Posts tagged antigens
Articles and news from the latest research reports.
Is Parkinson’s an Autoimmune Disease?
The cause of neuronal death in Parkinson’s disease is still unknown, but a new study proposes that neurons may be mistaken for foreign invaders and killed by the person’s own immune system, similar to the way autoimmune diseases like type I diabetes, celiac disease, and multiple sclerosis attack the body’s cells. The study was published April 16, 2014, in Nature Communications.
(Image caption: Four images of a neuron from a human brain show that neurons produce a protein (in red) that can direct an immune attack against the neuron (green). Credit: Carolina Cebrian.)
“This is a new, and likely controversial, idea in Parkinson’s disease; but if true, it could lead to new ways to prevent neuronal death in Parkinson’s that resemble treatments for autoimmune diseases,” said the study’s senior author, David Sulzer, PhD, professor of neurobiology in the departments of psychiatry, neurology, and pharmacology at Columbia University College of Physicians & Surgeons.
The new hypothesis about Parkinson’s emerges from other findings in the study that overturn a deep-seated assumption about neurons and the immune system.
For decades, neurobiologists have thought that neurons are protected from attacks from the immune system, in part, because they do not display antigens on their cell surfaces. Most cells, if infected by virus or bacteria, will display bits of the microbe (antigens) on their outer surface. When the immune system recognizes the foreign antigens, T cells attack and kill the cells. Because scientists thought that neurons did not display antigens, they also thought that the neurons were exempt from T-cell attacks.
“That idea made sense because, except in rare circumstances, our brains cannot make new neurons to replenish ones killed by the immune system,” Dr. Sulzer says. “But, unexpectedly, we found that some types of neurons can display antigens.”
Cells display antigens with special proteins called MHCs. Using postmortem brain tissue donated to the Columbia Brain Bank by healthy donors, Dr. Sulzer and his postdoc Carolina Cebrián, PhD, first noticed—to their surprise—that MHC-1 proteins were present in two types of neurons. These two types of neurons—one of which is dopamine neurons in a brain region called the substantia nigra—degenerate during Parkinson’s disease.
To see if living neurons use MHC-1 to display antigens (and not for some other purpose), Drs. Sulzer and Cebrián conducted in vitro experiments with mouse neurons and human neurons created from embryonic stem cells. The studies showed that under certain circumstances—including conditions known to occur in Parkinson’s—the neurons use MHC-1 to display antigens. Among the different types of neurons tested, the two types affected in Parkinson’s were far more responsive than other neurons to signals that triggered antigen display.
The researchers then confirmed that T cells recognized and attacked neurons displaying specific antigens.
The results raise the possibility that Parkinson’s is partly an autoimmune disease, Dr. Sulzer says, but more research is needed to confirm the idea.
“Right now, we’ve showed that certain neurons display antigens and that T cells can recognize these antigens and kill neurons,” Dr. Sulzer says, “but we still need to determine whether this is actually happening in people. We need to show that there are certain T cells in Parkinson’s patients that can attack their neurons.”
If the immune system does kill neurons in Parkinson’s disease, Dr. Sulzer cautions that it is not the only thing going awry in the disease. “This idea may explain the final step,” he says. “We don’t know if preventing the death of neurons at this point will leave people with sick cells and no change in their symptoms, or not.”
(Source: newsroom.cumc.columbia.edu)
Computer Simulations Shed New Light On How The Immune System Works
Researchers at McGill University in Montreal have developed computer simulations that better explain how a person’s immune cells can detect foreign antigens and fight infections.
In an effort to determine exactly how the body’s natural defenses are able to sort through large amounts of similar-looking proteins in order to locate and eliminate harmful invaders, physics professor Paul François and graduate student Jean-Benoît Lalanne used computational tools to study how the process works.
They discovered that the antigen-fighting process is related to the phenomenon of biochemical adaptation – a mechanism that enables organisms to cope with a variety of different environmental conditions. According to the authors of the study, their work could prove essential insight into AIDS and other immune diseases.
“For immune cells, singling out foreign proteins is like looking for a needle in a haystack – where the needle may look very much like a straw, and where some straws may also look very much like a needle,” François said. “Our approach provides a simpler theoretical framework and understanding of what happens” as the immune cells sort through that “haystack” in search of foreign antigens and to trigger the body’s immune response.
The researchers’ computer simulation used an algorithm that was inspired by Darwinian evolution, the university explained. The algorithm randomly creates mathematical models of biochemical networks, and then scores them by comparing their properties to those of an actual immune system. The highest-rated networks are duplicated in the next generation and mutated, a process that is repeated until the networks achieve a perfect score.
