25 Oct How Does RA Start? Specialized Cells May Hold The Answer
Scientists are diligently studying our immune systems to find what starts rheumatoid arthritis (RA). So how does RA start? To find out we need to begin by understanding a little about our immune system.
Our immune system has evolved to be complicated because the immune system is constantly on the alert to protect the body from outside threats. The immune system’s adaptive mechanisms include disease-fighting T-cells and B-cells with “immunological memory” – this type of memory gives the cells the capacity to remember and thwart same type of attack in the future.
In healthy people, B cells produce antibodies that circulate, seek out and destroy pathogens. Pathogens are infectious bacteria, viruses or harmful microorganisms in your body.
The T-cells are a crucial line of defense against infection. These specialized white blood cells tailor the immune response to the invading pathogens. Different kinds of T-cells stimulate the immune system by identifying and attacking disease-causing microbes, unleashing a storm of defenders to repel the assault.
As research breakthroughs continue to bring new hope for people with rheumatoid arthritis, scientists are looking deeper to understand how overproduction of certain specialized T-cells may fuel RA and other autoimmune diseases. With funding from the Arthritis National Research Foundation, Michela Locci, PhD, is investigating the body’s adaptive immune response. Dr. Locci, who works at La Jolla Institute for Allergy and Immunology in Dr. Shane Crotty’s laboratory, is studying highly specialized cells called T follicular helper (Tfh) cells.
“Tfh cells – defined by their particular function as B-cell helpers – are considered pivotal regulators of antibody responses,” she explains. “They are highly specialized in helping the B-cells react to pathogens, and produce antibodies that can efficiently block pathogen infection.”
Antibodies are strategic molecules, normally produced by our immune system to confer protection from infectious pathogens. When RA strikes, antibodies that are the body’s natural defense against infection and disease, instead turn on the body and attack self-tissue in the joints. For patients with RA this triggers painful disease flares of inflammation. As the autoantibodies accumulate in the joints they can amplify the swelling, stiffness and debilitating pain of RA.
“Autoantibodies contribute to the development of several autoimmune diseases, including rheumatoid arthritis,” says Dr. Locci. “Many RA patients produce autoantibodies, which are generally associated with a more severe form of the disease.”
The presence of autoantibody has been linked to abnormally high levels of Tfh cells in RA patients. “It’s consistent with the idea that Tfh cells are crucial for regulation of antibody responses,” she adds. “My goal is to understand what causes excessive Tfh production in rheumatoid arthritis.”
Could the excess production of the special Tfh helper cells be the answer to, how does RA start? Could blocking the generation of Tfh cells improve the clinical symptoms of RA?
In Dr. Crotty’s lab, Dr. Locci developed a high-throughput screen of human recombinant molecules that identified a particular molecule, activin A, as an important player in the regulation of human Tfh cells. As a result, Dr. Locci is now investigating a possible association between activin A levels and the type of Tfh cells produced in people affected by RA.
“We found that activin A is a potent stimulus in regulating multiple aspects of human Tfh cell biology in healthy people,” she says. “But what happens when the production of activin A is excessive? Does very high activin A production result in excessive generation of Tfh cells in RA? Studies in RA donors will be complemented by mouse studies in an effort to confirm a pathogenic connection between activin A and Tfh cells in RA.”
When normally protective antibodies disrupt the regulation of B-cells, the body releases a flood of inflammatory proteins.
“I am interested in understanding what drives excessive Tfh production in RA,” she adds. “Tfh cells are crucial for regulation of antibody responses and can be produced at abnormally high levels in RA patients.”
Dr. Locci relates that the grant from the Arthritis National Research Foundation arrived at a very critical moment in her scientific career as she transitioned to an independent career. In fact, Dr. Locci will now be setting up her own laboratory at the University of Pennsylvania in January 2018.
“Personally, this award is invaluable,” she says. “I’m especially grateful because it makes more real the possibility that my research might directly improve the health of sick people and reinforces my dedication to helping patients. Someday, I hope to translate my basic science findings into real treatment options and relief for the millions of patients suffering with RA.”
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