Patients receiving donated lungs may develop arrhythmias, including atrial fibrillation. Researchers from Baylor College of Medicine in Texas reviewed the charts of all lung transplant recipients in 2006 and 2007. Of the 75 patients who underwent lung transplant, 38 percent developed arrhythmias within 30 days of transplantation. The most common arrhythmia was atrial fibrillation, followed by atrial flutter. Researchers speculate that the donor-derived tissue (atrial cuff or pulmonary vein) is a likely source of the arrhythmias passed to lung recipients.

Current research suggests that stress may activate immune cells in your skin, resulting in inflammatory skin disease. The related report by Joachim et al., “Stress-induced Neurogenic Inflammation in Murine Skin Skews Dendritic Cells towards Maturation and Migration: Key role of ICAM-1/LFA-1 interactions,” appears in the November issue of The American Journal of Pathology.Skin provides the first level of defense to infection, serving not only as a physical barrier, but also as a site for white blood cells to attack invading bacteria and viruses. The immune cells in skin can over-react, however, resulting in inflammatory skin diseases such as atopic dermatitis and psoriasis.

Stress can trigger an outbreak in patients suffering from inflammatory skin conditions. This cross talk between stress perception, which involves the brain, and the skin is mediated the through the “brain-skin connection”. Yet, little is know about the means by which stress aggravates skin diseases.

Researchers lead by Dr. Petra Arck of Charité, University of Medicine Berlin and McMaster University in Canada, hypothesized that stress could exacerbate skin disease by increasing the number of immune cells in the skin. To test this hypothesis, they exposed mice to sound stress. Dr. Arck’s group found that this stress challenge resulted in higher numbers of mature white blood cells in the skin. Furthermore, blocking the function of two proteins that attract immune cells to the skin, LFA-1 and ICAM-1, prevented the stress-induced increase in white blood cells in the skin.

Taken together, these data suggest that stress activates immune cells, which in turn are central in initiating and perpetuating skin diseases. Fostered by the present observation, the goal of future studies in Dr. Arck’s group is to prevent stress-triggered outbreaks of skin diseases by recognizing individuals at risk and identifying immune cells suitable to be targeted in therapeutic interventions.

Researchers at Georgetown University Medical Center (GUMC) have successfully tested a genetic strategy designed to improve treatment of human infections caused by the yeast Candida albicans, ranging from diaper rash, vaginitis, oral infections (or thrush which is common in HIV/AIDS patients), as well as invasive, blood-borne and life-threatening diseases.Their findings confirm that inhibiting a key protein could provide a new drug target against the yeast, which inhabits the mucous membranes of most humans. The research was presented today at the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious Diseases Society of America (ICAAC/IDSA) in Washington, DC.

“This is a genetically intelligent approach to target identification and drug design,” says the study’s lead author, Richard Calderone, PhD, professor and chair of the department of microbiology and immunology and co-director of the PhD program in the global infectious disease program at GUMC.

“Candida infections are often treatable, however, in patients that are immunocompromised following cancer chemotherapy, bone marrow transplantation, or surgery, diagnosis is often delayed, postponing therapy,” he says. “Also when drug-resistant yeast pathogens cause the infection, clinical management of the patient becomes a problem.”

Candida invasive, blood-borne infections are the fourth most common hospital-acquired infection in the United States, costing the healthcare system about $1.8 billion each year, Calderone says.

“More drug resistance is being seen clinically, so there is significant room for improvement in the therapies used today,” he says

This study continues research in which Calderone and his colleagues identified a protein, the product of the Ssk1 gene that Candida needs to infect its host. To date, this protein has not been found in humans or in animals, which means it could be “targeted” with a novel drug without producing toxicity because such an agent should only attack the fungus.

The researchers found that if the Ssk1 gene is deleted from Candida albicans, the “triazole” drugs that are now used to treat these diseases are much more effective in the laboratory. “This allows the triazole drugs to do their job,” Calderone says. “We propose that this finding might lead to other, possibly more effective, treatment options.”

In this study, the researchers used a gene microarray analysis to further understand what knocking out the Ssk1 gene does to the organism, and they discovered that the gene is critical to the pathogenic nature of the fungi.

