Depression linked to brain inflammation

Years of depression can cause brain inflammation that has been linked to degenerative diseases like Alzheimer's and Parkinson's, an analysis of brain-changes among people whose depression lasted more than 10 years, done by the Canadian Centre for Addiction and Mental Health, suggested doctors may need to treat both depression and inflammation in these patients.

The average, untreated bout of depression typically lasts a few months, according to Harvard University. Everyone's symptoms vary in type, severity, and duration. Depression may look like irritability or simply a 'low mood.' But the staying power of depression may make it even more difficult to diagnose, as years of the disorder come to be seen as 'normal' for the person suffering the symptoms.

This may be why the average age of diagnosis for persistent depressive disorder (PDD) is relatively late, at 31 years old. The condition is also known to affect eating habits and experiences. Some tend to overeat when they are depressed, others lose their appetites, and still others will experience upset stomachs.

A high number of physical complaints may also be, in some cases, a warning sign that someone is depressed or in the throes of another mental health issue. Depression typically involves a shortage of serotonin, a neurochemical that nerve cells use to communicate a command for blood vessels to constrict. This is particularly important to the way that the digestive tract functions, as well as to the experience of pain.

Depression is a physical illness that could be treated with anti-inflammatory drugs, an overactive immune system may trigger the mental health condition by causing widespread inflammation that leads to feelings of hopelessness and unhappiness. The immune system may fail to 'switch off' after an illness or traumatic event. Previous research has shown people who suffer severe emotional trauma have signs of inflammation, which suggests their immune system is constantly 'fired-up'.

Researchers from the Center for Addiction and Mental Health (CAMH) found evidence that longer bouts of depression increased brain inflammation. To determine whether or not the duration of depression made a difference for its inflammatory effects, the research team, led by senior study author Dr Jeff Meyer of CAMH's Campbell Family Mental Health Research Institute recruited three groups of 25 people.

The first group had experienced more than a decade of depression, the second had experienced less than a decade, and the third had never experienced any depression, by their own reports. The difference between the PDD sufferers and the other two groups was dramatic. Those who had been depressed for more than 10 years had 30 percent more of a protein marker of brain-inflammation than those who had experienced depression, but for shorter amounts of time.

Their inflammation levels were also higher than the control group that had never been depressed. Greater inflammation in the brain is a common response with degenerative brain diseases as they progress, such as with Alzheimer's disease and Parkinson´s diseases.
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Helping the immune system thwart infections

Yale researchers have developed a set of synthetic molecules that may boost the strength of a key, virus-fighting protein. The protein, RIG-I, is an important sensor in the immune system of humans and other animals. It recognizes and responds to viral RNA by surrounding it, latching onto it, and launching the immune system into action.

The Yale team, led by biologists Anna Pyle and Akiko Iwasaki, has designed molecules that jump-start the process. These synthetic, stem-loop RNA (SLR) molecules can be visualized as short cords with a knot at one end. The configuration enables the SLRs to bind with RIG-I molecules in a way that prompts an aggressive response.

"When you tickle RIG-I with this small, RNA hairpin, it alerts the body that it's time to respond," said Pyle, professor of molecular, cellular, and developmental biology, and of chemistry. This gives a tool that can help with everything from the design of better vaccines to better antivirals and anti-cancer therapies.The new study represents the first time scientists have been able to specifically manipulate and analyze the RIG-I biosensor in a living animal-mice.
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How infection site affects the immune system

A new study by scientists at the Gladstone Institutes shows that infection sites could affect the immune system's response to a virus and the way the virus spreads through the body. The researchers focused on common routes of sexual transmission of viruses, such as the lower female reproductive tract and the lower gastrointestinal tract that includes the large intestine and the anus.

These mucosal barriers-the body's openings lined with a membrane called mucosa are responsible for distinguishing between harmless bacteria that normally reside in human and potentially dangerous pathogens, as well as other substances, such as food or sperm. Human body is constantly trying to balance between tolerating harmless elements and defending against the threats.

Reseachers discovered that the body's reaction is different based on the infection site. They showed that the vaginal and rectal cavities activate a distinct immune response to the same pathogen. To conduct the study, research team created a new model of viral infection through the rectum that uses lymphocytic choriomeningitis virus (LCMV), a rodent virus often used in research to model other pathogens. They then compared their findings to their previous work on vaginal infection by LCMV.

