Braking system for immune responses

For the first time, researchers have identified a receptor on human cells that specifically recognizes crystals. It is found on immune cells and binds uric acid crystals, which trigger gout but also control immune responses. The team, led by researchers from Technische Universitt Mnchen (TUM)’s Klinikum rechts der Isar hospital have published their findings in the Immunity journal.The surface of immune system cells is home to a number of receptors which are able to detect pathogens. As soon as these receptors are activated, inflammation occurs and the body’s defense mechanisms kick in. Immune cells also have receptors that regulate or even suppress immunological responses to prevent damage to individual cells.There are other immune receptors that recognize endogenous substances that are released when tissue damage or cell death occurs. As such, the organism can defend itself even in cases where the damage caused by the pathogen, but not the pathogen itself, is detected.With the discovery of the surface molecule Clec12a from the family of C-type lectin receptors, the team led by Prof. Jrgen Ruland of Klinikum rechts der Isar have found the first known immune receptor for uric acid crystals. Uric acid is a break-down product of nucleic acids like DNA in response to cell damage. Whenever a large number of cells die, for example when a tumor is being medically treated or during an infection, the uric acid becomes more concentrated and the molecules crystallize.Immune responses have to be regulatedUric acid crystals also form when tissue is damaged and they boost the immune response. However, Clec12a limits the immune response instead of increasing it. …

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Source of chlamydia reinfections may be GI tract

The current standard of care treatment for chlamydia sometimes fails to eradicate the disease, according to a review published ahead of print in Infection and Immunity, and the culprit may be in the gut.Chlamydia trachomatis not only infects the reproductive tract, but abides persistently — though benignly — in the gastrointestinal tract. There it remains even after eradication from the genitals by the antibiotic, azithromycin, says first author Roger Rank, of the Arkansas Children’s Research Institute, Little Rock. And that reservoir is likely a source of the all-too-common reinfections that follow treatment.The source of the reinfections has long been a conundrum. Some are blamed on continued intercourse with an infected partner. This is not surprising since chlamydia is usually asymptomatic in men.Chlamydiae have long been assumed often to persist within the genital tract in a non-replicating form, but Rank says there is no evidence for this. “While all agree that chlamydiae may persist in a patient for long periods of time, and that recurrent infections do develop, there has been no agreement on how and where and in what form chlamydiae persist,” says Rank.In a recent study, coauthor and Arkansas colleague Laxmi Yeruva showed in mice that azithormycin eradicated the genital infection, but not the GI infection.Rank showed further — also in mice — that chlamydial infection of the GI does not elicit an inflammatory response, and never resolves, unlike in the genital tract.”However, we found that GI infection does produce a strong immune response that can actually be effective against a genital infection, but that is unable to cure the GI infection,” says Rank.While chlamydial persistence in the GI tract has largely escaped notice of late, it was documented in the veterinary literature in numerous animals as early as the 1950s, says Rank. His reading of that early literature was a major factor motivating his and Yeruva’s studies, and this review, Rank says.Chlamydia trachomatis is the most common cause of sexually transmitted disease in the world. In the US, approximately 1.4 million cases occur annually, according to the Centers for Disease Control and Prevention. Adolescents are most affected, and 6.8 percent of sexually active females ages 14-19 become infected annually.Story Source:The above story is based on materials provided by American Society for Microbiology. Note: Materials may be edited for content and length.

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Body’s ‘safety procedure’ could explain autoimmune disease

Sep. 5, 2013 — Monash University researchers have found an important safety mechanism in the immune system that may malfunction in people with autoimmune diseases, such as Multiple Sclerosis, potentially paving the way for innovative treatments.Published today in Immunity, the research, led by Head of the Monash Department of Immunology Professor Fabienne Mackay, described for the first time how the body manages marginal zone (MZ) B cells, which form a general first line of attack against germs, but are potentially harmful.MZ B cells are integral to our defenses as they rapidly produce polyreactive antibodies that are capable of destroying a variety of pathogens. This first response gives the body time to put in place an immune reaction specific to the invading microbe.However, MZ B cells have the potential to turn against the body. Some are capable of producing antibodies which attack healthy, rather than foreign, cells — known as an autoimmune response. Bacteria trigger MZ B cells irrespective of whether these cells are dangerous or benign, effectively placing anyone with a bacterial infection at risk of developing an autoimmune disease.Professor Mackay’s team has discovered the mechanism that regulates this response, ensuring that that the majority of infections do not result in the body attacking its own tissue.”We found that while MZ B cells are rapidly activated, they have a very short life span. In fact, the very machinery which triggers a response leads to MZ B cells dying within 24 hours,” Professor Mackay said.”This means that in a healthy person, the potentially harmful immune cells are not active for long enough to cause in tissue damage. We now need to look at whether a malfunction in this safety feature is leading to some autoimmune diseases.”When MZ B cells are activated by bacteria, they express greater amounts of a protein known as TACI. When TACI binds to another protein as part of the immune response, this triggers the activation of the ‘death machinery’ inside MZ B cells. The detection of a pathogen sets of a chain reaction that both activates and then destroys MZ B cells.Professor Mackay said this was an entirely new way of looking at the immune system.”The research suggests that through evolution the immune system has not solely been vulnerable to infections but has learned to take advantage of pathogens to develop its own internal safety processes,” Professor Mackay said.”This says something important about our environment — pathogens are not always the enemy. They can also work hand in hand with our immune system to protect us against some immune diseases.”