What this means is that an Ssk1 inhibitor might work in synergy with a triazole or perhaps as an effective stand-alone drug to treat Candida infections, the researchers say. If it works in Candida, it may have broader activity in other pathogens because Ssk1p is found in other fungi.

“Using the genome of the organism to find genes to target is a logical approach to drug design,” he says. The researchers are now working with other groups to find the right agent to target the Ssk1protein.

Amoebas glide toward their prey with the help of a protein switch that controls a molecular compass, biologists at the University of California, San Diego have discovered.

Their finding, detailed in this week’s issue of the journal Current Biology, is important because the same molecular switch is shared by humans and other vertebrates to help immune cells locate the sites of infections.

The amoeba Dictyostelium finds bacteria by scent and moves toward its meal by assembling a molecular motor on its leading edge. The active form of a protein called Ras sets off a cascade of signals to start up that motor, but what controlled Ras was unknown.

Richard Firtel, professor of biology along with graduate student Sheng Zhang and postdoctoral fellow Pascale Charest tested seven suspect proteins by disrupting their genes. One called NF1, which matches a human protein, proved critical to chemical navigation.

NF1 turns Ras off. Without this switch mutant amoebas extended false feet called pseudopodia in all directions and wandered aimlessly as Ras flickered on and off at random points on their surfaces. “You have to orient Ras in order to drive your cell in the right direction,” Firtel said.

In contrast, normal amoebas with working versions of NF1 elongate in a single direction and head straight for the most intense concentration of bacterial chemicals, the team reports.

The biochemical components of the system match those found in vertebrate immune cells called neutrophils that hunt down bacterial invaders, suggesting that the switch might be a key navigational control for many types of cells, Firtel said. “The pathway and responses are very similar and so are the molecules.”

A potentially blinding neurological disorder, often confused with multiple sclerosis (MS), has now become a little less mysterious.  A new study by researchers at the Mayo Clinic in Rochester, Minnesota, may have uncovered the cause of Devic’s disease.  Their new study, which will appear online on October 6th in the Journal of Experimental Medicine, could result in new treatment options for this devastating disease.

Devic’s disease, also known as neuromyelitis optica (NMO), results in MS-like demyelinating lesions along the optic nerves and spine.  Affected individuals often experience rapid visual loss, paralysis, and loss of leg, bladder, and bowel sensation.  Some lose their sight permanently.  Unlike MS, Devic’s disease can be diagnosed by the presence of a specific self-attacking immune protein—an autoantibody referred to as NMO-IgG—in the blood.  Until now, however, clinicians didn’t know how that protein damaged nerves and contributed to disease symptoms.

The Mayo team, lead by Dr. Vanda Lennon, now show that NMO-IgG sets off a chain of events that leads to a toxic build-up of a neurotransmitter called glutamate.  NMO-IgG binds to a protein that normally sops up excess glutamate from the space between brain cells.  When NMO-IgG is around, this sponge-like action is blocked, allowing glutamate to accumulate.  And too much glutamate can kill the cells that produce myelin—the protein that coats and protects neurons.  The authors suggest that glutamate-induced damage to nerve cells and their insulating myelin coats might account for the neurological symptoms associated with Devic’s disease.

If the groups’ results—generated using nerve cell cultures—are confirmed in vivo, drug development could be very straightforward.  Therapeutic trials for glutamate blockers, created to treat other neurodegenerative diseases like Lou Gehrig’s disease (or ALS), are already underway.

Scientists report online this week in Nature that they have linked the health of specialized gut immune cells to a gene associated with Crohn’s disease, an often debilitating and increasingly prevalent inflammatory bowel disorder.

The link to immune cells intrigued researchers at Washington University School of Medicine in St. Louis because they and others believe Crohn’s disease is caused by misdirected immune responses in the intestine that damage gut tissue.  In addition, cells in the mouse model scientists used for the study had altered genetic activity that could lead to increased production of certain hormones.  Those same hormones are elevated in some Crohn’s patients.

