AUTOIMMUNE
May 31, 2013

Fat Cells Spark RA

Rheumatoid arthritis begins with factor D, secreted by fat cells in joints. Stop Factor D, stop RA.

Rheumatoid arthritis (RA), the chronic and painful inflammation of the small joints in hands and feet, has long puzzled researchers and clinicians. There have been no clear answers to the questions, what causes RA and how is it best treated?

But now a study has identified a chemical that is a key player in the autoimmune response behind Arthritis (Rheumatoid) and that may allow scientists to develop gene therapies that would offer relief and mobility to millions of people.

What we didn't know until now was that the fat is secreting this protein which actually triggers arthritis in the joints.

Factor D is part of the complement system, an array of over 40 proteins that the body uses to fight off bacteria and other pathogens. As Nirmal Banda, lead author on the study, tells TheDoctor, "Without factor D, mice cannot get rheumatoid arthritis."

The factor begins as pro-factor D secreted by fat cells in the knees of mice. So the team wanted to see if they could shut down production of pro-factor D, before it gives rise to factor D, and prevent RA from developing. The pro-factor D produced by the fat in the knee joints can cause localized disease there. The enzyme that converts pro-factor D to factor D, MASP-1/3, is present in the synovial tissue in the knee joint.

“So if someone gets an injury or infection in the knee, this RA disease process can occur locally in the knee joint,” says Banda, an associate professor of medicine at the University of Colorado School of Medicine.

Fat is present around every organ of the body, including the knee joint. “What we didn't know until now was that the fat is secreting this protein which actually triggers arthritis in the joints," says Banda. He says that fat does the same thing in all the joints, not just the knees, so that drugs resulting from this discovery could treat inflammatory arthritis throughout the body.

Although scientists could shut down the entire complement system to try and prevent arthritis, the system, along with the risk of developing arthritis, would eventually return; in the meantime, the lack of the complement system would leave people vulnerable to infections. Finding the specific cause of rheumatoid arthritis was key, and that is what the team believes it has found in factor D and its precursor, pro-factor D.

Banda and his colleagues have spent the last 14 years tracking down the causes of rheumatoid arthritis. Now, with the discovery of pro-factor D in mice with rheumatoid arthritis, they are working on gene therapies to eliminate the protein in localized areas. These findings still need to be translated into clinical studies in humans.

"We are looking at vaccines, drugs or inhibitors to stop the local secretion of pro-factor D in the mouse," he says. "Our goal would be to stop the disease before it progresses and leads to joint destruction."

"We believe we can shut down one part of the complement system that triggers disease without shutting down the rest,” says Banda. “If so, we will be making a major stride toward treating, and perhaps even curing, rheumatoid arthritis."

The study is published in the Journal of Immunology.

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