Observatory and Fast Facts

Feb. 23, 2022

Study identifies how Epstein-Barr virus triggers multiple sclerosis

Scientists have long suspected, but failed to prove, a link between certain viral infections and the development of multiple sclerosis (MS). Now, a study led by Stanford Medicine researchers has proved that the Epstein-Barr virus, a common type of herpes virus, triggers multiple sclerosis by priming the immune system to attack the body’s own nervous system, according to a news release from the university.

The study, published in Nature, shows that approximately 20% to 25% of patients with multiple sclerosis have antibodies in their blood that bind tightly to both a protein from the Epstein-Barr virus, called EBNA1, and a protein made in the brain and spinal cord, the glial cell adhesion molecule, or GlialCAM.

“Part of the EBV protein mimics your own host protein — in this case, GlialCAM, found in the insulating sheath on nerves,” said William Robinson, MD, PhD, Professor of Immunology and Rheumatology at Stanford. “This means that when the immune system attacks EBV to clear the virus, it also ends up targeting GlialCAM in the myelin.”

Myelin forms the protective coating around nerve cells, and when it’s damaged, electrical impulses can no longer jump efficiently from one nerve to the next, resulting in the numbness, muscle weakness, and severe fatigue of multiple sclerosis.

Previous research has shown that multiple sclerosis patients have increased antibodies to a variety of common viruses, including measles, mumps, varicella-zoster, and Epstein-Barr virus. In fact, more than 99% of MS patients have EBV antibodies in their blood, indicating a prior infection, compared with 94% of healthy individuals. But despite this epidemiologic correlation, scientists have struggled to prove a causal connection.

To find this mechanistic link, the researchers started by examining the antibodies produced by immune cells in the blood and spinal fluid of nine MS patients. Unlike in healthy individuals, the immune cells of MS patients’ traffic to the brain and spinal cord, where they produce large amounts of a few types of antibodies. Patterns of these antibody proteins, called oligoclonal bands, are found during analysis of the spinal fluid and are part of the diagnostic criteria for MS.

“So, the first thing we did was analyze the antibodies from the oligoclonal bands and showed that they come from B cells in the spinal fluid,” Robinson said.

B cells are a type of white blood cell made in the bone marrow, and the technology to sequence these cells individually was developed by the Robinson lab about eight years ago.

The discovery of how EBV triggers multiple sclerosis could also have ramifications for research into other autoimmune diseases, such as lupus and rheumatoid arthritis, which, like MS, have been significantly associated with EBV infection in epidemiologic studies.

Method to detect toxic brain cells could be a step to a new Alzheimer’s treatment

Emerging evidence suggests it may be possible to treat Alzheimer’s disease by targeting therapy at senescent cells in the brain.

A team from The University of Texas Health Science Center at San Antonio and Wake Forest School of Medicine reported in the journal, Nature Aging, a method, based on computational analysis, to objectively identify and quantify these toxic cells. In addition to having value in monitoring the effectiveness of senescent cell therapy, this method could prove to be a highly effective diagnostic tool in detecting Alzheimer’s.

If a cell is old, stressed, or damaged by insults such as radiation, it may enter a state in which it can no longer divide or function properly. This is senescence. These cells cannot properly repair themselves and don’t die off when they should. They have been called “zombie cells” for this reason. Instead, senescent cells function abnormally and release substances that kill surrounding healthy cells and cause inflammation. Over time, they continue to build up in tissues throughout the body, contributing to the aging process, cognitive decline, and cancer.

Having a signature for senescence will be important clinically for baseline measurements at the time patients are first seen by a neurologist and then to track the impact of medication. Identifying populations of senescent cells is also important to understand how and why cells become senescent.

Using statistical analyses, the research team was able to evaluate large amounts of data. In total, they profiled tens of thousands of cells from the postmortem brains of people who had died with Alzheimer’s disease. The researchers looked for the presence of senescent cells and then their quantity and types.

The team found that approximately 2% of the brain cells were senescent. The researchers also identified the type of cell and the characteristic features. The study findings indicated that the senescent cells were mostly neurons, which are central nervous system cells in the brain that are lost in Alzheimer’s disease.

Study examines treatment options for patients with high-risk prostate cancer

An international study consisting of a consortium of 16 research centers in collaboration with two international cooperative trial groups found that patients receiving high-dose external beam radiation therapy alone may benefit from androgen deprivation therapy (ADT) lasting longer than 18 months, while those with external beam radiation therapy and a brachytherapy boost — the implantation of radioactive seeds to deliver a higher total dose to the prostate — may be optimally managed with 18 months of ADT or possibly less, according to a news release from UCLA, which was involved in the study.

