Trigger for autoimmune disease identified

Researchers at National Jewish Health have identified a trigger for autoimmune diseases such as lupus, Crohn’s disease and multiple sclerosis. The findings, published in the April 2017 issue of Journal of Clinical Investigation, help explain why women suffer autoimmune disease more frequently than men, and suggest a therapeutic target to prevent autoimmune disease in humans.

“Our findings confirm that Age-associated B Cells (ABCs) drive autoimmune disease,” said Kira Rubtsova, PhD, an instructor in biomedical science at National Jewish Health. “We demonstrated that the transcription factor T-bet inside B cells causes ABCs to develop. When we deleted T-bet inside B cells, mice prone to develop autoimmune disease remained healthy. We believe the same process occurs in humans with autoimmune disease, more often in elderly women.”

Autoimmune diseases occur when the immune system attacks and destroys the organs and tissue of its own host. Dozens of autoimmune diseases afflict millions of people in the United States. Several autoimmune diseases, including lupus, rheumatoid arthritis and multiple sclerosis strike women two to 10 times as often as men. Overall, about 80 percent of autoimmune patients are women. There is no cure for autoimmune disease.

B cells are important players in autoimmune disease. The National Jewish Health research team, led by Chair of Biomedical Science Philippa Marrack, PhD, previously identified a subset of B cells that accumulate in autoimmune patients, autoimmune and elderly female mice. They named the cells Age-associated B cells, or ABCs. Subsequent research showed that the transcription factor T-bet plays a crucial role in the appearance of ABC.

Transcription factors bind to DNA inside cells and drive the expression of one or several genes. Researchers believe that T-bet appears inside cells when a combination of receptors on B-cell surfaces — TLR7, Interferon-gamma and the B-cell receptor — are stimulated.

Through breeding and genetic techniques the research team eliminated the ability of autoimmune-prone mice to express T-bet inside their B cells. As a result, ABCs did not appear and the mice remained healthy. Kidney damage appeared in 80 percent of mice with T-bet in the B cells and in only 20 percent of T-bet-deficient mice. Seventy-five percent of mice with T-bet in their B cells died by 12 months, while 90 percent of T-bet-deficient mice survived 12 months.

“Our findings for the first time show that ABCs are not only associated with autoimmune disease, but actually drive it,” said Dr. Rubtsova.

ABCs have attracted increasing interests since their discovery in 2011. Dr. Rubtsova and her colleagues at National Jewish Health have expanded their study of ABCs beyond autoimmune disease and are looking at their involvement in sarcoidosis, hypersensitivity pneumonitis and chronic beryllium disease.

Tailoring Nanoparticles to Evade Immune Cells and Prevent Inflammatory Response

A Houston Methodist-led research team showed that the systemic administration of nanoparticles triggers an inflammatory response because of blood components accumulating on their surface. This finding may help researchers create more effective ways to avoid activating the immune system and more precisely direct therapies in patients.

In the journal ACS Nano, the team of nanomedicine and regenerative medicine scientists recently described how specially-engineered nanoparticles (leukosomes) injected into mice can prevent the formation of a layer of biomolecules (protein corona) around their surface. The body’s natural defense response to the formation of this protein is to filter out the foreign objects, in this case the nanoparticles. The presence of immune system regulators, known as macrophage receptors, on the surface of the leukosomes improved the amount of time these nanoparticles remained in the body to reach their target.

Last year, Ennio Tasciotti, Ph.D, senior author and director of the Center for Biomimetic Medicine at Houston Methodist Research Institute and team created these leukosomes and evaluated their ability to treat localized inflammation (May 23, 2016, Nature Materials). Leukosomes are able to target inflamed tissues because their design mimics immune cell membranes.

“Now we have a clearer understanding of how to use our leukosomes to evade those immune cells and prevent the body’s inflammatory response,” Tasciotti said. “We’ve known overactive immune cells can behave like Pac Men, gobbling up the nanoparticles and ridding the body of these ‘foreign invaders’ before they reach the intended target.”