In 2016, they showed that vaginal infection causes a delayed response by protective cells. As a result, the immune system takes longer to clear the virus from the female reproductive tract. They also noticed that the virus stayed in the vagina and didn't spread to other parts of the body. In contrast, the new study indicates that, after infection through the rectum, the virus rapidly spreads throughout the body. The scientists also found that the virus wasn't being carried through the blood. Instead, LCMV infects the body's own immune cells, which in turn spread the virus systemically. Interestingly, this is the same dissemination process used by the HIV virus.

The initial immune response elicited depends on the route of infection, and can actually dictate the dissemination of the virus. The researchers revealed that mucosal barriers have different tolerance mechanisms that affect the immune system's response to invading pathogens. Once a virus breaches one of the barriers, early events in the body's response to that virus can play a key role in determining the outcome of an infection.
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Treating aggressive colon tumor with immunotherapy

Immunotherapy against cancer cells has become a powerful approach to treat cancers such as melanoma and lung cancer. However, to date, most colon tumours appeared to be unresponsive to this kind of therapy. Given this observation, researchers hypothesized that this kind of tumour was simply invisible to the immune system.

A team headed by ICREA researcher Eduard Batlle, at the Institute for Research in Biomedicine (IRB Barcelona), explains that the hormone TGF-beta is responsible for the "blindness" of the immune system to colon cancer cells. The few clinical immunotherapy trials done in patients with the most common subtype of colon cancer were not giving good results.

By inhibiting the activity of TGF-beta, the cells of the immune system infiltrate and recognise the tumour, fight the cancer, and even stop colon tumours from metastasizing to the liver and lung in a preclinical mouse model that mimics the human disease. In addition, and more importantly, the researchers demonstrated that the combination of a TGF-beta inhibitor with available immunotherapies boost the anti-tumour effect, allowing the immune system to efficiently eliminate already established metastases that would otherwise kill the individual in a question of weeks.

Scientist Daniele Tauriello, postdoctoral fellow and first author of the article, induced four of the most common mutations present in advanced human colon tumours in mice. After confirming the similarity of the mouse tumours with those in humans, they built a biobank of tumour organoids3-D mini-tumours and grafted them in a controlled manner in immunocompetent mice.

For studies of the immune system, the tumour has to be of mouse origin. Otherwise, the animal would reject it.This animal model which mimics the main features of metastatic colon cancer in humans, allowed the researchers to examine how cancer cells evade the immune system. Around 40 to 50 percent of colon cancer patients relapse in the form of metastasis, with the tumours reproducing mainly in the liver and lung.

Once advanced stage colon cancer is diagnosed, oncologists do not have access to efficient treatments to cure the patient. This study paves the way for the development of the first immunotherapy treatment for patients with metastatic colon cancer and for those patients with poor prognosis but who have not yet developed metastasis. Oncologists and pharmaceutical companies will soon start clinical assays that combine TGF-beta inhibitors, which are already in clinical use, with immunotherapies.

The researchers are convinced that many colon cancer patients will benefit from this therapeutic strategy. In the same issue of Nature, another study addresses the lack of response of bladder cancer patients to immunotherapy.  It appears that many types of tumour use the same strategy-increasing the expression of TGF-beta in the environment to evade the immune system. Patients with these tumours may also benefit from immunotherapies based on the inhibition of this hormone.
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Cancer-killing virus alerts immune system

A new UC San Francisco study has shown that a cancer-killing ("oncolytic") virus currently in clinical trials may function as a cancer vaccine-in addition to killing some cancer cells directly, the virus alerts the immune system to the presence of a tumor, triggering a powerful, widespread immune response that kills cancer cells far outside the virus-infected region.

Using novel approaches to examine exactly how oncolytic viruses attack tumors, issue of Cancer Research provided surprising insights about how a viral infection can cooperate with the immune system to attack cancer cells. The study highlights an opportunity to combine this form of therapy with cancer immunotherapy drugs such as checkpoint inhibitors, which unleash the immune system's full cancer-fighting power.

The idea that viruses could fight cancer goes back to the early 20th century, when doctors noted that cancer patients sometimes experienced dramatic remission after getting viral infections. Researchers have been developing oncolytic viruses since the 1980s, but following the U.S. Food and Drug Administration's 2015 approval of Amgen's Imlygic (T-Vec) as the first oncolytic viral therapy in the U.S., such viruses have become a closely watched area of therapeutic development.

