Researchers at the School of Medicine have identified an unexpected contributor to rheumatoid arthritis that may help explain the painful flare-ups associated with the disease. The discovery points to a potential new treatment for the autoimmune disorder and may also allow the use of a simple blood test to detect people at elevated risk for developing the condition.
The arthritis discovery originated in the lab of UVA’s Kodi Ravichandran, PhD, and was facilitated by combining his team’s resources and expertise with that of Inova researcher Thomas Conrads, PhD, through a THRIV UVA-Inova seed grant.
The new findings about rheumatoid arthritis came in an unexpected fashion. Sanja Arandjelovic, PhD, a research scientist in the Ravichandran group, was seeking to better understand what causes the inflammation associated with inflammatory arthritis when she noted that deleting a gene called ELMO1 alleviated arthritis symptoms in mice. This was particularly surprising because Arandjelovic and Ravichandran initially thought that loss of ELMO1 would result in increased inflammation.
“This was a complete surprise to us initially,” recalled Ravichandran, chairman of UVA’s Department of Microbiology, Immunology and Cancer Biology. “I love those kinds of results, because they tell us that, first, we did not fully comprehend the scientific problem when we began exploring it, and, second, such unexpected results challenge us to think in a different way. Given that rheumatoid arthritis affects millions of people worldwide, we felt the need to understand this observation better.”
Digging deeper into the unusual outcome, the researchers determined that ELMO1 promotes inflammation via their function in white blood cells called neutrophils. Ravichandran described neutrophils as the body’s “first line of defence” because they sense and respond to potential threats. “Normally they are good for us, against many bacterial infections,” he said. “But also there are many times when they produce a lot of friendly fire that is quite damaging to the tissues – when they hang around too long or there are too many neutrophils coming in – in this case, infiltrating into the joints during arthritis.”
The researchers also discovered that there is a natural variation in the ELMO1 gene that can prompt neutrophils to become more mobile and have the potential to invade the joints in greater numbers and induce inflammation. (The potential blood test would detect this variation.)
Here things take a particularly cool turn: Normally, doctors are reluctant to try to block the effect of genes like ELMO1 in people, because such genes can play diverse roles in the body. But Ravichandran believes that ELMO1 is different. “ELMO1 partners with very specific set of proteins only in the neutrophils but not in other cells types we tested,” he said. “So, presumably, you may be able to affect only a select cell type.” This latter result came about from a collaborative study where Conrads’ group at Inova performed sophisticated analysis of ELMO1 proteomic partners in neutrophils, many of which also have previously known links to human arthritis. This provided further validation for the role of ELMO1 in rheumatoid arthritis.
Encouragingly, blocking ELMO1 in lab mice alleviated arthritis inflammation without causing other problems, Ravichandran noted. His laboratory is now seeking to identify drugs that could inhibit the function of ELMO1 and is also designing a test for the variation (also called polymorphism) in the ELMO1 gene.
“This is another example of how fundamental basic research can lead to novel discoveries on clinically relevant problems that affect a large number of people,” Ravichandran said.

University of Virginia
newsroom.uvahealth.com/2019/02/07/surprise-rheumatoid-arthritis-discovery-points-to-new-treatment/