Learning how to treat inflammation by overcoming the body’s own defense mechanisms may lead to broader applications for treating diseases characterized by inflammation such as cancer, cardiovascular and autoimmune diseases.

While the research in ACS Nano helps to improve understanding of the overall properties of leukosomes, further studies are needed to confirm the benefits to patients and ways to prevent the human body from rejecting targeted therapies.

The research was supported by the Italian Ministry of Health, National Institutes of Health and National Cancer Institute, the Department of Defense (BCRP Innovator Expansion), William Randolph Hearst Foundation, and The Cullen Trust for Health Care.

New Assay May Lead to a Cure for Debilitating Inflammatory Joint Disease

Current treatments for rheumatoid arthritis relieve the inflammation that leads to joint destruction, but the immunologic defect that triggers the inflammation persists to cause relapses, according to research conducted at NYU Langone Medical Center and the University of Pittsburgh.

Known as autoantibodies and produced by the immune system’s B cells, these defective molecules mistakenly attack the body’s own proteins in an example of autoimmune disease. Now the results of a study just published in Arthritis & Rheumatology suggest that clinical trials for new rheumatoid arthritis (RA) drugs should shift from their sole focus on relieving inflammation to eliminating the B cells that produce these antibodies.

“We have developed a test for measuring the underlying autoimmunity in rheumatoid arthritis patients that should be used to evaluate new treatment regimens,” says senior author Gregg Silverman, MD, professor in the Departments of Medicine and Pathology at NYU Langone and co-director of its Musculoskeletal Center of Excellence. “We believe this provides a road to a cure for rheumatoid arthritis.”

Rheumatoid arthritis is a chronic inflammatory autoimmune disease that affects 1.5 million people in the United States. The current standard of care begins with methotrexate, a drug that reduces inflammation. It is often followed by drugs that block a molecule called tumor necrosis factor (TNF), which promotes inflammation. Both of these classes of drugs can blunt the swelling and inflammation associated with rheumatoid arthritis and at times even allow patients to go into clinical remission that requires continued treatment. But when patients halt these medications, symptoms generally flare up either sooner or later. According to Silverman, the reduction of inflammation does not directly reflect the autoimmune disease that causes rheumatoid arthritis.

In the study, researchers focused on “memory” B cells, immune system cells that remember the initial errant immune encounter that recognized the body’s own proteins as foreign. In rheumatoid arthritis, memory B cells secrete molecules called anti-citrullinated protein antibodies (ACPAs). Doctors currently confirm an RA diagnosis with a blood test that looks for ACPAs, which are present in 80 percent of RA patients.

Silverman and his colleagues developed sensitive assays to detect a range of different autoantibodies present in the disease. The researchers then established a cell culture system to stimulate memory B cells, and used the assays to test what kind of antibodies the B cells produced.

The researchers tested blood samples from RA patients and from healthy donors. They found high levels of APCA-secreting memory B cells in the blood of patients with these autoantibodies, but not in patients without autoantibodies or in the healthy volunteers.

They then looked at patients who had achieved remission with either methotrexate or a TNF inhibitor. The researchers found that APCA levels were directly proportional to the recirculating memory B cells in the blood stream, confirming that current drug treatments do not affect the underlying autoimmunity in rheumatoid arthritis.

The next step, Silverman says, is to conduct long-term prospective clinical trials of new RA drugs, using the team’s new test to determine each drug’s effect on autoimmunity. The current metrics for evaluating the effectiveness of new rheumatoid arthritis drugs remain focused on reducing inflammation but not curing the disease, he says.

“We need to develop longer-term vision of how to improve the treatment of rheumatoid arthritis,” Silverman says. “This new tool may show that agents that target other molecules or cells have advantages that were previously not considered now that we can better measure those effects.”