Viruses appear capable of attacking tumors in a number of different ways by directly infecting them, by releasing tumor proteins that trigger a broad immune response against the cancer, and by damaging the blood supply tumors need to survive. To better understand the underlying mechanisms of these viral therapies, a collaboration was forged between UCSF vascular researcher Donald McDonald, MD, Ph.D., and researchers at San Francisco-based biotech SillaJen Biotherapeutics Inc. (formerly Jennerex Biotherapeutics, Inc.)

SillaJen is developing an oncolytic viral therapy called Pexa-Vec, currently in phase III and phase Ib/II clinical trials for use against primary liver and colorectal cancers, respectively. Pexa-Vec is an engineered virus based on the harmless vaccinia cowpox virus, also the basis for the original smallpox vaccine. Early observations suggesting that the virus might attack cancer in part by damaging blood vessels that feed tumor growth.

To study how the modified virus attacks tumors, researchers in the McDonald lab injected it intravenously into mice genetically modified to develop neuroendocrine pancreatic cancer. They found that the virus failed to infect healthy organs or make the animals ill, but succeeded in infecting blood vessels within tumors. These initial infections caused the vessels to leak and expose the tumor cells to the virus. In these experiments, the virus managed to infect and destroy only a small proportion of tumor cells directly, the researchers found, but within five days of the initial infection, the rest of the tumor began to be killed by a powerful immune reaction.

At first small spots of the tumor were infected, but then most of the tumor started to die. The researchers found that by killing some tumor cells directly, the viral infection exposed tumor proteins that could be detected by the immune system, triggering an immune attack on the rest of the tumor. The researchers demonstrated this by temporarily getting rid of the immune system's cancer-killing cells, called CD8+ or cytotoxic T cells, and showing that without these cells, the virus killed only the initial five percent of cancer cells.

When the researchers examined the tumors, they discovered that the second drug acted by making the immune system hyper-alert to tumor proteins released by the viral infection, rather than through effects on tumor blood vessels. This finding suggests that pairing Pexa-Vec's ability to awaken the immune system to previously ignored signs of cancer with the newest generation of checkpoint inhibitors, which act by unleashing the immune system's full force, might be an extremely potent combination therapy.
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Molecular magnet could improve cancer immunotherapy

According to new research in cell, chemicals that attract specialised immune cells toward tumours could be used to develop better immunotherapies for cancer patients Scientists at the Francis Crick Institute have discovered that immune cells called Natural Killer cells accumulate in tumours and release chemicals that attract specialised dendritic cells (cDC1)-white blood cells known for triggering anti-cancer immune responses to the tumour.

Genes associated with Natural Killer cells and cDC1 correlated with cancer patient survival in a dataset of over 2,500 patients with skin, breast, neck and lung cancers. A similar correlation was seen in an independent group of breast cancer patients, with a particularly positive outcome for women with triple negative breast cancer, which typically has a poor prognosis. The findings have given a renewed appreciation of the importance of Natural Killer cells and cDC1 in the immune response against cancer.

The team showed that prostaglandin E2 (PGE2), a molecule produced by some cancer cells, suppresses Natural Killer cell activity and reduces the responsiveness of cDC1 to the chemical attractants. This suggests that blocking PGE2 with aspirin might help boost the effectiveness of immunotherapies by restoring cDC1 levels in tumours. The research reveals more about the way the body's immune system interacts with cancer, exposing one way in which cancer can avoid attack. It highlight the complexity of this relationship and reveal another way in which the immune system can be harnessed to treat cancer.
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Mechanism behind autoimmune disorder

Northwestern Medicine scientists discovered a previously-unknown mechanism of disease behind a specific autoimmune disorder. The scientists observed antibodies that targeted phosphatidylethanolamine, an important phosopholipid, from within the endosomes of cells. This discovery was the first observation of a pathogenic mechanism behind anti-phosphatidylethanolamine (aPE) autoimmunity, an immune system disorder that's been correlated with thrombosis, transplant failure and pregnancy loss.

It was first reported decades ago, but exactly how aPE autoimmunity worked had remained a mystery despite a large body of literature documenting its prevalence, according to Ming Zhao, PhD, associate professor of Medicine in the Division of Cardiology and senior author on the paper. Autoimmune diseases usually develop when antibodies-proteins which neutralize pathogens erroneously attack cells while circulating through the bloodstream. To target those cells, the antibodies bind to accessible antigen targets on the exterior surface of cells.

