Deactivating a cell protein may halt progress of rheumatoid arthritis

Date: Sep-11-2014Rheumatoid arthritis is an autoimmune disease that leads to inflammation and bone

erosion in the joints. One of the hallmarks is swelling and pain caused by white blood cells

flooding into the fluid around the joints. Now researchers have shown for the first time

that the activation of a single protein on the surface of these cells could be the trigger for

the disease.

The cell protein they investigated is toll-like receptor 5 (TLR5) that is found on

myeloid - or marrow-derived - cells that migrate from the blood into affected joints.

"TLR5 does it all," says one of the researchers, Shiva Shahrara, associate professor of

rheumatology at the University of Illinois at Chicago College of Medicine.

She and her colleagues write about the study in the Journal of Immunology. They

suggest the findings may lead to new drugs that target the cell protein and break the vicious

cycle of inflammation and bone degradation in rheumatoid arthritis.

Myeloid cells of rheumatoid arthritis patients have far more TLR5 receptors

When they compared the myeloid cells from the joints of healthy people with those of

rheumatoid arthritis sufferers, they found the myeloid cells from the arthritis patients had

far more TLR5 on their surfaces.

One of the hallmarks of rheumatoid arthritis is swelling and pain caused by white blood cells flooding into the fluid around the joints.

From previous work, they had already established that activation of the receptor leads to

abnormal development of blood vessels in the joints of patients with rheumatoid arthritis.

In this latest work, they discovered the receptor also boosts the activity of TNF-alpha, an

inflammatory molecule that summons even more myeloid cells into the joints, whereupon they

change into osteoclasts, cells that cause bone erosion.

The researchers also carried out a series of experiments to show activating TLR5 triggers

several disease processes.

For example, they showed if myeloid cells with active TLR5 are placed next to joint fluid

taken from rheumatoid arthritis patients, they migrate into the fluid, but switching TLR5 off

reduces migration significantly.

Prof. Shahrara says it is as though something in the joint fluid attracts the myeloid cells

when their TLR5 receptors are switched on. She suggests perhaps a protein that binds to the

receptor is present in the fluid of joints affected by rheumatoid

arthritis.

Switched on TLR5 may trigger 'vicious feedback loop' of inflammation and erosion

In other experiments, the researchers showed that when the joint fluid of patients with rheumatoid

arthritis contained myeloid cells with activated TLR5, this increased levels of TNF-alpha, and

the myeloid cells of patients taking anti-TNF-alpha drugs have fewer TLR5 receptors.

This suggests there is a positive feedback loop between TLR5 and TNF-alpha: when one

increases, so does the other, as Prof. Shahrara explains:

"Not only do TLR5 and TNF-alpha regulate each other, but they work synergistically to

attract more myeloid cells into the joint, where they are transformed into bone-eroding

cells."

In a final set of experiments, the team showed giving mice with rheumatoid arthritis an

antibody to block TLR5 significantly reduced joint swelling and bone erosion compared to mice

that did not receive the drug.

The team suggests that blocking TLR5 with the antibody reduced myeloid cells migrating into

the joints and turning into bone-eroding osteoclasts.

Prof. Shahrara believes this means a drug that stops TLR5 activation could slow or even

prevent the joint inflammation and bone erosion that occurs in later-stage rheumatoid

arthritis.

She suggests when the receptor is switched on, it triggers a "vicious feedback loop" that

worsens the inflammation and bone erosion of rheumatoid arthritis.

"The receptor is a major driver of inflammation and bone degradation," she explains.

"Blocking this receptor could have significant therapeutic value in interrupting joint

swelling and bone loss in patients with rheumatoid arthritis."

Funds from the National Institutes of Health, the Department of Defense, the American

College of Rheumatology and the Arthritis Foundation helped finance the study.

In June 2014, Medical News Today learned how researchers identified the T cells that drive rheumatoid arthritis. Using

cutting-edge tetramer technology, the scientists studied how the disease starts, how current therapies

may affect the immune response directed to the joint, and how to target these specific cells

with drugs.

Written by Catharine Paddock PhD

View all articles written by Catharine, or follow her on:

Courtesy: Medical News Today Note: Any medical information available in this news section is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional.