A gene called triggering receptor expressed on myeloid cells 2, or TREM2, has been associated with numerous neurodegenerative diseases, such as Alzheimer’s disease, Frontotemporal lobar degeneration, Parkinson’s disease, and Nasu-Hakola disease. Recently, a rare mutation in the gene has been shown to increase the risk for developing Alzheimer’s disease.
Independently from each other, two research groups have now revealed the molecular mechanism behind this mutation. Their research sheds light on the role of TREM2 in normal brain function and suggests a new therapeutic target in Alzheimer’s disease treatment.
Alzheimer’s disease, just like other neurodegenerative diseases, is characterized by the accumulation of specific protein aggregates in the brain. Specialized brain immune cells called microglia strive to counter this process by engulfing the toxic buildup. But as the brain ages, microglia eventually lose out and fail to rid all the damaging material.
TREM2 is active on microglia and enables them to carry out their protective function. The protein spans the microglia cell membrane and uses its external region to detect dying cells or lipids associated with toxic protein aggregates. Subsequently, TREM2 is cut in two. The external part is shed from the protein and released, while the remaining part still present in the cell membrane is degraded. To better understand TREM2 function, the two research groups took a closer look at its cleavage. They were led by Christian Haass at the German Center for Neurodegenerative Diseases at the Ludwig-Maximilians-University in Munich, Germany, and Damian Crowther of AstraZeneca’s IMED Neuroscience group in Cambridge, UK together with colleagues at the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto and the Cambridge Institute for Medical Research, University of Cambridge, UK.
Using different technological approaches, both groups first determined the exact site of protein shedding and found it to be at amino acid 157. Amino acid 157 was no unknown. Only recently, researchers from China had uncovered that a mutation at this exact position, referred to as p.H157Y, increased the risk of Alzheimer’s disease. Together, these observations indicate that protein cleavage is perturbed in the p.H157 mutant and that this alteration promotes disease development.
As a next step, Haass and Crowther’s groups investigated the biochemical properties of the p.H157Y mutant protein more closely. They found that the mutant was cleaved more rapidly than a healthy version of the protein. "Our results provide a detailed molecular mechanism for how this rare mutation alters the function of TREM2 and hence facilitates the progression of Alzheimer’s disease," said Crowther.
While most TREM2 mutations affect protein production, the mechanism behind p.H157Y is somewhat different. The p.H157Y mutation allows the protein to be correctly manufactured and transported to the microglia cell surface, but then it is cleaved too quickly. "The end result is the same. In both cases, there is too little full-length TREM protein on microglia," said Haass. "This suggests that stabilizing TREM2, by making it less susceptible to cleavage, may be a viable therapeutic strategy."

EurekAlert
www.eurekalert.org/pub_releases/2017-08/e-st-083017.php

Interactions among proteins that relay information from one immune cell to another are weakened in the blood of brain cancer patients within five years before the cancer is diagnosed, said lead researcher Judith Schwartzbaum of The Ohio State University.
That information could one day lead to earlier diagnosis of brain cancer, said Schwartzbaum, an associate professor of epidemiology and member of Ohio State’s Comprehensive Cancer Center.
The study focused on gliomas, which make up about 80 percent of brain cancer diagnoses. Average survival time for the most common type of glioma is 14 months.
Symptoms vary and include headaches, memory loss, personality changes, blurred vision and difficulty speaking. On average, the cancer is diagnosed three months after the onset of symptoms and when tumours are typically advanced.
“It’s important to identify the early stages of tumour development if we hope to intervene more effectively,” Schwartzbaum said. “If you understand those early steps, maybe you can design treatments to block further tumour growth.”
While widespread blood testing of people without symptoms of this rare tumour would be impractical, this research could pave the way for techniques to identify brain cancer earlier and allow for more-effective treatment, Schwartzbaum said.
Schwartzbaum evaluated blood samples from 974 people, half of whom went on to receive a brain-cancer diagnosis in the years after their blood was drawn. The samples came from Norway’s Janus Serum Bank.
Because of previous research – including her own on the relationship between allergies and brain cancer – Schwartzbaum was interested in the role of cytokines, proteins that communicate with one another and with immune cells to spark immune responses. Schwartzbaum’s previous work found that allergies appeared to offer protection against brain cancer.
In this study, Schwartzbaum evaluated 277 cytokines in the blood samples and found less cytokine interaction in the blood of people who developed cancer.
“There was a clear weakening of those interactions in the group who developed brain cancer and it’s possible this plays a role in tumour growth and development,” Schwartzbaum said.
Cytokine activity in cancer is especially important to understand because it can play a good-guy role in terms of fighting tumour development, but it also can play a villain and support a tumour by suppressing the immune system, she said.
In addition to discovering the weakening of cytokine interactions in the blood of future cancer patients, the researchers found a handful of cytokines that appear to play an especially important role in glioma development.
The results of this study must be confirmed and further evaluated before it could translate to changes in the earlier diagnosis of brain cancer, but the discovery offers important insights, Schwartzbaum said.
“It’s possible this could also happen with other tumours – that this is a general sign of tumour development,” she said.