Stressed Out Interferons Reveal Potential Key to Alternative Lupus Treatment

Only one new drug has become available over the past 50 years for the estimated 1.5 million Americans and five million-plus people worldwide suffering from lupus, but new research has identified a previously unknown mechanism involved in the immune response that could provide an alternative therapy target.

Lupus (also known as systemic lupus erythematosus) is a chronic autoimmune disease in which the immune system is unable to distinguish the difference between foreign invaders, such as viruses and bacteria, from its own healthy body tissue, so it attacks itself, damaging skin, joints, and kidneys – among other organs – in the process. The disease is also marked by elevated levels of type I interferon, a substance normally secreted by immune cells in response to viral infections. The origin of the interferon signature in lupus has remained a mystery for years.

While working to solve this enigma, researchers, including Iwona Buskiewicz, Ph.D., and Andreas Koenig, Ph.D., assistant professors of pathology and laboratory medicine at the University of Vermont’s Larner College of Medicine, uncovered an unexpected finding: a protein that normally signals an immune system pathway during viral infections was spontaneously activated in lupus patients, even in the absence of viral infection.

Their results were published recently in the journal Science Signaling.

“Typically, this protein – mitochondrial antiviral signaling or MAVS – is responsible for recognizing viral infections,” explains Buskewicz, who adds that her team’s publication is “the first paper showing that the interferon pathway can be activated by something other than viral infection or nucleic acids.”

The culprit of this phenomenon? Oxidative stress in cells, which is sufficient to induce the clustering of MAVS at the mitochondria – the energy-producing organelles within each cell – and drive interferon production in the absence of viruses.

Why it is located at the mitochondria is still a missing piece of the puzzle, Buskewicz admits. She and her colleagues’ findings suggest that in lupus patients, environmental stress may contribute to their production of type I interferon, which normally helps regulate immune system activity. In their study, introduction of an anti-oxidant reversed the clustering of MAVS and prevented the subsequent production of interferon.

Buskiewicz and her colleagues believe that MAVS could be targeted therapeutically with antioxidants directed to the mitochondria.

The next step for the research team members, who in addition to the Larner College of Medicine at the University of Vermont, hail from the Wellcome Trust, University of Glasgow, SUNY Upstate Medical Center, and Weill Cornell Medical College, is to collaborate with rheumatologists to further explore a potential therapy, by examining the degree of MAVS clustering and interferon levels before and after antioxidant therapy.

Mayo Clinic Researchers Find Association Between Therapy for Autoimmune Disease and Bone Marrow Disorders

Mayo Clinic researchers have found that azathioprine, a drug commonly used to treat autoimmune disease, may increase the risk of myeloid neoplasms. Myeloid neoplasms include a spectrum of potentially life-threatening bone marrow disorders, such as myelodysplastic syndromes and acute myeloid leukemia. The results are published in JAMA Oncology.

Researchers analyzed more than 40,000 patient cases with 27 common autoimmune diseases, such as Lupus, rheumatoid arthritis, among others, that were seen over a decade at Mayo Clinic. They identified 86 patients with therapy-related myeloid neoplasm. Detailed data on each patient’s drug exposures, duration and disease characteristics were collected and compared to autoimmune patients without bone marrow disorders of myelodysplastic syndromes or acute myeloid leukemia. The results concluded that only azathioprine was statistically significantly associated with an increased risk of therapy-related myeloid neoplasm. However, other agents used showed a similar trend that was not statistically significant.

“Similar associations were already documented in case reports and case series, but have never been evaluated in a broad spectrum of autoimmune diseases in that many patients and in context of individual medications,” says Raoul Tibes, M.D., Ph.D., senior author of the study and former director of the Acute and Chronic Leukemia Program at Mayo Clinic’s Arizona campus. “Interestingly, there was no association with length of time on therapy and resulting myeloid neoplasm.”

“This study, along with our current knowledge of therapy-related myeloid neoplasm, suggests that individualized drug selection and monitoring during treatment could be possible,” says Natalie Ertz-Archambault, M.D., co-author of the study. “Future genomic profiling studies may help to identify patients at risk for myeloid neoplasms when exposed to azathioprine or other drugs,” adds Dr. Tibes.