The internalization happens through the endosome, a part of the cell that samples the external environment and gathers in signaling molecules. In this case, the endosome also draws in the antibodies, making the cells vulnerable.This creates an opportunity for anti-PE antibodies that are brought into the cells to bind to the PE in these tiny vesicles and attack the cells from within a miniature 'Trojan Horse' process, this causes chaos within the cell, sending it into an inflammatory state, leading to a greater risk of blood clot formation and pregnancy complications.

It's important to note the inflammatory response may be the principal effect of aPE because it means anti-inflammatory treatment is likely to be more effective than anti-coagulants. These novel discoveries shed light on how cellular vulnerability to aPE is mediated and explain some of its clinical symptoms, according to the study. Because endosomes are an integral part of nearly every type of cell, linking the activity of aPE antibodies to clinical symptoms will be a priority for scientists in future investigations.
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Immune system may prevents MRSA infection

Researchers at Johns Hopkins, the University of California, Davis, and the National Institute of Allergy and Infectious Diseases have discovered how the immune system might protect a person from recurrent bacterial skin infections caused by Staphylococcus aureus (staph). "There's a huge, unmet clinical need for new approaches against staph skin infections because of declining antibiotic development and rising drug resistance," says Lloyd Miller, M.D., Ph.D., associate professor of dermatology at the Johns Hopkins University School of Medicine.

Staph is a common bacterium and the most common cause of skin infections in people. Additionally, multidrug resistant strains, such as methicillin-resistant Staphylococcus aureus (MRSA), are causing severe skin infections in healthy people outside of hospitals. And once you've had an infection, the recurrence rate is 50 percent within six months. Staph can also spread from the skin and cause invasive and life-threatening infections such as sepsis, osteomyelitis and pneumonia.

Using mice with defective immune systems, research team found that after an initial exposure of the skin to staph, they were surprisingly protected against a second skin exposure with the same bacteria. After testing for antibodies and other usual suspects of the immune system against this infection, it was not clear what immune response was protecting the mice. The researchers then tested a drug FDA-approved for treatment of multiple sclerosis, which acts by preventing certain immune cells from leaving lymph nodes for sites of inflammation.

That genetic sequencing data revealed that specific cells substantially multiplied after the initial infection, then moved to the infection site and provided protection against the second infection. These so-called gamma delta T cells account for less than 1 percent of all the cells in the lymph node prior to infection. After infection, they accounted for more than 20 percent.

Working with collaborators from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, the researchers tested blood from healthy individuals and people with a rare immune disorder that makes them highly susceptible to staph skin infections. Half of people with the disorder die by age 10, but if they survive to adulthood they somehow overcome their susceptibility to staph infections.

In blood samples from these patients, the researchers found an increase in the percentage of gamma delta T cells, similar to what they observed in mice, which remained stable over years. The findings and especially gamma delta T cells may be targeted for developing new therapies or a vaccine against staph skin infections.

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How viruses affect the immune system

Fighting infections depends on bodies' capacity to quickly recognize infected cells and destroy them, a job done by a class of immune cells known as CD8+ T cells. These soldiers get some of their orders from chemical mediators known as cytokines that make them more or less responsive to outside threats. In most cases, CD8+ T cells quickly recognize and destroy infected cells to prevent the infection from spreading.

When it comes to viruses that lead to chronic infection, immune cells receive the wrong set of marching orders, which makes them less responsive," says Martin Richer, an assistant professor at McGill's Department of Microbiology & Immunology and senior author of the study. The research, conducted in Richer's lab by graduate student Logan Smith, revealed that certain viruses persist by driving the production of a cytokine that leads to modification of glycoproteins on the surface of the CD8+ T cells, making the cells less functional.

That maneuver creates time for the pathogen to outpace the immune response and establish a chronic infection. Importantly, this pathway can be targeted to restore some functionality to the T cells and enhance the capacity to control infection. The discovery of this regulatory pathway could help identify new therapeutic targets for a variety of diseases.
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Breast cancer therapies linked to heart failure

According to American Heart Association, women should consider the risks and benefits of any therapies that may hurt hearts during breast cancer treatment, patients should have a conversation with their doctor about the side effects of the treatment. Some treatments for different types of cancer may pose heart risks, but they are growing more common for breast cancer patients.

Side effects can include abnormal rhythms, valve problems or heart failure, where the heart slowly weakens and can't pump effectively. Symptoms may not appear until long after treatment ends.
Herceptin and similar drugs for a specific type of breast cancer can cause heart failure. Sometimes it's temporary and goes away if treatment is stopped, but it can be permanent.