Thermo Fisher Scientific and NX Prenatal Inc., a recognized leader in the detection, monitoring and management of pregnancy-related complications using novel exosome-based methods, have entered into a collaboration to develop clinical mass spectrometry-based proteomics assays to monitor fetal health in utero and assess the risk of adverse outcomes, including preterm birth and preeclampsia.
This new collaboration recognizes the challenges faced by medical professionals who have few tools available for noninvasive risk stratification for adverse pregnancy outcomes. By combining NX Prenatal’s NeXosome platform with Thermo Fisher’s leading liquid chromatography-mass spectrometry (LC-MS) instrumentation, the workflows can address the reliability, accuracy and precision of the analytical solutions currently available to clinical scientists.
"Our collaboration with NX Prenatal is aiming to enable us to better evaluate maternal and fetal biomarkers during pregnancy that correlate with adverse outcomes, such as preterm birth," said Brad Hart, senior director, clinical research, chromatography and mass spectrometry, Thermo Fisher Scientific. "The co-development of a commercially available clinical mass spectrometry-based proteomics assay has the potential to provide a diagnostic solution to both clinical scientists and medical professionals offering more confidence in the evaluation of novel biomarkers that can support a safe delivery and healthy future for mother and baby."
"At NX Prenatal, we are developing novel assays and noninvasive early warning systems to detect subtle molecular changes in the maternal-fetal environment, all with the goal of improving the rate of healthy pregnancy outcomes," said Brian D. Brohman, CEO of NX Prenatal. "Our collaboration with Thermo Fisher Scientific brings together our novel NeXosome platform with their leading analytical technology with the goal of optimizing clinical mass spectrometry-based workflows, in an effort to provide the precision necessary for personalized diagnostic solutions to improve health outcomes for both mother and child."
The unique NeXosome technology is used to enrich maternal blood samples for microparticles, such as exosomes, which play key roles in maintaining certain balances between the mother and fetus during pregnancy. Aberrations in these balances have been shown to correlate with the likelihood of adverse pregnancy outcomes. Merging the NeXosome platform with Thermo Fisher LC-MS technology has the potential to generate fast, efficient and accurate data for the analysis of exosome-derived proteomic biomarkers, which may lead to increased information about maternal and fetal health during pregnancy. Ultimately, the analysis has the potential to support obstetrical care decisions in conjunction with traditional clinical assessments. www.thermofisher.com

Researchers at Vanderbilt University Medical Center and colleagues have identified a gene that increases the risk for a severe and potentially life-threatening reaction to the commonly prescribed antibiotic vancomycin.
Routine testing for this gene could improve patient safety and reduce unnecessary avoidance of other antibiotics, they report.
 “We think this test will be important in the clinical care of patients starting vancomycin and will prevent mortality and short- and long-term complications,” said the paper’s senior author, Elizabeth Phillips, MD.
Vancomycin is commonly given in the hospital or as home intravenous therapy for several weeks in combination with other powerful antibiotics to treat serious and potentially life-threatening bacterial infections.
Within two to eight weeks of initiating antibiotic therapy, however, some patients develop a severe reaction known as DRESS — Drug Rash with Eosinophilia and Systemic Symptoms — characterized by fever, widespread skin rash and internal organ damage caused by an aberrant T-cell mediated immune response to the drug.
When DRESS develops, all treatment is stopped. The mortality rate that results, often from a combination of organ damage, the need for strong immunosuppressants such as steroids and compromised treatment options for the underlying infection, approaches 10 percent.
While the true incidence of DRESS is not known, every year in the United States “hundreds of thousands of patients are at risk,” said Phillips, the John A. Oates Professor of Clinical Research and professor of Medicine, Pharmacology and Pathology, Microbiology and Immunology at VUMC and Vanderbilt University School of Medicine.
For several years, vancomycin has been known to be a common antibiotic trigger for DRESS, however the genetic risk factors predisposing specific patients were not known.
This new finding shows that vancomycin-associated DRESS occurs in patients who carry specific variations in human leukocyte antigen (HLA) genes. HLA genes encode proteins that present foreign peptides (antigens) to T cells (a kind of white blood cell) to stimulate an immune response.
Vanderbilt University Medical Center https://tinyurl.com/y4ukodbb