The researchers emphasize that, while the results of the study are intriguing, they should not change or replace the clinical judgments, monitoring and current standard treatments at this stage for patients with an autoimmune disease.

Despite its large size, the researchers note this study’s limitations. It was a retrospective study. Many different autoimmune diseases were analyzed, which can each affect the results. Only myelodysplastic syndromes and acute myeloid leukemia were assessed. And no definitive causal association was made between taking a particular drug and myelodysplastic syndromes or acute myeloid leukemia. Further, the number of patients with autoimmune disease developing myelodysplastic syndromes or acute myeloid leukemia is still low overall, and no prediction for individual patients can be concluded from the study.

The researchers plan to perform molecular investigations into the genetic susceptibility for therapy-related myeloid neoplasm as the next phase of the study.

Researchers Discover a New Gatekeeper Role for Thymic Dendritic Cells in Controlling T Cell Release into the Bloodstream

Better Understanding of Cell’s Role Could Lead to New Strategies to Treat Autoimmune Diseases, Cancer

Newswise — Oakland, CA (December 6, 2016) – A team of scientists led by Julie Saba, MD, PhD at UCSF Benioff Children’s Hospital Oakland, has unveiled a novel role of thymic dendritic cells, which could result in new strategies to treat conditions such as autoimmune diseases, immune deficiencies, prematurity, infections, cancer, and the loss of immunity after bone marrow transplantation.

The study “Dendritic cell sphingosine-1-phosphate lyase regulates thymic egress,” appeared in the ‘Journal of Experimental Medicine’ (October 17, 2016 issue), published by Rockefeller University Press.

T lymphocytes are blood cells that carry out the main functions of our immune system. Dendritic cells and B lymphocytes are other types of immune cells that present foreign substances (such as microbial proteins) and “self” substances from our own tissues to T lymphocytes. In this way, T lymphocytes are “educated” to distinguish between self and non-self, so they can mount an immune response to pathogens but recognize and remain tolerant of one’s own bodily tissues. When this system fails to operate properly, autoimmune disease and immune deficiencies can result.

T lymphocytes undergo maturation in the thymus, a small gland located just above the heart, and are then released into the bloodstream. T lymphocyte egress from the thymus is essential for immune surveillance and to fight various types of infections. Sphingosine-1-phosphate (S1P) is a lipid molecule found at high levels in the blood and low levels in most tissues. Mature T cells produce a cell surface receptor that recognizes S1P, allowing the S1P chemical gradient to attract them into the bloodstream once they have completed their education in the thymus. However, the precise mechanisms that control T lymphocyte egress are not fully understood.

Thymic dendritic cells have a well-established role in antigen presentation and immune tolerance in the body. In addition to this role, dendritic cells also act as metabolic gatekeepers of lymphocyte trafficking. The team showed that thymic dendritic cells take up S1P, a blood borne lipid mediator, and metabolize it through the actions of an enzyme called S1P lyase, generating a localized S1P gradient that facilitates T lymphocyte egress into the blood In light of the fact that dendritic cells are known to continually traffic throughout the body surveying for the presence of infectious agents, the team’s observations raise the possibility that dendritic cells could potentially control the release of T lymphocytes in response to various disease states or conditions. These findings provide a deeper understanding of how the body regulates lymphocyte trafficking.

“T cells are needed to orchestrate the body’s immune response against pathogenic organisms and also against cancer cells,” says UCSF Benioff Oakland’s Dr. Julie Saba, one of the study’s authors. “In addition to natural T cells, genetically engineered T cells are being used in revolutionary ways to treat cancer. However, conditions such as chronic infection, aging, cancer and bone marrow transplantation can reduce T cell output from the thymus, compromising immune function. By learning what controls T cell output, we hope to be able to restore T cell production when it is low and provide more T cells for therapeutic purposes. ”

In addition to Saba, other co-authors are Jesus Zamora-Pineda, Ashok Kumar, Jung H. Suh, and Meng Zhang,

The research is supported by the (CA129438) and Swim Across America funds (to J.D. Saba). Confocal images were acquired at the Children’s Hospital Oakland Research Institute Microimaging Facility supported by an NIH grant (S10RR025472) and the Children’s Hospital Branches, Inc. S1P measurements were obtained using the Children’s Hospital Oakland Research Institute Mass Spectrometry Facility supported by an NIH Health grant (S10OD018070).

