes, systemic lupus erythematosus or asthma.

Hoebe led the study, together with Andrew Patterson, a PhD student in Hoebe's lab, and Jack Bleesing, MD, PhD, in the Division of Bone Marrow Transplantation and Immune Deficiency. Immune system disorders lead to abnormally low immune activity (deficiency) or overactivity (autoimmunity). Immune deficiency diseases decrease the body's ability to fight infection, while autoimmunity prompts the body to attack its own tissues. Both are common causes of illness, and malfunctioning T cells are linked to both.

The Gimap5 gene controls its associated protein Gimap5 (GTPase of immunity associated protein 5). As the name suggests, its role is mainly linked to immune system function, lymphocyte white blood cell survival and T cell formation in the thymus. Genetic variants in Gimap5 were already associated with autoimmunity and colitis.
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How to live longer

Many cells in human body, such as those which make up brain need to last a lifetime. To do this human cells have developed ways of protecting themselves. One way is through a process called autophagy, which literally means self-eating, where damaged components are collected together and removed from the cell.This is very important as accumulation of damage in cells has been linked to several diseases including dementia.

Lead author, Dr Viktor Korolchuk explains: "As we age, we accumulate damage in our cells and so it is thought that activating autophagy could help us treat older people suffering from dementia. In order to be able to do this we need to understand how we can induce this cell cleaning." In this study the authors were able to identify how a protein called p62 is activated to induce autophagy. They found that p62 can be activated by reactive oxygen species (ROS). ROS are by-products of our metabolism that can cause damage in the cell.

This ability of p62 to sense ROS allows the cell to remove the damage and to survive this stress. In lower organisms, such as fruit flies, p62 is not able to do this. The team identified the part of the human p62 protein which allows it to sense ROS and created genetically modified fruit flies with 'humanised' p62. These 'humanised' flies survived longer in conditions of stress. Abilities like sensing stress and activating protective processes like autophagy may have evolved to allow better stress resistance and a longer lifespan.

Specific mutations in human p62, which cause a neurodegenerative disease called amyotrophic lateral sclerosis (ALS), can prevent activation of p62 by ROS. These cells are then unable to induce protective autophagy, and the authors explain that this could underlie the premature death of neurons in patients with this devastating age-related disease. In contrast, 'humanised' p62 fruit flies did not live longer suggesting that other mechanisms may be required. The research demonstrates that a collection of small adaptations like that of human p62 could have accumulated over time and these adaptations could underlie our increased natural defences and longer lifespans. The discovery of these adaptations allows a better understanding of how to treat age-related diseases.
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Brain cells may prevent Parkinson's disease

A Norwegian study shows that impairment in mitochondria may actually protect the brain in Parkinson's disease. Mitochondria are microscopic power stations found inside human cells. They convert foodstuffs into fuel, providing the required energy. Studies in brain tissue from individuals with Parkinson's disease showed that an essential component of the mitochondrial energy generators, called respiratory complex-I, becomes impaired in an area of the brain called the "substantia nigra" .

A new study from the University of Bergen (UiB), in Norway, in collaboration with the University of Cambridge, shows that the function of mitochondria, the microscopic powerhouses of the cell, is altered throughout the entire brain of individuals with Parkinson's disease. This new study shows that complex I deficiency is a global phenomenon in the brain of people with Parkinson's disease, and is found indiscriminately in both affected and healthy brain regions.

 Intriguingly, brain cells (neurons) with decreased complex I levels are significantly less likely to contain Lewy bodies, the abnormal protein-aggregates that characterize Parkinson's disease. These discoveries suggest that, contrary to mainstream theory, mitochondrial complex I deficiency may not be entirely deleterious for the brain in Parkinson's disease. It is possible that complex I deficiency is part of a compensatory regulation attempting to protect the brain in Parkinson's disease.

Parkinson's disease is one of the most common brain disorders. It affects millions of people worldwide. It starts after the age of 50 and causes a combination of debilitating symptoms, including shaking and other abnormal movements, loss of balance, low blood pressure, bladder and intestinal problems, sleeping disorders and dementia. Presently, there is no cure and patients die prematurely due to increasing disability.
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How weather increases the risk of cancer

Living in a cold climate could make people more likely to get cancer, people are at greater risk in colder countries because of their genes. The same genes which stop human cells from dying in freezing temperatures are also linked to breast and bowel cancer and leukaemia. A researcher says the genes contributing to cooler climates are the same which increase the risk of malignant tumours forming in the body.

Genetic variants found to be beneficial in extreme environments, can also predispose for cancer. Cell resistance at low temperatures and at high altitude probably increases the probability for malignancy.’Previous research from 2010 found grim weather in northern parts of the world may make men more vulnerable to prostate cancer, perhaps due to a lack of vitamin D from the sun.