Radiation can affect arteries and spur narrowing or blockages. Other drugs can lead to abnormal heart rhythms or artery spasms, which can cause chest pain and possibly lead to a heart attack. Some research suggests that powerful new drugs that harness the immune system to fight cancer may in rare cases cause heart damage, especially when used together.

Certain chemotherapies such as doxorubicin, sold as Adriamycin and in generic form, might be less risky if given more slowly, rather than all at once. Some research suggests that a drug called dexrazoxane may minimize damage if given to women with advanced breast cancer who are getting high doses of doxorubicin.

Cancer patients should make sure doctors are monitoring their heart before, during and after breast cancer treatment. Common risk factors of breast cancer are: obesity, smoking, sedentary lifestyle and eating of junk food.
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Bacteria in milk linked to rheumatoid arthritis

A strain of bacteria found in milk and beef may be a trigger for developing rheumatoid arthritis in people who are at risk, according to a new study from the University of Central Florida. A team of UCF College of Medicine researchers has discovered a link between rheumatoid arthritis and Mycobacterium avium subspecies paratuberculosis, known as MAP, a bacteria found in about half the cows in the United States. The bacteria can be spread to humans through the consumption of infected milk, beef and produce fertilized by cow manure.

For the study, researchers recruited 100 of her patients who volunteered clinical samples for testing. Seventy-eight percent of the patients with rheumatoid arthritis were found to have a mutation in the PTPN2/22 gene, the same genetic mutation found in Crohn's patients, and 40 percent of that number tested positive for MAP. People born with this genetic mutation and who are later exposed to MAP through consuming contaminated milk or meat from infected cattle are at a higher risk of developing rheumatoid arthritis.

Rheumatoid arthritis is an autoimmune and inflammatory disease that causes the immune system to attack a person's joints, muscles, bones and organs. Patients suffer from pain and deformities mostly in the hands and feet. It can occur at any age but the most common onset is between 40 and 60 years old and is three times more prevalent in women. Some RA patients suffer from Crohn's disease and vice versa, the researchers say a national study needs to investigate the incidence of the two diseases in the same patients.
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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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Cure for skin cancer

The newly discovered drugs combination for skin cancer can help if chemotherapy fails, extending patients’ lives by at least a year. In almost half of kidney cancer patients, by the time the disease is diagnosed it has already spread to other areas of the body due to a lack of symptoms, slashing life expectancy from five years to two. While chemotherapy, which kills both cancer and healthy cells, is used to treat most other advanced cancers, the treatment does not work for most kidney cancers.

The established treatment for the condition is either radiotherapy-which shrinks tumours or tyrosine-kinase inhibitor drugs, including one called sunitinib, which interrupt the blood supply to cancer. However, these only hinder the growth of tumours for four or five months. The drugs, ipilimumab and nivolumab, are already used with remarkable success in the treatment of deadly melanoma skin cancer.

Nivolumab is also used to treat advanced lung tumours. The new trial found that the combination achieved significant kidney tumour shrinkage in 42 per cent of the 425 patients in a trial and reduced the risk of death within two years by 37 per cent. Ipilimumab and nivolumab are immunotherapy drugs that work by enhancing the ability of the body’s immune system cells to attack and destroy cancer. Rather than just putting the cancer into remission for a period, like standard treatments, they appear to carry on working even after treatment has stopped

During the trial, 840 kidney cancer patients were given either sunitinib or the combination immunotherapy. Those on the combination had four infusions of the two drugs at three-weekly intervals. One-fifth of patients experienced severe side effects such as inflammation of the bowel or liver, and had to stop early. The median overall survival rate [the time at which 50 per cent of patients have died after treatment] for sunitinib was 26 months, but for the combination immunotherapy arm, it has still not been reached 36 months on. More than half the patients are still alive.
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Omega-3s for cancer prevention

Omega-3s from fish is better than flaxseed and other oils for cancer prevention, according to a first-ever University of Guelph study. Prof. David Ma has discovered that marine-based omega-3s are eight times more effective at inhibiting tumour development and growth. This study is the first to compare the cancer-fighting potency of plant- versus marine-derived omega-3s on breast tumour development.

There is evidence that both omega-3s from plants and marine sources are protective against cancer and we wanted to determine which form is more effective. There are three types of omega-3 fatty acids : a-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). ALA is plant-based and found in such edible seeds as flaxseed and in oils, such as soy, canola and hemp oil. EPA and DHA are found in marine life, such as fish, algae and phytoplankton.