About UCSF Benioff Children’s Hospital Oakland
UCSF Benioff Children’s Hospital Oakland (formerly Children’s Hospital & Research Center Oakland) is a premier, not-for-profit medical center for children in Northern California, and is the only hospital in the East Bay 100% devoted to pediatrics. UCSF Benioff Children’s Hospital Oakland affiliated with UCSF Benioff Children’s Hospital San Francisco on January 1, 2014. UCSF Benioff Children’s Hospital Oakland is a national leader in many pediatric specialties including cardiology, hematology/oncology, neonatology, neurosurgery, endocrinology, urology, orthopedics, and sports medicine. The hospital is one of only five ACS Pediatric Level I Trauma Centers in the state, and has one of largest pediatric intensive care units in Northern California. UCSF Benioff Children’s Hospital Oakland is also a leading teaching hospital with an outstanding pediatric residency program and a number of unique pediatric subspecialty fellowship programs.

UCSF Benioff Children’s Hospital Oakland’s research arm, Children’s Hospital Oakland Research Institute (CHORI), is internationally known for its basic and clinical research. CHORI is at the forefront of translating research into interventions for treating and preventing human diseases. CHORI has 250 members of its investigative staff, a budget of about $50 million, and is ranked among the nation’s top ten research centers for National Institutes of Health funding to children’s hospitals. For more information, go to www.childrenshospitaloakland.org and www.chori.org.

Successfully Treating Genetically Determined Autoimmune Enteritis

Using targeted immunotherapy, doctors have succeeded in curing a type of autoimmune enteritis caused by a recently discovered genetic mutation. This report comes from researchers at the Department of Biomedicine of the University of Basel and University Hospital Basel. Their results raise new possibilities for the management of diarrhea, which is often a side effect of melanoma treatment.

Immunodeficiencies can arise due to gene mutations in immune system proteins. As such mutations rarely occur, these immunodeficiencies often go unrecognized or are detected too late for effective treatment. Currently, there are more than 300 different known genetically determined immunodeficiencies, with new examples being described almost every week.

Prof. Mike Recher’s research group at the Department of Biomedicine of the University of Basel and University Hospital Basel recently discovered a genetic immunodeficiency associated with serious, chronic autoimmune enteritis in an adult patient. Happily, according to the researchers’ report in the Journal of Allergy and Clinical Immunology, they were able not only to describe the new mutation, but also to successfully treat the patient with targeted therapy.

Autoimmune reaction caused by mutation

The patient had a rare mutation in the CTLA-4 protein found on the surface of T-cells. Normally, this protein prevents immune cells from attacking an patient’s own body. However, as it was not functioning adequately due to the mutation, T-cells attacked the patient’s own intestinal cells, causing chronic inflammation. This resulted in the patient suffering from severe diarrhea and weight loss.

These unusual symptoms led the cantonal hospital of Graubünden to refer the patient to the special clinic for immunodeficiency at the University Hospital Basel. Initial immunological investigations suggested a genetically determined dysregulation of the immune system. The new CTLA-4 gene mutation was discovered following subsequent analysis of the entire genome at the University Hospital Zurich. Further investigations showed that the mutation causes reduced CTLA-4 function, which led to increased infiltration of the intestinal mucosa by T-cells and therefore to chronic diarrhea.