“We now have a significant new piece of the puzzle that is Crohn’s disease, but not the solution just yet,” says senior author Herbert W. “Skip” Virgin, M.D., Ph.D., the Edward Mallinckrodt Professor and head of the Department of Pathology and Immunology.  “As many as 30 different areas in human DNA have potential links to Crohn’s disease, and to develop new treatments it’s going to be essential to find out how each of them, as well as environmental factors, contribute to the disorder.”

Crohn’s disease is one of the most common inherited bowel disorders.  In 2002, epidemiologists estimated that it affected 400,000 to 600,000 patients in North America.  Symptoms include diarrhea, abdominal pain, vomiting and weight loss.  The condition can lead to partial or full intestinal blockages, which can require surgical treatment.

Research previously revealed that some Crohn’s disease patients have a mutation in a gene known as Atg16L1.  The mutation increases risk but doesn’t automatically lead to Crohn’s disease.  To learn more, Ken Cadwell, Ph.D., a postdoctoral student in Virgin’s lab, created and studied two lines of mice with a genetic alteration that reduced their ability to make the Atg16L1 protein.

Cadwell and his colleagues found decreased Atg16L1 protein had pronounced effects on Paneth cells, which are immune cells in the lining of a portion of the small intestine.  These cells make proteins and antimicrobial peptides that they package as granules and secrete into the intestine to defend the body against infection.

“When they have less Atg16L1, the Paneth cells survive, but their ability to secrete granules is significantly impaired,” Cadwell says.

Virgin consulted with co-authors Ellen Li, M.D., Ph.D., and Thaddeus Stappenbeck, M.D., Ph.D., Washington University researchers who study and treat Crohn’s disease patients at Barnes-Jewish Hospital.  When surgery becomes necessary to repair a patient’s bowel, Li collects samples removed from the intestine for research.  Selecting tissue from patients with mutated Atg16L1, researchers compared human Paneth cells to cells from their mouse model and found what Virgin calls “striking similarities.”

To learn how Atg16L1 helps the Paneth cell, scientists conducted a follow-up experiment where a related gene, Atg5, was knocked out in mice.  Like Atg16L1, Atg5 contributes to an important process called autophagy that lets cells consume and reuse their own resources and may have other functions as well.  Paneth cells in this line of mice had impairments similar to the first line, suggesting that Atg16L1’s contributions to the Paneth cell may be linked to autophagy.

“We don’t yet know why having abnormal Paneth cells would predispose a person to Crohn’s disease or to what degree other genes linked to Crohn’s may affect the Paneth cell, but those are just a few of the very interesting questions to follow up on from these results,” Virgin says.

A novel anti-tumor vaccine for neuroblastoma and melanoma developed by scientists and clinicians at Children’s National Medical Center in collaboration with investigators from the University of Iowa is showing significant impact on tumor growth in mice, according to new research published in the October edition of the research journal Cancer Immunology, Immunotherapy.  The vaccine uses the tumor’s own protein to induce an immune system response, allowing for a personalized approach to treatment.

The vaccine and delivery system, developed in the laboratory of Children’s National Chief of General and Thoracic Surgery Anthony Sandler, MD, involves the creation of synthetic microparticles known as “immune stimulatory antigen loaded particles” (ISAPs), that consist of tumor antigens (proteins) from the specific tumor to be targeted, as well as immune stimulatory agents.  The ISAPs are detected and engulfed by specialized immune cells and sensed to be immune-stimulating “foreign bodies.”

The study shows that ISAPs are effective at blocking the growth of tumors in mice by inducing activation of immune cells that then stimulate the immune system to specifically target the tumor whose antigens match those that are loaded in the particles – known as tumor specific immunity.

The research team also discovered, however, that the impact of ISAPs on tumor growth was partially mitigated by an increased presence of regulatory t-cells (T-reg) when ISAPs are introduced into the body.  The researchers believe that T-regs play a key role in how the vaccine impacts tumor growth by suppressing the development of the specific immune cells needed to combat the tumor.  By adding a T-reg suppressor such as cyclosphosphamide or anti-CD25 antibody, the scientists were able to have a greater impact on preventing tumor growth using the ISAP approach.