The study involved feeding the different types of omega-3s to mice with a highly aggressive form of human breast cancer called HER-2. HER-2 affects 25per cent of women and has a poor prognosis. Researchers exposed the mice to either the plant-based or the marine-based omega-3s, beginning in utero. The mice were exposed to the different omega-3s even before tumours developed, which allowed comparing how effective the fatty acids are at prevention.

EPA and DHA can inhibit breast tumour growth, but no one has looked directly at how effective these omega-3s are compared to ALA, exposure to marine-based omega-3s reduced the size of the tumours by 60 to 70 per cent and the number of tumours by 30 per cent. However, higher doses of the plant-based fatty acid were required to deliver the same impact as the marine-based omega-3s.

Omega-3s prevent and fight cancer by turning on genes associated with the immune system and blocking tumour growth pathways. Humans should consume two to three servings of fish a week to have the same effect. Besides certain foods containing EPA and DHA, supplements and functional foods, such as omega-3 eggs or DHA milk, can offer similar cancer prevention effects.
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Blocking inflammation to improve the effect of vaccines

UCL-led research team has found that an anti-inflammatory pill could make vaccines more effective for elderly people. An excessive inflammation reaction in older people can obstruct the immune system. The immune system declines with age, and people can be affected by pathogens they were once immune to, when it comes to cutaneous immunity - specific to skin - the immune system was being obstructed by skin cells that were too prone to producing inflammation responses.

To investigate immune responses, the researchers injected an antigen - a derivative of a pathogen that creates an immune response without inducing illness - into the skin of 175 participants (78 were over 65 years old and the rest were under 40). The pathogen was the varicella zoster virus (VZV), which causes chicken pox. After a person contracts chicken pox, they become immune to VZV, but it can re-activate in old age and cause shingles if T cell immune responses aren't strong enough.

All study participants had previously had chicken pox, meaning they should be immune. The researchers found that the older subjects exhibited weaker immune responses, as there was less T cell activation, and less reddening and swelling of the skin. The reduced response was not due to a lack of resident memory T cells present in the skin. As a control, they also injected a benign saline solution into the other arm of each participant.

 The researchers noticed that even the saline solution brought about an inflammation response in some of the older participants. Those who had the strongest inflammation responses to the saline solution had the weakest immune responses to the VZV, suggesting that the excessive inflammation was inhibiting VZV-specific immunity. Normally inflammation is a healthy part of the body's immune response, too much inflammation was getting in the way of the rest of the body's defences.

By analysing skin biopsies post-injection, the researchers found that the excessive inflammation was associated with activation of the p38 MAP kinase pathway. To test whether this enzyme was to blame, they conducted a follow-up test with 18 of the over-65 participants, who took Losmapimod, a drug that inhibits the enzyme in order to reduce acute inflammation responses. While the drug was designed for long-term use and has been trialled for treatments of COPD and arthritis, the participants only took the pill for 4 days, before once again being injected with the VZV antigen. Losmapimod treatment successfully increased the immune responses to the VZV antigen.
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Artificial molecules boost cancer therapy

Researchers at EPFL have created artificial molecules that can help the immune system to recognize and attack cancer tumors. Immunotherapies are breakthrough treatments that stimulate the patient's immune cells to attack the tumor through the recognition of tumor antigens.

Dendritic cells are specialized immune cells whose role is to capture antigens from foreign bodies and present them to the immune system's killer T cells, which will then attack and destroy the invaders. For the vaccine, dendritic cells are taken out of the patient, "force-fed" with tumor antigens, and finally re-injected back into the patient. The idea is to facilitate the ability of the dendritic cells to prime killer T cells against the tumor, which is notoriously skilled in concealing itself from the patient's immune system.

Dendritic cell vaccines have achieved some clinical success but not without several limitations. For example, the tumor antigens used to "feed" the dendritic cells are generally not taken from the patient's tumor but from lab-grown cancer cells that are only partially similar to those of the patient. This can limit the power of the vaccine because its tumor antigens may differ from those of the patient's tumor, meaning that the killer T cells would not be properly activated to recognize and attack the tumor.

A group of researchers led by Michele De Palma at EPFL have now created artificial receptors called EVIR (extracellular vesicle-internalizing receptors), which enable the dendritic cells in the vaccine to selectively and efficiently capture antigens from the actual patient's tumor. This is achieved by inserting the EVIR into the dendritic cell, where it recognizes a protein on small vesicles called exosomes.