Treatment with therapeutic antibodies

Working in close cooperation with University Hospital Basel’s gastroenterology department, the doctors opted for a therapy that uses a new drug from the monoclonal antibody group to prevent the T-cells from penetrating the intestinal mucosa. This drug (vedolizumab) blocks a specific adhesion molecule on the surface of the T-cell and thereby inhibits immune cells from binding themselves to receptors present in the intestine, preventing the T-cells from penetrating the blood vessels in the intestinal tissue. This treatment produced the desired outcome: after three months, the patient’s chronic diarrhea had stopped completely.

Preventing diarrhea in melanoma patients

In some diseases, however, CTLA-4 inhibition can be used therapeutically, as in the treatment of skin cancer (melanoma). The drug Ipilimumab works similarly to the CTLA-4 mutation, meaning that immune system T-cells are no longer properly inhibited and can more efficiently attack the malignant skin cancer cells. One of the side-effects of this therapy is autoimmune intestinal inflammation – analogous to the inflammation that occurs in patients with the CTLA-4 gene mutation. It is possible that melanoma patients, who suffer severe diarrhea due to the inhibition of their CTLA-4 function, will benefit from this new insight, which opens up new therapeutic possibilities for Vedolizumab.

Cooperation between regional hospitals, basic research and university medical departments

This case demonstrates the importance of precise diagnosis of the molecular causes of an illness in enabling targeted, personalized treatment. “In order to expand our knowledge in these areas, doctors in clinics and regional hospitals must be on the alert for unusual disease phenotypes and refer such patients to specialized university hospital clinics for further evaluation,” says study author Mike Recher. “We also need clinical university centers that are closely linked to research laboratories.”

New Data From Harvard & Yale Researchers Reveal Breakthrough Oral Fully Human Anti-CD3 Antibody, for the Treatment of NASH, Diabetes & Autoimmune Diseases

Immunotherapies have shown great promise to treat a wide range of diseases including auto-immune disease and NASH. However, they are typically administered through IV instead of orally because if taken orally, they would be degraded and inactivated by the harsh conditions in the gastrointestinal tract. New data from preclinical studies conducted by Prof. Kevan Herold of Yale University and Prof. Howard Weiner of Harvard University show that Foralumab, a drug from London-based Tiziana Life Sciences, has shown consistent efficacy via oral administration. Oral efficacy with Foralumab is a potential game-changer for the treatment of autoimmune diseases and NASH.

Foralumab is a long half-life therapeutic mAb candidate with high affinity and potency for CD3 epsilon. It is the only fully human engineered anti CD3 monoclonal antibody (mAb) in clinical development.  The unique oral technology stimulates the natural gut immune system and potentially provides a therapeutic effect in inflammatory and autoimmune diseases with virtually no toxicity.

According to Prof. Kevan Herold, a member of Tiziana’s Scientific Advisory Board at Yale University, “This study demonstrates that oral administration works consistently in our pre-clinical models with human immune cells. This suggests that oral CD3-specific mAb has the potential for treating NASH, diabetes, and other autoimmune diseases in humans – an entirely novel approach for the treatment of currently unmet needs.”

Further animal studies conducted in a member of Tiziana’s Scientific Advisory Board, Prof. Howard Weiner’s laboratory at Harvard University, supported the potential of oral treatment with Foralumab for autoimmune and inflammatory diseases. Prof. Weiner stated, “Our data suggest that oral treatment with anti-CD3 mAb induces an anti-inflammatory response through induction of regulatory T cells (Tregs). This proof of concept of foralumab in humanized mice demonstrates that this approach could be used successfully in humans as well.”

Foralumab has applications in chronic inflammatory and autoimmune diseases with high unmet medical needs such as ulcerative colitis, inflammatory bowel diseases, multiple sclerosis, lupus, as well as in non-alcoholic steatohepatitis (NASH) and type 1 diabetes.