“For tumors like neuroblastoma, reduction to minimal residual disease with standard therapies like chemotherapy and/or surgical resection and subsequent treatment with this vaccine could quite possibly cure the patient of the disease in the not too distant future,” said Dr. Sandler, lead author of the study.  “Creation of ISAPs allows us to target our treatments to the specific tumor of interest, a capability that will more effectively combat a wide range of these tumors in a personalized fashion.”

In contrast to Barrette et al., Horn al. report that macrophages may hinder regeneration in the spinal cord of rats by promoting axonal retraction. Central nervous system axons normally retract from a site of injury. To examine the role of macrophages in this process, Horn et al. specifically targeted phagocytic cells with toxin enclosed in liposomes. Depleting macrophages after a spinal cord crush did not affect the initial retraction of injured axons, but prevented later retraction that normally occurs after macrophages invade the spinal cord. In vitro studies on dorsal root ganglion neurons revealed that when an activated macrophage contacts a dystrophic axon, the macrophage adheres to and tugs on the axon, pulling it from the substrate and causing retraction. Together, these two studies suggest that whether myeloid cells help or hinder axon regeneration may depend on what type of myeloid cells are present (i.e., what subtypes of macrophages and granulocytes) and where and how macrophages are activated (e.g., by peripheral or CNS cues). Many macrophages (green) but few astrocytes (blue) were present at a lesion site 7 d after nerve crush (left). Treatment with toxic liposomes greatly reduced the number of macrophages, but astrocytes remained.

The role of macrophages in recovery from nerve injury is controversial. Some studies show that macrophages improve regeneration, but others show the opposite effect. This week, each side of the controversy gains support. After crushing a peripheral nerve in mice, Barrette et al. locally depleted myeloid white blood cells (both granulocytes and macrophages) that expressed a specific protein. This reduced axonal regeneration and functional recovery. Depletion of myeloid cells in peripheral nerve grafts, which normally permit some regeneration of spinal axons, rendered the grafts unable to support such growth. Additional experiments suggested that myeloid cells normally enhance regeneration by clearing myelin debris (which is likely to contain growth-inhibiting molecules), secreting growth-promoting neurotrophic factors (likely from granulocytes, rather than macrophages), and stimulating the growth of new blood vessels, which axons often grow along as they regenerate.

Oliver Söhnlein and colleagues, at the Karolinska Institutet, Sweden, have identified a new function for a number of proteins secreted by human immune cells known as neutrophils or PMNs: they enhance the uptake of bacteria by other immune cells (known as macrophages) that are capable of destroying the microbes.

In the study, proteins secreted by human PMNs, specifically HBP and HNP1-3, were found to enhance the in vitro ability of human and mouse macrophages to take up bacteria coated in the immune molecule IgG. Mechanistically, HBP and HNP1-3 activated the macrophages to secrete soluble factors that, in turn, induced the macrophages to express proteins to which IgG can bind (CD32 and CD64). The authors therefore suggest that HBP and HNP1–3 secreted by PMNs have a role in clearing bacterial infections.

Yeast fungus cells that kill thousands of AIDS patients every year escape detection by our bodies’ defences by hiding inside our own defence cells, and hitch a ride through our systems before attacking and spreading, scientists heard today (Tuesday 9 September 2008) at the Society for General Microbiology’s Autumn meeting being held this week at Trinity College, Dublin.

Cells of the Cryptococcus yeast responsible for one of the three most life-threatening infections that commonly attack HIV infected patients, causing cryptococcal meningitis, are using a previously unknown way to avoid detection, according to scientists from the University of Birmingham, UK.

“We have shown that these airborne yeast cells can hide inside our bodies’ own white blood cells, called macrophages, and then use them as vehicles to travel around inside our bodies, using them just like a bus,” said Miss Hansong Ma of the University of Birmingham.  “The yeast cells then escape from inside the macrophages when they arrive at the right destination – but importantly, they do this without killing the macrophage, which would trigger alarm bells.”

When a host’s cells are invaded by bacteria, fungi or viruses the invaders usually use the opportunity to multiply inside the cells and escape by bursting out, killing the host and releasing thousands of copies of the pathogen to attack other cells.  The death of the host cell releases debris and by-products which usually triggers our bodies into mounting an immune response, causing inflammation.