Exosomes are profusely released by the tumor and contain a variety of tumor antigens. They are also increasingly implicated in the promotion of metastasis and other processes that may facilitate the growth and spreading of cancer. By capturing exosomes coming from tumors, the EVIR helps the dendritic cells to precisely acquire tumor antigens from the cancer cells. The dendritic cells then present these antigens more efficiently to killer T cells, thus amplifying the patient's immune response against their tumor.

Imaging techniques also revealed that EVIRs promote the direct transfer of tumor antigens from the exosome surface to the outer membrane of the dendritic cell. This is a fascinating and unconventional route for antigen presentation to T cells,  which does not require complex and rate-limiting molecular interactions inside the dendritic cell.

The EVIR technology can intercept a natural phenomenon - the release of exosomes from tumors - to the patient's benefit, it exploits pro-tumoral exosomes as selective nanocarriers of tumor antigens, making them available to the immune system for cancer recognition and rejection. Although the new technology has the potential to increase the efficacy and specificity of dendritic cell vaccines, further pre-clinical work is required before it can be translated into a cancer treatment.
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High salt diet hobbles the brain

A new study has shown that mice fed with a very high-salt diet experienced declined blood flow to their brain, the integrity of blood vessels in the brain suffered, and performance on tests of cognitive function plummeted.

Researchers found that those effects were not as long has been widely believed, a natural consequence of high blood pressure. Instead, they appeared to be the result of signals sent from the gut to the brain by the immune system.

The study, conducted by researchers at Weill Cornell Medicine in New York. The research sheds light on a subject of keen interest to scientists exploring the links between what we eat and how well we think, and the mediating role that the immune system plays in that communication.

This suggests that even before a chronic high-salt diet nudges blood pressure up and compromises the health of tiny blood vessels in the brain, the oversalted gut is independently sending messages that lay the groundwork for corrosion throughout the vital network.

In the small intestines of mice, the authors of the new research found that a very high-salt diet prompted an immune response that boosted circulating levels of an inflammatory substance called interleukin-17. These high levels of IL-17 set off a cascade of chemical responses inside the delicate inner linings of the brain's blood vessels.

The result in mice fed with the high-salt diet: blood supply to two regions crucial for learning and memory-the cortex and hippocampus slowed markedly. And mental performance slid. Compared to mice fed a diet lower in salt, the maze-running skills of the mice who consumed high-salt levels faltered, and they failed to respond normally to whisker stimulation, or a new object in their cage.

In mice, that evidence of cognitive impairment was apparent even in the absence of high blood pressure. The immune system's role in sending signals between brain and gut is also seen in diseases like multiple sclerosis, rheumatoid arthritis, psoriasis and inflammatory bowel disease-all disorders that are linked to poor functioning of the brain's blood vessels.
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How immune system's organ regenerates

A molecule called BMP4 that plays a key role in the thymus's extraordinary natural ability to recover from damage. Dr. Jarrod Dudakov of Fred Hutchinson Cancer Research Center, one of the study's leaders, talks about the importance of the thymus, the discoveries he and his colleagues have made about how it regenerates. The researchers hope to translate their work into new therapies to improve the function of the immune system in old age and make immunotherapies more effective.

The thymus is like a boot camp for new recruits to the immune system. From their birthplace in the bone marrow, immature white blood cells go to the thymus to mature into disease-killing machines. A healthy, active thymus gets you a diverse set of different T cells, each equipped to recognize and kill a slightly different foreign target. Thus, the organ is critical for a strong immune system that's ready to prevent any threat.

The thymus is sensitive to damage from everything from infections to life stress, it is also naturally resilient. Its power to bounce back from injury, however, fades with age, and it can take a serious hit from certain aggressive cancer therapies. BMP4, the molecule identified in the team's new study, is only the second known driver of natural thymic regeneration.

 The researchers found that BMP4 is produced by certain cells lining the inside of the organ. That molecule signals other cells of the thymus to turn on genes that promote development and repair.
Now, the team is working to figure out whether there's a master trigger that activates the whole regeneration process and then translate that knowledge into new therapies that help patients.
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Links between stress and sickness

A Michigan State University researcher is providing new insight into how certain types of stress interact with immune cells and can regulate how these cells respond to allergens, ultimately causing physical symptoms and disease. A stress receptor, known as corticotropin-releasing factor, or CRF1, can send signals to certain immune cells, called mast cells, and control how they defend the body.

Mast cells become highly activated in response to stressful situations the body may be experiencing. When this happens, CRF1 tells these cells to release chemical substances that can lead to inflammatory and allergic diseases such as irritable bowel syndrome, asthma, life-threatening food allergies and autoimmune disorders such as lupus.