Flesh-Eating Infections In Rheumatoid Arthritis Patients Spur New Discovery

Rheumatoid arthritis patients taking medications that inhibit interleukin-1beta (IL-1beta), a molecule that stimulates the immune system, are 300 times more likely to experience invasive Group A Streptococcal infections than patients not on the drug, according to University of California San Diego School of Medicine researchers. Their study, published August 19 in Science Immunology, also uncovers a critical new role for IL-1beta as the body’s independent early warning system for bacterial infections.

“The more we know about each step in the body’s immune response to bacterial infections, the better equipped we are to design more personalized, targeted therapies for autoimmune diseases — therapies that are effective, but minimize risk of infection,” said senior author Victor Nizet, MD, professor of pediatrics and pharmacy at UC San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences.

IL-1beta is a molecule that stimulates an immune response, calling white blood cells to the site of an infection so they can engulf and clear away invading pathogens. The body first produces the molecule in a longer, inactive form that must be cleaved to be activated. The scientific community long believed that only the body itself could cleave and activate IL-1beta, by employing a cellular structure known as the inflammasome. But in experiments using cell cultures and mouse models of infection, Nizet and team found that SpeB, an enzyme secreted by strep bacteria, also cleaves and activates IL-1beta, triggering a protective immune response.

“This finding may explain why some of the more invasive, flesh-eating strep strains have a genetic mutation that blocks SpeB production — it helps them avoid tripping the alarm and setting off an immune response,” said first author Christopher LaRock, PhD, a postdoctoral researcher in Nizet’s lab.

The researchers hypothesize that for less invasive strains, like those that cause strep throat, producing SpeB and activating IL-1beta might be advantageous — the resulting immune response may wipe out competing bacteria and help strep establish a foothold in the body.

While the human immune system can quickly recognize and respond to bacterial infections, sometimes this reaction can go overboard, leading to autoimmune diseases such as rheumatoid arthritis. In this case, a person’s own immune system attacks “self” proteins instead of just foreign invaders.

In their efforts to investigate IL-1beta function, Nizet, LaRock and team analyzed a U.S. Food and Drug Administration (FDA) database on adverse events in rheumatoid patients who took anakinra, a drug that dampens autoimmunity by inhibiting IL-1beta. They found that patients receiving anakinra were more than 300 times more likely to experience invasive, flesh-eating strep infections than patients not taking the drug.

“A likely explanation for this increased risk is that with IL-1beta out of the picture, as is the case with patients taking anakinra, strep strains can progress to invasive infection even while producing SpeB, which goes unnoticed by the immune system,” LaRock said.

This finding underscores IL-1beta’s importance as an early warning system that’s triggered not only by the host, but also directly by bacterial enzymes, essentially “taking out the middle man,” Nizet said. The UC San Diego researchers believe this capacity for direct pathogen detection represents IL-1beta’s original role in immunity, going all the way back in evolution to simpler animals, such as fish.

“Inhibiting the body’s bacterial sensor can put a person at risk for invasive infection,” Nizet said, “but just the fact that we now know that this patient population is at higher risk and why means we can take simple steps — such as close monitoring and prophylactic antibiotics — to prevent it from happening. ”

New Research Studies Identify Potential Cause of and New Treatment for Autoimmune Diseases

The American Autoimmune Related Diseases Association, Inc. (AARDA) is spotlighting two new research studies originally reported in ScienceDaily. The first study advances understanding of a potential cause of autoimmune disease, while the second examines a new treatment approach that could have wide-ranging implications for many autoimmune diseases.

In both cases, AARDA believes the research is promising and additional studies are needed to confirm the findings.

Potential Genetic Trigger of ADs Identified

Researchers at the Hospital for Special Surgery (HSS) in New York City, reporting in the June issue of Arthritis and Rheumatism, have found virus-like elements within the human genome that may be a potential genetic trigger of systemic autoimmune disease.

According to ScienceDaily (June 27, 2016):
“For their study, the HSS researchers hypothesized that the abnormal expression of genetic elements known as LINE-1 ( L1) retroelements might trigger an innate immune response similar to that produced by outside viruses and contribute to an overproduction of interferons.