“This new method of remaining inside the host cells means that the pathogen can spread more efficiently round our bodies and is protected from the natural defences in our bloodstream that would normally kill the yeast or other invader,” said Hansong Ma.  “Yeast cells avoid killing or damaging the macrophages.  They leave by a method that we call ‘vomocytosis’; the yeast cells are acting like spies rather than terrorists, and go unnoticed, giving them more time to establish an infection.”

Although the use of antiretroviral drugs is cutting the number of AIDS patients with Cryptococcus infections there is still a major epidemic in Southeast Asia and Africa.  Up to 30% of AIDS patients there are infected, and up to 44% will die from the disease within 8 weeks.  Even in the USA or European countries like France where antiretroviral drug treatments are readily available, one in ten infected patients will die.

“We badly need to better understand the interaction between hosts, viruses and attacking pathogens like the yeast fungus to help us find new drug targets and so design new ways to treat these patients,” said Hansong Ma.

“We used time-lapse microscope photography to identify this new escape mechanism, and watched the yeast cells escaping into the fluid surrounding cells or, remarkably, directly into other host cells through cell-to-cell transmission, continuing to avoid detection by using this extremely rapid vomocytosis,” said Hansong Ma.  “Worryingly, this enables the cryptococci to avoid antifungal drugs and other treatments as well as our normal immune system, and may allow the yeast to become latent, achieving a long-term infectious state which could then be spread even further, to other individuals, without anyone realising.”

An athlete’s ability to sweat may do more than keep the body cool.  It also may prevent the development of exercise-induced asthma (EIA), a common respiratory condition among trained athletes.  New research appearing in the September issue of CHEST, the peer-reviewed journal of the American College of Chest Physicians (ACCP), shows that athletes with EIA produce less sweat, tears, and saliva than those who do not have breathing problems.  Warren Lockette, MD, lead study author and advisor to the University of Michigan’s NCAA Division I women’s swimming team, has worked with many Olympians and future professional athletes with EIA.  “It is unclear why so many elite athletes have exercise-induced asthma,” he said.  “It is possible that they manifest symptoms of exercise-induced asthma simply because their levels of exertion and breathing rate are so high compared with the average, competitive sportsman.” As the head of clinical research at Naval Medical Center San Diego and a former medical officer with the US Navy SEALS, Dr. Lockette also knew that a diagnosis of asthma would preclude many young sailors from becoming Navy divers or special warfare operators.  He teamed up with investigators at Naval Medical Center San Diego to try to understand the mechanisms by which asthma attacks are precipitated during exercise in otherwise healthy individuals.  Lockette and colleagues analyzed the relationship between fluid secretion rates (sweat, saliva, and tears) in 56 athletic subjects suspected of having EIA.  Air movement through the lungs, i.e., the “FEV1,” was measured in otherwise healthy volunteers before and after the administration of methacholine, a drug that can cause airways to constrict in patients with EIA.  Researchers then measured responses to the application of pilocarpine, an agent used to induce sweating and saliva production.  Individuals who were most sensitive to methacholine, i.e., who had the greatest fall in FEV1, were the least sensitive to pilocarpine-induced sweat secretion—meaning, those subjects who had the most hyperreactive airways tended to sweat the least.  Conversely, mean sweating rates were significantly higher among those subjects who were relatively unresponsive to methacholine—the subjects who showed no signs of EIA.  Researchers also found a correlation between the net sweat fluid excretion and net sweat sodium excretion, with sodium excretion rates being higher in subjects who were unresponsive to methacholine compared with those who were responsive.  Additionally, a significant correlation was found between sweat secretion and unstimulated salivary gland flow rates and tear secretion.  “There were many Olympic hopefuls whose competitive chances were potentially limited by exercise-induced asthma,” said Dr. Lockette.  “We found that by controlling air quality during workouts, as well as by providing individualized attention to our athletes’ hydration and nutrition, we could reduce the limitations imposed by hyperreactive airways in many individuals.” Although Dr. Lockette and his team were not able to establish a cause-effect relationship between the increased incidence of EIA and diminished sweat sodium excretion, they speculate that the mechanism responsible for determining sweat volume is the same mechanism responsible for the volume of water secreted by the airways.  As a result, individuals who sweat less also have drier airways.  “It now appears that how much fluid your airways secrete could be a key determinant in protecting you from exercise-induced asthma,” he said.  “So, if athletes sweat, drool, or cry, at least they won’t gasp.” “Exercise-induced asthma may be common among elite or highly trained athletes, but recreational athletes can also suffer from this condition,” said Alvin V. Thomas, Jr., MD, FCCP, and President of the American College of Chest Physicians.  “Otherwise healthy individuals who experience asthma symptoms, such as chest tightness, unusual shortness of breath, or extreme fatigue during exercise, should consult with their physician.”