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A first in front-line immunity research

July 21, 2013 — Monash University researchers have gained new insight into the early stages of our immune response, providing novel pathways to develop treatments for diseases from multiple sclerosis to cancer.In a study published today in Nature Immunology, a team of researchers led by Professor Paul Hertzog, of the Monash Institute of Medical Research (MIMR) and Professor Jamie Rossjohn, of the School of Biomedical Sciences, have characterised for the first time how interferon beta (IFNβ) proteins bind to cells and activate an immune response.Produced when viral and bacterial infections are detected, interferon proteins are vital to the body’s defences. They activate immune cells, such as macrophages, can interfere with virus replication, and can boost cells’ resilience to infection. They also enhance later immune responses to cancers and other stresses.There are at least 20 subtypes of interferons that are produced at different stages of the immune response. They appear to have different functions, but these functions and their triggers are generally not well understood. The mapping of INFβ — cell interaction is a breakthrough in the field.Professor Hertzog of MIMR’s Centre for Innate Immunity and Infectious Diseases said interferon function was vital for developing and refining therapies for incurable diseases such as lupus and multiple sclerosis.”Interferon therapy is useful in treating a number of diseases; however these treatments have dose-limiting side effects. Further, interferons appear to drive some autoimmune diseases, raising the prospect of interferon blockers as treatment,” Professor Hertzog said.”The more refined our understanding of interferon function, the more we can tailor treatments to optimise effectiveness — whether by boosting or blocking their actions.”Lead author on the paper, Dr Nicole de Weerd, also of the Centre for Innate Immunity and Infectious Diseases, said the research provided new pathways for rational drug design.”We found that when IFNβ binds to a cell, it transmits an unusual signal that seems linked to some of the toxic side effects of interferon therapy, like sepsis. This provides a promising avenue to pursue more selective activation of interferon action,” Dr de Weerd said.Professor Rossjohn and Julian Vivian from the Department of Biochemistry and Molecular Biology collaborated closely on determining the IFNβ interactions at the molecular level.”During this seven-year study, we have had great support from the Australian Synchrotron,” Professor Rossjohn said.

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Novel research model for study of auto-immune diseases developed

July 3, 2013 — A team of researchers at the IRCM, led by Dr. Javier M. Di Noia in the Immunity and Viral Infections research division, discovered a novel research model for the study of auto-immune diseases. The Montréal scientists are the first to find a way to separate two important mechanisms that improve the quality of antibodies. This study was featured in a recent issue of The Journal of Immunology.Dr. Di Noia’s team studies B cells, a group of white blood cells known as lymphocytes whose main function is to produce antibodies to fight against antigens. Antibodies are proteins used by the immune system to identify and neutralize foreign objects (antigens), such as bacteria and viruses, by precisely binding to them, thus making them an essential part of the immune system. Antibodies can come in different varieties (or classes), which perform different roles and adapt the immune response to eliminate each different toxin or pathogen they encounter. The body’s great diversity of antibodies therefore allows the immune system to specifically neutralize an equally wide variety of antigens.”Our project focused on two mechanisms that produce this wide variety of antibodies,” says Dr. Di Noia, Director of the Mechanisms of Genetic Diversity research unit at the IRCM. …

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Two mutations triggered an evolutionary leap 500 million years ago

June 24, 2013 — Evolution, it seems, sometimes jumps instead of crawls. A research team led by a University of Chicago scientist has discovered two key mutations that sparked a hormonal revolution 500 million years ago.In a feat of “molecular time travel,” the researchers resurrected and analyzed the functions of the ancestors of genes that play key roles in modern human reproduction, development, immunity and cancer. By re-creating the same DNA changes that occurred during those genes’ ancient history, the team showed that two mutations set the stage for hormones like estrogen, testosterone and cortisol to take on their crucial present-day roles.”Changes in just two letters of the genetic code in our deep evolutionary past caused a massive shift in the function of one protein and set in motion the evolution of our present-day hormonal and reproductive systems,” said Joe Thornton, PhD, professor of human genetics and ecology & evolution at the University of Chicago, who led the study.”If those two mutations had not happened, our bodies today would have to use different mechanisms to regulate pregnancy, libido, the response to stress, kidney function, inflammation, and the development of male and female characteristics at puberty,” Thornton said.The findings were published online June 24 in the Proceedings of the National Academy of Sciences.Understanding how the genetic code of a protein determines its functions would allow biochemists to better design drugs and predict the effects of mutations on disease. Thornton said the discovery shows how evolutionary analysis of proteins’ histories can advance this goal, Before the group’s work, it was not previously known how the various steroid receptors in modern species distinguish estrogens from other hormones.The team, which included researchers from the University of Oregon, Emory University and the Scripps Research Institute, studied the evolution of a family of proteins called steroid hormone receptors, which mediate the effects of hormones on reproduction, development and physiology. Without receptor proteins, these hormones cannot affect the body’s cells.Thornton’s group traced how the ancestor of the entire receptor family — which recognized only estrogens — evolved into descendant proteins capable of recognizing other steroid hormones, such as testosterone, progesterone and the stress hormone cortisol.To do so, the group used a gene “resurrection” strategy. They first inferred the genetic sequences of ancient receptor proteins, using computational methods to work their way back up the tree of life from a database of hundreds of present-day receptor sequences. They then biochemically synthesized these ancient DNA sequences and used molecular assays to determine the receptors’ sensitivity to various hormones.Thornton’s team narrowed down the time range during which the capacity to recognize non-estrogen steroids evolved, to a period about 500 million years ago, before the dawn of vertebrate animals on Earth. They then identified the most important mutations that occurred during that interval by introducing them into the reconstructed ancestral proteins. By measuring how the mutations affected the receptor’s structure and function, the team could re-create ancient molecular evolution in the laboratory.They found that just two changes in the ancient receptor’s gene sequence caused a 70,000-fold shift in preference away from estrogens toward other steroid hormones. The researchers also used biophysical techniques to identify the precise atomic-level mechanisms by which the mutations affected the protein’s functions. …

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