Researchers have created a huge resource for investigating the biological mechanisms that cause cancer. The scientists from the Wellcome Sanger Institute and their collaborators identified which patterns of DNA damage – mutational fingerprints that represent the origins of cancer – were present in over a thousand human cancer cell lines. They also revealed that a major mutation pattern found in human cancer, previously linked to a virus-fighting immune response, occurred in bursts in cancer cell lines with long periods of silence in between, but the cause of these mutational bursts remains mysterious.
The resource will enable scientists to study what causes mutations that lead to the development of cancer, directly in human cancer cells. Further understanding into these mutational processes could help researchers find novel avenues for research towards cancer prevention and treatment.
All cancers are caused by DNA mutations, and these mutations form molecular fingerprints in the DNA called mutational signatures. More than 50 different signatures have been found, many of which are caused by external factors, for example ultraviolet light exposure or tobacco smoking. Others are due to factors inside the cell such as the failure of DNA repair mechanisms. However, the causes of many mutational signatures are unknown and they are extremely challenging to study experimentally.
The researchers studied the genome sequences of 1,001 human cancer cell lines and 577 grafts of human cancers, including the most widely used models in cancer research and therapeutics testing. They used all the known mutational signatures and catalogued which signature is present in each cancer model. This resource then allowed the scientists to choose specific cell lines and study how each mutational pattern changed over time in cancer cells.
They found that mutational signatures from known external factors like smoking or UV light stopped being created in cell lines, whereas most signatures associated with factors inside the cell continued to be generated, and at a steady rate. Surprisingly however, they discovered that two common mutational signatures associated with a DNA editing protein known as APOBEC, actually switched on and off over time in cell lines, a phenomenon they called “episodic mutagenesis”.
APOBEC DNA editing enzymes are part of the innate immune system, protecting us from infections by causing mutations in viruses such as HIV, leaving APOBEC mutational signatures in the viral genomes. APOBEC-like signatures are a major mutation pattern in cancers, found in more than 70 per cent of cancer types. A theory for this is that viruses or inflammation could activate the enzymes to mutate the human genome instead of the virus. However, cell lines are not subject to inflammation and no viruses were found, suggesting other factors are involved. Importantly, cell lines found to generate these and other signatures over time can now be used by researchers to investigate the underlying causes of mutations in cancer.
Wellcome Sanger Institute https://tinyurl.com/y2fga87n

Proteins that normally reside inside cell nuclei have never been found in the blood, until now. A new blood test developed at the Johns Hopkins University by Shih-Chin Wang and Chih-Ping Mao—graduate students in Jie Xiao’s lab in the Department of Biophysics and Chien-Fu Hung’s lab in the Department of Pathology—can identify individual molecules in human blood samples with minimal detection errors. Among the molecules that they used their new test to find was a mutated protein thought to be restricted to the inside of cells, mostly within the nucleus. It is the first time that single-molecule imaging has been applied to visualize disease-causing molecules in blood.
Wang and colleagues call their new approach Single-Molecule Augmented Capture (SMAC). They used this new technique to detect molecules commonly screened for in standard blood tests, like prostate-specific antigen. And they were also able to detect rare intracellular proteins, secreted proteins and membrane proteins, including the cancer-associated proteins mutant p53, anti-p53 autoantibodies and programmed death-ligand 1 (PD-L1).
Mutant p53 is a well-known tumour-specific nuclear protein and has never before been detected in the blood, likely because current tests cannot detect its extremely low blood concentrations. Wang and colleagues found mutant p53 or anti-p53 autoantibodies in samples from patients with ovarian cancer, but not in patients without cancer. PD-L1 is also found on the surface of some cancer cells and has recently been effectively targeted with immunotherapy to combat cancer. Knowing whether or not a patient’s tumour expresses PD-L1 is a crucial first step in this treatment—and SMAC may be able to identify cancers that have PD-L1 at low levels that are undetectable by standard blood tests.
“With SMAC, we have brought single-molecule imaging into the clinical arena. By visualizing and examining individual molecules released from diseased cells into the blood, we aim to detect diseases more accurately and gain new insights into their mechanisms,” Mao said.
Biophysics Society https://tinyurl.com/yynccngq