Antibodies are proteins that are a crucial component of the immune system.  They are produced in large amounts by immune cells known as plasma cells, which live in just a few parts of the body, including the bone marrow and special areas of the various parts of the body that are exposed to the outside (e.g., the gut, nose, and airways).  These areas are known as mucosa-associated lymphoid tissue (MALT) and include tissues such as the tonsils, but what regulates plasma cell survival in MALT has not been determined.  Now, however, Bertrand Huard and colleagues, at Geneva University Medical Center, Switzerland, have provided new insight into the molecular mechanisms controlling plasma cell survival in MALT.

In the study, analysis of tonsils and MALT from the lower gut indicated that a protein known as APRIL is important for promoting the survival of plasma cells in human MALT.  APRIL was found to work by increasing plasma cell expression of proteins that protect cells from a form of death known as apoptosis.  Expression of APRIL was shown to be greater in tonsils infected with a microbe than in noninfected tonsils and the cells producing the increased APRIL were identified as immune cells known as neutrophils that had been recruited to the site of infection.  APRIL from the neutrophils was retained in the tonsils bound to molecules known as heparan sulfate proteoglycans, creating an APRIL-rich niche for the plasma cells to survive in.  The authors therefore suggest that the longevity of plasma cells in MALT is controlled, in part, by APRIL-secreting neutrophils recruited to sites of infection.

Among the first cells of the immune system to respond to microorganisms that invade our body are neutrophils.  Although neutrophils are considered the “good guys” in such circumstances, they also contribute to the noninfectious chronic inflammation that underlies various diseases, including autoimmune diseases such as rheumatoid arthritis.  One mechanism by which neutrophils protect us is to internalize microorganisms and destroy them using proteins known as neutrophil serine proteases (NSPs), but whether NSPs have a role in noninfectious chronic inflammation has not been clearly determined.  However, using mice lacking two very similar NSPs, PR3 and NE, a team of researchers at the Max-Planck-Institute of Neurobiology, Germany, have now shown that these two NSPs have a crucial role in one form of noninfectious chronic inflammation.  Detailed analysis revealed that PR3 and NE destroy an anti-inflammatory molecule known as PGRN and in this way help to promote inflammation in the absence of invading microorganisms.  The authors therefore suggest that these data provide rationale for considering inhibitors of NSPs as anti-inflammatory drugs.

Individuals inhale measles virus particles in aerosols and it is currently thought that these particles infect the cells that line the airways (respiratory epithelial cells) before being passed to immune cells that carry the virus particles to other parts of the body and then back to the airways, which again become infected and shed virus into exhaled aerosols.  In the study, a measles virus unable to bind to and infect epithelial cells was found to cause symptoms of measles virus infection in monkeys even though it did not infect respiratory epithelial cells and was not being shed into exhaled aerosols.  These data suggest that, in fact, inhaled measles virus particles first infect lymphocytes and are only passed to respiratory epithelial cells from the lymphocytes in the tissues.  Further, they indicate that the protein that measles virus particles bind to on respiratory epithelial cells, which has yet to be identified, is likely to be found on the surface of the cells that faces the tissues rather than the surface that faces the airways, as previously assumed.  As discussed in an accompanying commentary by Makoto Takeda, at Kyushu University, Japan, the results of this study should help researchers identify this protein.