Second in a two-part series on transplant tolerance. (See part one.)
Our immune system has two major kinds of T cells. T helper cells, also known as effector T cells, tend to rev up our immune responses, while T regulatory cells tend to suppress or downregulate them. Last week we reported that bolstering populations of T regulatory cells might help people tolerate organ transplants better. A new study turned its focus to T helper cells, and found that an imbalance of these cells causes an exaggerated immune response that may also contribute to transplant rejection.
The study also showed, in mice and in human cells in a dish, that the immune imbalance can be potentially reversed pharmacologically. Findings were published yesterday in the Journal of Clinical Investigation. …
The basic biological mechanisms that underpin autoimmune disorders are finally coming to light. Researchers in Boston’s Longwood medical area — a neighborhood where the streets are flanked by hospitals, research institutions and academic centers — are setting the stage for a new wave of future therapies that can prevent, reduce or even reverse symptoms of disease.
Inside the lab of Michael Carroll, PhD, scientists are working to understand how and why immune cells start to attack the body’s own tissues; it turns out the immune system’s B cells compete with each other in true Darwinian fashion. On the way to this discovery, the lab has flushed out new potential drug targets that could ease autoimmune symptoms — or stop them entirely — by “resetting” the body’s tolerance to itself.
The implications for a link between inflammation and synapse loss go beyond lupus because inflammation underpins so many diseases and conditions, ranging from Alzheimer’s to viral infection and even to to chronic stress. In which case, are we all losing synapses to some varying degree? Carroll plans to find out.
“We’ve found that chronic inflammation and autoinflammatory disorders can originate from genetic mutations to MDA5 that cause it to misrecognize ‘self’ as ‘non-self,’ essentially launching the immune system into self-attack mode,” said Hur. …
The human body’s innate immune system employs a variety of “sensors” for identifying foreign invaders such as viruses. One such viral sensor is a receptor called MDA5, found in every cell of the body.
Inside each cell, MDA5 constantly scans genetic material, checking if it’s native to the body or not. As soon as MDA5 identifies the genetic signature of a viral invader, it trips a system-wide alarm, triggering a cascade of immune activity to neutralize the threat.
But if a genetic mutation to MDA5 causes it to confuse some of the body’s own genetic material for being foreign, “false alarms” can lead to unchecked inflammation and disease. Scientists from Boston Children’s Hospital have discovered a new link between MDA5’s ability to discriminate between “self” and “non-self” genetic material — called RNA duplexes — and a spectrum of autoimmune disorders. …
The health of our immune system is increasingly linked with the health of our intestinal bacteria. A mouse study from Harvard Medical School now hammers this home for autoimmune disorders, in which the body attacks its own cells. It looked specifically at type 1 diabetes, in which the body destroys the cells that make insulin.
Scientists have long known that the human leukocyte antigen (HLA) complex of proteins (also known as the major histocompatibility complex, or MHC) keep autoimmune responses in check. Certain common variants of the HLA/MHC genes are known to protect against a type 1 diabetes. But until now, how these genes prevent autoimmune reactions has been a mystery. …
A newly-unveiled discovery, four years in the making, could change the way we look at autoimmune diseases and our understanding of how and why immune cells begin to attack different tissues in the body.
“Once your body’s tolerance for its own tissues is lost, the chain reaction is like a runaway train,” says Michael Carroll, PhD, of Boston Children’s Hospital and Harvard Medical School (HMS). “The immune response against your own body’s proteins, or antigens, looks exactly like it’s responding to a foreign pathogen.”
A team led by Carroll has spent years investigating mouse models of lupus to better understand the ins and outs of autoimmune diseases. Its latest findings, published in Cell, reveal that rogue B cells — immune cells that produce antibodies and program the immune system to attack certain antigens — can trigger an “override” that launches the body into an autoimmune attack. Adding insult to injury, B cells’ immune targeting instructions can rapidly expand to order an attack on additional tissue types within the body. …
Autoimmune disease is usually treated using general immunosuppressants. But this non-targeted therapy leaves the body more susceptible to infection and other life-threatening diseases.
Now, scientists at Boston Children’s Hospital, the Massachusetts Institute of Technology (MIT) and the Whitehead Institute for Biomedical Research think they may have found a targeted way to protect the body from autoimmune disease. Their approach, published in Proceedings of the National Academy of Sciences, uses transfusions of engineered red blood cells to re-train the immune system. Early experiments in mice have already shown that the approach can prevent — and even reverse — clinical signs of two autoimmune diseases: a multiple-sclerosis (MS)-like condition and Type 1 diabetes. …
Programmed cell death, or apoptosis, helps keep us healthy by ensuring that excess or potentially dangerous cells self-destruct. One way cells know it’s time to die is through signals received by so-called death receptors that stud cells’ surfaces. When these signals go awry, the result can be cancer (uncontrolled cell growth) or autoimmune disease (cells self-destructing too readily).
Researchers at Harvard Medical School (HMS) and the Program in Cellular and Molecular Medicine at Boston Children’s Hospital deconstructed a death receptor called Fas to learn more about its workings, using nuclear magnetic resonance (NMR) spectroscopy to reveal its structure.
They found that for immune cells to hear the “time to die” signal, a portion of Fas called the transmembrane region must coil into an intricate three-part formation, allowing the signal to pass into the cell. The NMR imaging also revealed that the amino acid proline is critical for the formation’s stability. Cancer-causing mutations in the transmembrane region (one of them affecting proline itself) deformed this delicate structure and prevented signals from passing through.
This better understanding of the Fas death receptor, published last week in Molecular Cell, could lead to new approaches that bypass Fas to encourage apoptosis in cancer or, conversely, inhibit Fas in autoimmune disease.
For decades, patients have managed their type 1 diabetes by injecting themselves with insulin to regulate the glucose in their blood. While this form of medical management addresses the immediate danger of low insulin levels, long-term complications associated with diabetes, like heart and kidney diseases, still threaten more than 215,000 children currently living with the disease in the United States.
“Insulin injections can manage hyperglycemia by reducing the patient’s glucose levels, but it is not the cure,” says Paolo Fiorina, MD, PhD, of the Nephrology Division at Boston Children’s Hospital.
Fiorina is currently involved in new research targeting a molecular pathway that triggers diabetes in the first place—potentially providing a permanent cure. It could potentially change the face of diabetes treatment in children. …