Ohio State Universityhttps://news.osu.edu/news/2015/09/09/a-hint-of-increased-brain-tumor-risk-5-years-before-diagnosis/

Yale experts and their partners in a national research consortium have identified several genes and gene clusters associated with the immune response to influenza (“flu”) vaccination. The findings point to the prospect of using genetic profiles to predict individual responses to the flu vaccine.
The global impact of influenza is substantial, with seasonal epidemics estimated to result in 3-5 million cases of severe illness, and 250,000 to 500,000 deaths annually worldwide. Vaccination is the best way to protect against flu infection, but the composition of the seasonal vaccine changes from year to year. Moreover, effectiveness of the vaccine varies widely among individuals.
Previous studies, including a study done at Yale, have sought to identify changes in gene expression associated with successful flu vaccination but focused on relatively small numbers of participants. The new study included six different cohorts receiving the flu vaccine from across the country; research centres included Yale, the Baylor Research Institute, Emory University, the Mayo Clinic, and the National Institutes of Health. The size of the cohort — more than 500 individuals — allowed researchers to not only identify genes and gene clusters associated with vaccine response, but also confirm these findings in an independent cohort of participants.
Analysing the data, the research team identified several gene “signatures,” or groups of genes, that were associated with a stronger response to the flu vaccine. The response was determined by increases in antibodies that protect against infection.
We “were able to identify genes at baseline, before vaccination, that would predict how individuals would respond to the vaccine,” said Ruth Montgomery, associate professor of medicine at Yale School of Medicine and a co-author.
The researchers also found that the while the genes were predictive of a robust vaccine response in adults younger than age 35, those same genes did not improve responses in adults over age 60. “Another finding is that genes that contribute to good immune response are different in young and older people,” Montgomery noted.
“Surprisingly, we found that baseline differences, both at the gene and module level, were inversely correlated between young and older participants,” added Steven Kleinstein, associate professor of pathology at Yale School of Medicine and a corresponding author on the study. The reasons for these age differences warrant further study, said the researchers.
The findings offer new insights into the biology of vaccine response. They may also help investigators predict responses in individuals and develop strategies to improve vaccines, or treatments to boost the immune system’s response to vaccination, the researchers noted.

Yale University
news.yale.edu/2017/08/25/study-identifies-genes-linked-better-immune-response-flu-vaccine
 
 