“Our model shares many similarities with real immune networks,” explained François. “Strikingly, the simplest evolved solution we found has both similar characteristics and some of the blind spots of real immune cells we studied in a previous collaborative study with the groups of Grégoire Altan-Bonnet (Memorial Sloane Kettering, New York), Eric Siggia (Rockefeller University, New York) and Massimo Vergassola (Pasteur Institute, Paris).”
The Natural Sciences and Engineering Research Council of Canada and the Human Frontier Science Program provided funding for the research, which was published in a recent edition of the journal Physical Review Letters.
Big Multiple Sclerosis Breakthrough
Phase 1 trial safely resets patients’ immune systems, reduces attack on myelin protein
A phase 1 clinical trial for the first treatment to reset the immune system of multiple sclerosis (MS) patients showed the therapy was safe and dramatically reduced patients’ immune systems’ reactivity to myelin by 50 to 75 percent, according to new Northwestern Medicine research.
In MS, the immune system attacks and destroys myelin, the insulating layer that forms around nerves in the spinal cord, brain and optic nerve. When the insulation is destroyed, electrical signals can’t be effectively conducted, resulting in symptoms that range from mild limb numbness to paralysis or blindness.
“The therapy stops autoimmune responses that are already activated and prevents the activation of new autoimmune cells,” said Stephen Miller, the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. “Our approach leaves the function of the normal immune system intact. That’s the holy grail.”
Miller is the co-senior author of a paper on the study, which was published June 5 in the journal Science Translational Medicine. The study is a collaboration between Northwestern’s Feinberg School, University Hospital Zurich in Switzerland and University Medical Center Hamburg-Eppendorf in Germany.
The human trial is the translation of more than 30 years of preclinical research in Miller’s lab.
In the trial, the MS patients’ own specially processed white blood cells were used to stealthily deliver billions of myelin antigens into their bodies so their immune systems would recognize them as harmless and develop tolerance to them.
Current therapies for MS suppress the entire immune system, making patients more susceptible to everyday infections and higher rates of cancer.
While the trial’s nine patients — who were treated in Hamburg, Germany — were too few to statistically determine the treatment’s ability to prevent the progression of MS, the study did show patients who received the highest dose of white blood cells had the greatest reduction in myelin reactivity.
The primary aim of the study was to demonstrate the treatment’s safety and tolerability. It showed the intravenous injection of up to 3 billion white blood cells with myelin antigens caused no adverse affects in MS patients. Most importantly, it did not reactivate the patients’ disease and did not affect their healthy immunity to real pathogens.
As part of the study, researchers tested patients’ immunity to tetanus because all had received tetanus shots in their lifetime. One month after the treatment, their immune responses to tetanus remained strong, showing the treatment’s immune effect was specific only to myelin.
The human safety study sets the stage for a phase 2 trial to see if the new treatment can prevent the progression of MS in humans. Scientists are currently trying to raise $1.5 million to launch the trial, which has already been approved in Switzerland. Miller’s preclinical research demonstrated the treatment stopped the progression of relapsing-remitting MS in mice.
“In the phase 2 trial we want to treat patients as early as possible in the disease before they have paralysis due to myelin damage.” Miller said. “Once the myelin is destroyed, it’s hard to repair that.”
In the trial, patients’ white blood cells were filtered out, specially processed and coupled with myelin antigens by a complex GMP manufacturing process developed by the study co-senior authors, Roland Martin, Mireia Sospedra, and Andreas Lutterotti and their team at the University Medical Center Hamburg-Eppendorf. Then billions of these dead cells secretly carrying the myelin antigens were injected intravenously into the patients. The cells entered the spleen, which filters the blood and helps the body dispose of aging and dying blood cells. During this process, the immune cells start to recognize myelin as a harmless and immune tolerance quickly develops. This was confirmed in the patients by immune assays developed and carried out by the research team in Hamburg.
This therapy, with further testing, may be useful for treating not only MS but also a host of other autoimmune and allergic diseases simply by switching the antigens attached to the cells. Previously published preclinical research by Miller showed the therapy’s effectiveness for type 1 diabetes and airway allergy (asthma) and peanut allergy.
The MS human trial relates directly to Miller’s recently published research in mice in which he used nanoparticles — rather than a patient’s white blood cells — to deliver the myelin antigen. Using a patient’s white blood cells is a costly and labor-intensive procedure. Miller’s study showed the nanoparticles, which are potentially cheaper and more accessible to a general population, could be as effective as the white blood cells as delivery vehicles. This nanoparticle technology has been licensed to Cour Pharmaceutical Development Company and is in preclinical development.
Miller’s research represents several pillars of Northwestern’s Strategic Plan by discovering new ways to treat disease in the biomedical sciences and translating those discoveries into ideas and products that make the world a better place for everyone.
(Source: northwestern.edu)