One chemical substance, histamine, is known to help the body get rid of invading allergens such as pollen, dust mites or the protein of a particular food like a peanut or shellfish. The histamine causes an allergic reaction and in a normal response, helps the body clear the allergen from its system.
If a patient has a severe allergy or is under a lot of stress, then this same response can be amplified, resulting in more severe symptoms ranging from trouble breathing, anaphylactic shock or death.

Researchers compared the histamine responses of mice to two types of stress conditions - psychological and allergic - where the immune system becomes overworked. One group of mice was considered "normal" with CRF1 receptors on their mast cells and the other group had cells that lacked CRF1. While the 'normal' mice exposed to stress exhibited high histamine levels and disease, the mice without CRF1 had low histamine levels, less disease and were protected against both types of stress. This shows that CRF1 is critically involved in some diseases initiated by these stressors.

The CRF1-deficient mice exposed to allergic stress had a 54 percent reduction in disease, while those mice who experienced psychological stress had a 63 percent decrease. The results could change the way everyday disorders such as asthma and the debilitating gastrointestinal symptoms of irritable bowel syndrome are treated.
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How immune system react to junk food

The immune system reacts similarly to a high fat and high calorie diet as to a bacterial infection. This is shown by a recent study led by the University of Bonn. Particularly disturbing: unhealthy food seems to make the body's defenses more aggressive in the long term. Even long after switching to a healthy diet, inflammation towards innate immune stimulation is more pronounced. These long-term changes may be involved in the development of arteriosclerosis and diabetes, diseases linked to Western diet consumption.

The scientists placed mice for a month on western diet- high in fat, high in sugar, and low in fiber. The animals consequently developed a strong inflammatory response throughout the body, almost like after infection with dangerous bacteria. The unhealthy diet led to an unexpected increase in the number of certain immune cells in the blood of the mice, especially granulocytes and monocytes. This was an indication for an involvement of immune cell progenitors in the bone marrow.

Bone marrow progenitors for major immune cell types were isolated from mice fed a western diet or healthy control diet and a systematic analysis of their function and activation state was performed.
Genomic studies show that the western diet had activated a large number of genes in the progenitor cells. The genes affected included those responsible for proliferation and maturation. Fast food makes the body to activate strong immune system. When the researchers offered the rodents their typical cereal diet for another four weeks, the acute inflammation disappeared.

What did not disappear was the genetic reprogramming of the immune cells and their precursors, many of the genes that had been switched on during the fast food phase were still active after four weeks. It has only recently been discovered that the innate immune system has a form of memory. After an infection, the body's defenses remain in an alarm state, so that they can respond more quickly to a new attack-this is "innate immune training." In the mice, this process was not triggered by a bacterium, but by an unhealthy diet.

The scientists were further able to identify the responsible "fast food sensor" in immune cells. They examined blood cells from 120 subjects. In some of the subjects, the innate immune system showed a particularly strong training effect. In these subjects, the researchers found genetic evidence of the involvement of a so-called inflammasome. Inflammasomes are key intracellular signaling complexes that recognize infectious agents and other harmful substances and subsequently release highly inflammatory messengers.

The activation by Western diet changes the way in which the genetic information is packaged. The genetic material is stored in the DNA and each cell contains several DNA strands, which together are about two meters long. However, they are typically wrapped around certain proteins in the nucleus and thus many genes in the DNA cannot be read as they are sinaccessible.

Unhealthy eating causes some of these normally hidden pieces of DNA to unwind, similar to a loop hanging out of a ball of wool. This area of the genetic material can then be read much easier as long as this temporary unwrapping remains active. The inflammasome triggers such epigenetic changes, the immune system consequently reacts even to small stimuli with stronger inflammatory responses.

These inflammatory responses can in turn accelerate the development of vascular diseases or type 2 diabetes. In arteriosclerosis for example, the typical vascular deposits, the plaques, consist largely of lipids and immune cells. The inflammatory reaction contributes directly to their growth, because newly activated immune cells constantly migrate into the altered vessel walls.

When the plaques grow too large, they can burst, leading to blood clotting and are carried away by the bloodstream and can clog vessels causing stroke or heart attack. Wrong nutrition can thus have dramatic consequences. In recent centuries, average life expectancy has steadily increased in Western countries. This trend is currently being broken for the first time: Individuals born today will live on average shorter lives than their parents.
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