ClearLLab reagents are the first to receive Food and Drug Administration (FDA) clearance (via the De Novo Process) to market them in the US.  They deliver the first preformulated, IVD antibody cocktails for leukemia and lymphoma immunophenotyping in the clinical lab. For clinical laboratories it means they no longer have to develop their own laboratory developed test (LDT), a technically demanding, manual, time-consuming, and potentially error-prone process. Previously, labs would have had to make and validate their own antibody cocktails.  ClearLLab reagents simplify and standardize the process.
 ‘FDA allows marketing of test to aid in the detection of certain leukemias and lymphomas’ with the FDA confirming that the test ‘provides consistent results to aid in the diagnoses of these serious cancers’.  The FDA evaluated data from a multi-site clinical study which compared panel results to alternative detection methods.
Dr Mario Koksch, Vice President and General Manager of Beckman Coulter’s Cytometry Business Unit said: “Flow cytometry is a powerful tool for the detailed and fast analysis of complex populations, with the technique becoming increasingly valuable to the clinical hematology laboratory. “Clearance to market the first IVD L&L reagents in the US has opened the door to the expansion globally of our clinical reagent and instrument portfolio.”  
ClearLLab reagents deliver fast and accurate qualitative identification of various hematolymphoid cell populations by immunophenotyping on the FC500 flow cytometer.  With the reliability of a standardized kit and protocols, the preformulated combinations offer LEAN-focused benefits which reduce manual preparation and validation time, accelerate sample preparation time, improve workflow, streamline lab inventory management and provide confidence in the accuracy and reliability of results.
As Dr Koksch added: “The routine use of ready-to-use ClearLLab reagents delivers greater efficiency and cost savings.  Preformulated antibody combinations enable the lab to avoid the potential errors of manual antibody cocktail preparation, with the reassurance of standardized reporting to international guidelines.”
ClearLLab reagents follow the 2006 Bethesda International Consensus Recommendations on the Flow Cytometric Immunophenotypic Analysis of Hematolymphoid Neoplasia. They are compatible with the World Health Organization (WHO) 2016-revised classification of myeloid neoplasms and acute leukemia.  WHO, in collaboration with the European Association for Hematopathology and the Society for Hematopathology, recently made important changes to the classification of these diseases. These included new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. www.beckman.com

In autoimmune diseases, the immune system wrongly identifies its "enemy", and produces antibodies that attack the patient’s own cells. One of these diseases, the anti-phospholipid antibody syndrome (APS), is still poorly understood, even though it can have serious consequences. APS is caused by antibodies circulating in the blood plasma that are directed against a protein, which increase the blood’s tendency to form clots. This can lead to a range of vascular accidents, such as venous thromboses, strokes or repeated miscarriages. Although the prevalence of APS is very difficult to assess, it is likely to affect around 0.5% of the general population. Diagnosing the disease is a complicated affair: the test currently used has a number of problems in terms of variability, specificity and sensitivity. This situation, however, is set to change: researchers at the University of Geneva (UNIGE), Switzerland, and the Geneva University Hospitals (HUG) have succeeded in identifying the exact spot where the anti-phospholipid antibodies attach themselves. This means a more accurate and standardized diagnostic test can now be devised– an undeniable improvement for patients.
In people suffering from APS, antibodies called "anti-Β2GP1" attach themselves to elements found on the surface of certain cells, particularly those of the blood vessels and placenta. They bind themselves to receptors located on the cell membrane, generating a signal that produces the pro-inflammatory and pro-thrombotic factors that cause vascular accidents. By identifying the exact location where these antibodies bind, the research team at UNIGE and HUG have been able to clarify how they function. Karim Brandt, a researcher at the UNIGE Faculty of medicine, explains the importance of this discovery: "The current diagnostic tests use the entire protein, which reduces its specificity and leads to standardization issues.
Consequently, two tests are required at an interval of 12 weeks after a thrombotic episode or following one or more miscarriages. Our new test specifically targets this pathogenic antibody, with rapid and more accurate results."

An antibody with a rather special behaviour
The researchers managed to isolate a "motif", which is a small part of the membrane protein. Motifs are recognized by the antibody, which then binds to it, like a key in a lock. In this instance, the key can open several locks, which correspond to the proteins found on the surface of the cells and induce the pathogenic effects. And if the target protein was identified as such, it is because it is the only protein in all the human proteome to have five of these motifs; it has therefore as many potential binding points for the pathogenic antibody.
APS is usually treated with oral anticoagulants such as low-molecular-weight heparin and aspirin, long-term treatments that are not without side effects, and that must be used with caution by pregnant women. Moreover, treatment becomes very burdensome in patients suffering from the most severe form of the disease, called "catastrophic APS". As Karim Brandt is keen to stress, the researchers are also focusing their working in this direction: "Our breakthrough could also give rise to a targeted treatment that would neutralize specific pathogenic antibodies, reducing not just their actions but also the side effects associated with the current treatment. It would involve injecting the protein motif we have identified into a patient’s circulatory system so that it explicitly binds itself to the pathogenic antibody and prevents it from causing harm."
For the time being, the diagnostic test needs to be optimized for prototypes to be developed. To ensure its validity, the researchers will reanalyze hundreds of samples already tested with the old method and compare results.

EurekAlert
www.eurekalert.org/pub_releases/2017-06/udg-ant061417.php