However the new study - which compared international rates of cancer with 240 genetic studies of cancer and seven others in cold and high-altitude countries - suggests where people live affects their genes.Extreme cold weather can cause human cells to die, so that people in freezing countries have genetic mutations to prevent cell death and repair DNA.
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Traffic jam causes tumor growth

When cells lose track of their orientation, they can start to grow out of control, and develop into cancer. Researchers has identified a new regulator for cell orientation, offering a future target for precision medicine in cancer treatment.

Tissues in the breast, pancreas, colon and lungs are all organised as single cell layers called epithelia. Cells sit side by side, and use internal signals to orient themselves. The signals for telling which way is up are connected to the waste handling system, a series of miniature vesicle sorting stations.

Traffic jam in the sorting inside cells can cause tumor development Liver Kinase B1 LKB1 activity promotes tumor growth. Human cells contain tumor suppressor genes that act as gate-keepers to prevent tumor growth. One such classical tumor suppressor, Liver Kinase B1 LKB1 was identified as being responsible for the hereditary cancer predisposition syndrome, Peutz-Jeghers syndrome.

It has later been shown to be mutated in a range of cancers, including lung and colon cancer. The new results suggest that the enzyme LKB1 exists on vesicle sorting stations and is shut off in normal cells, but the traffic jam allows LKB1 to remain active for a longer time.

High activity of LKB1 contributes to tumor growth by sending confusing signals to the cell about which way is up. The researchers investigated epithelial tissues in the fruit fly Drosophila melanogaster, a powerful animal model system for medical research, in addition to human cells grown in 3-D cultures in the laboratory.

In both systems, high activity of LKB1 increased stress signals in the cells and disrupted cellular orientation. Targeting LKB1 as potential therapy, researchers tested the effect of genetically removing LKB1 from cells that otherwise would form tumors due to loss of orientation.

Reducing LKB1 activity restored normal epithelial organization and prevented
tumor growth. These results suggest that pharmacological inhibition of LKB1 may be beneficial as treatment in some cancer types. It will be important to determine if pharmacological agents can specifically target LKB1 in animals or in human cells in culture, and how such potential treatment may be transferred to the clinic.
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How hepatitis C hides in the body

The Hepatitis C (HCV) virus is invisible to the immune system by breaking down communication between the immune cells, it builds virus factories that multiply easily. It takes one to three months from infection to disease, it can lead to liver failure and death. Hepatitis C virus is transmitted through blood and infects the cells in the liver, it is difficult to detect because it does not have symptoms when you get infected.

The virus causes chronic infection that lasts a lifetime. It may take decades before the infection leads to liver failure or cancer, so a lot of people are unaware that they have the virus in their body. They only notice it when they get seriously ill, which may be too late for the treatments that are available. Hepatitis C virus destroys important proteins in the immune system to promote its own growth. The ability to directly manipulate their host cells is the reason some viruses are very harmful to human.

Human cells have a complex inner structure that is divided into different areas, with different sacs that are formed from fatty membranes. Viruses that have the same genetic material as HCV (positively polarized single-stranded RNA) cause major changes in these membrane sacs.

Liver cells infected with HCV had altered membrane sacs. To study whether the IRGM protein caused the changes, researchers employed the CRISPR-Cas system, a technique that is used for regulating cells, in this case to turn off the IRGM protein in the liver cells. When the IRGM is removed from the liver cells, the virus is unable to grow.

The reason for this is that the hepatitis C virus utilizes some of the cells, called the Golgi apparatus, where the protein IRGM has an important function. The Golgi apparatus is a kind of transport centre in the cells. It packs proteins into small sacs called vesicles and sends them where they need to go within the cell, or out to other cells.

The hepatitis C virus utilizes this to build its virus factories by taking over and redirecting these vesicles with the necessary building blocks to the site where the factories are being built. These vesicles are rich in lipids that the virus is entirely dependent on to anchor its factory construction.

When this protein is removed, the virus is no longer able to infiltrate the Golgi apparatus and thus it can't build up its secret network of virus factories. Hepatitis C is transmitted via the blood. Infection is spread primarily through unclean syringes, non-sterilized medical devices, or unsafe blood transfusions.
HVC can also be passed on from mother to child, and through bodily fluids.
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Drinking of alcohol makes you older

 Alcoholic patients had shortened telomere lengths, placing them at greater risk for age-related diseases, like cardiovascular disease, diabetes, cancer, dementia and liver disease. The more alcohol people drink, the more their cells age.

Telomeres are parts of human cells that affect how cells age, the protein caps on the ends of human chromosomes are markers of aging and complete health.

Excess drinking of alcohol leads to lost of replication of cell tiny bit of telomere so they get shorter with age. But some people may have shorter telomeres for other reasons.

Alcoholic patients have a shortened telomere length because excess drinking causes biological aging at a cellular level.

Scientists examined patients undergoing alcoholism treatment in hospital, they also examined their habits, DNA samples and drinking histories

They discovered that they have thiamine deficiency TD and it causes neuron impairments such as Wernicke-Korsakoff Syndrome which can leads to braid disorder, coma and death in alcoholic patients.

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