Interferons are molecules our body produces in the presence of viruses and other pathogens to mobilize the immune system. They’re part of the complex immune response to combat danger. However, if levels of interferon are too high, instead of playing a protective role it can contribute to the development of autoimmune disease.”
The researchers sought to understand why a class of interferon known as type 1 interferon, is excessively produced in patients with SLE and Sjogren’s syndrome.

“Our genomes are packed with sequences derived from viruses that were inserted many thousands of years ago, and these virus-like sequences can move around, causing genetic mutations and contributing to the evolution of our genomes. We hypothesized that they sometimes generate virus-like RNA sequences that can be detected by the immune system,” said Mary K. Crow, MD, physician-in-chief at Hospital for Special Surgery and senior study author.

“Our findings support the hypothesis that L1 retroelements, perhaps along with other virus-derived genomic elements, may contribute to the development of autoimmune disorders characterized by high levels of type 1 interferon,” said Dr. Crow, chair, Department of Medicine, and Benjamin M. Rosen Chair in Immunology and Inflammation Research at HSS. “Although it may not be the only cause, it’s intriguing to think that virus-derived elements in our own genome are either quiet and don’t cause any trouble, or they get stirred up and contribute to disease.”

Commenting on the study, Noel R. Rose, MD, Ph.D., chairman emeritus of AARDA’s Scientific Advisory Board, said the findings, “Iook very much like what I have always called the “adjuvant effect”. All of us are prone to develop some autoimmunity (self-reactive lymphocytes) depending upon our genetics. But we need an extra push — the adjuvant to move from benign autoimmunity to autoimmune disease. Often the adjuvant is supplied by infection or the body’s response to infection. This study suggests that an interferon-like molecule is the adjuvant.”

Promising New AD Treatment in PreClinical Study Reported
A new treatment approach used in a preclinical study may hold promise for a wide array of autoimmune disease. Scientists at the University of Pennsylvania School of Medicine (Penn) have developed “a method for removing the subset of antibody-making cells that produce autoimmune disease without harming the immune system,”

ScienceDaily (June 30, 2016) reports:
“The key element in the new strategy is based on an artificial target-recognizing receptor, called a chimeric antigen receptor, or CAR, which can be engineered into patients’ T cells. In human trials, researchers remove some of patients’ T cells through a process similar to dialysis and then engineer them in a laboratory to add the gene for the CAR so that the new receptor is expressed in the T cells. The new cells are then multiplied in the lab before re-infusing them into the patient. The T cells use their CAR receptors to bind to molecules on target cells, and the act of binding triggers an internal signal that strongly activates the T cells — so that they swiftly destroy their targets.

Current therapies for autoimmune disease, such as prednisone and rituximab, suppress large parts of the immune system, leaving patients vulnerable to potentially fatal opportunistic infections and cancers.

The Penn researchers demonstrated their new technique by successfully treating pemphigus vulgaris, an otherwise fatal autoimmune disease, in a mouse model, without apparent off-target effects which could harm healthy tissue. The results are published in an online First Release paper in Science.

“This is a powerful strategy for targeting just autoimmune cells and sparing the good immune cells that protect us from infection,” said co-senior author Aimee S. Payne, MD, PhD, the Albert M. Kligman Associate Professor of Dermatology.
Payne and her co-senior author Michael C. Milone, MD, PhD, an assistant professor of Pathology and Laboratory Medicine, adapted the technique from the promising anti-cancer strategy by which T cells are engineered to destroy malignant cells in certain leukemias and lymphomas.

“Our study effectively opens up the application of this anti-cancer technology to the treatment of a much wider range of diseases, including autoimmunity and transplant rejection,” Milone said.

AARDA’s Rose said of the study, “What a great example of the ‘Ying-Yang’ synergy between cancer research and research on the autoimmune diseases. Many of the key ideas behind CAR T cells arose from years of fundamental research on autoimmunity. Now a new method of cancer immunotherapy is being applied to treating autoimmune disease.
“You never know where basic research will take you.”