The researchers analyzed individual patient data from three cohorts of patients: a retrospective cohort of patients from 16 cancer treatment referral centers between 2000 and 2014 who received either high-dose external beam radiotherapy or external beam radiotherapy with a brachytherapy boost; a cohort of patients enrolled in a randomized phase 3 trial that included patients from 23 treatment centers in Australia and New Zealand; and a cohort of patients enrolled in a randomized phase 3 trial conducted across 10 treatment centers in Spain.

In the retrospective cohort — looking at ADT durations of less than six months, six to 18 months, and greater than 18 months — a significant interaction was seen between treatment type and ADT duration. A duration of 18 months or more was associated with improved outcomes, relative to shorter durations, for patients receiving high-dose external beam radiation therapy without a brachytherapy boost.

In contrast, among patients receiving radiation therapy and brachytherapy, an ADT duration of at least six months but less than 18 months was associated with improved metastasis-free survival and overall survival, compared to receipt of less than six months of ADT. But there appeared to be no improvement in metastasis-free survival for those receiving both forms of radiation therapy and more than 18 months of ADT.

With further analysis, the researchers determined that for patients receiving radiation therapy, without brachytherapy, the optimal ADT duration was 26.3 months; for those treated with radiation therapy and a brachytherapy boost, the minimum threshold was 12 months.

Their hypotheses, drawn from the retrospective study, appeared to be supported by effects observed in the randomized clinical trials 

Newly developed inhaled vaccine delivers broad protection against SARS-CoV-2, variants of concern

Scientists at McMaster University have developed an inhaled form of COVID vaccine and confirmed it can provide broad, long-lasting protection against the original strain of SARS-CoV-2 and variants of concern.

The research, recently published in the journal, Cell, reveals the immune mechanisms and significant benefits of vaccines being delivered directly into the respiratory tract, rather than by traditional injection. The laboratory and the researchers are part of McMaster’s Global Nexus for Pandemics and Biological Threats.

Because inhaled vaccines target the lungs and upper airways where respiratory viruses first enter the body, they are far more effective at inducing a protective immune response, the researchers report.

The reported preclinical study, which was conducted on animal models, has provided the critical proof of concept to enable a Phase 1 clinical trial that is currently under way to evaluate inhaled aerosol vaccines in healthy adults who had already received two doses of a COVID mRNA vaccine.

The tested COVID vaccine strategy was built upon a robust tuberculosis vaccine research program established by Zhou Xing, a co-lead author of the new study and a professor at the McMaster Immunology Research Centre and Department of Medicine.

“What we’ve discovered from many years’ research is that the vaccine delivered into the lung induces all-around protective respiratory mucosal immunity, a property that the injected vaccine is lacking,” Xing says.

Currently authorized COVID vaccines are all injected.

“We wanted, first and foremost, to design a vaccine that would work well against any variant,” explains the study’s co-lead author Matthew Miller, Associate Professor at McMaster’s Michael G. DeGroote Institute for Infectious Disease Research.

The McMaster COVID vaccine represents one of only a handful developed in Canada. The urgent work is a critical mission of Canada’s Global Nexus for Pandemics and Biological Threats, which is based at McMaster.

Researchers compared two types of adenovirus platforms for the vaccine. The viruses serve as vectors that can deliver vaccine directly to the lungs without causing illness themselves.

“We can remain ahead of the virus with our vaccine strategy,” says Miller. “Current vaccines are limited because they will need to be updated and will always be chasing the virus.”

Both types of the new McMaster vaccine are effective against highly transmissible variants because they are designed to target three parts of the virus, including two that are highly conserved among coronaviruses and do not mutate as quickly as spike. All COVID vaccines currently approved in Canada target only the spike protein, which has shown a remarkable ability to mutate.

“This vaccine might also provide pre-emptive protection against a future pandemic, and that’s really important because as we’ve seen during this pandemic — and as we saw in 2009 with the swine flu— even when we are able to rapidly make a vaccine for a pandemic virus, it’s already way too late. Millions of people died, even though we were able to make a vaccine in record time,” says Miller.

“We have revealed in our report that, besides neutralizing antibodies and T cell immunity, the vaccine delivered into the lungs stimulates a unique form of immunity known as trained innate immunity, which is able to provide very broad protection against many lung pathogens besides SARS-CoV-2,” Xing adds.

In additional to being needle and pain-free, an inhaled vaccine is so efficient at targeting the lungs and upper airways that it can achieve maximum protection with a small fraction of the dose of current vaccines — possibly as little as 1 per cent — meaning a single batch of vaccine could go 100 times farther, the researchers say.

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