A team of researchers from the University of Michigan sheds new light on why certain people are more likely to suffer from rheumatoid arthritis (RA). The new research in mice identifies how a specific group of genes works behind the scenes to activate the cells that cause severe rheumatoid arthritis.
“We believe this could be a significant breakthrough in our understanding of why certain genes are associated with higher risk of rheumatoid arthritis and other autoimmune diseases—a link that has been a mystery in the field for decades, ” says lead author Joseph Holoshitz, M.D., professor of internal medicine and associate chief of research in the division of rheumatology at the U-M School of Medicine, in the January 24, 2013 news release.
“Human leukocyte antigen” (HLA) genes are associated with autoimmune disorders. A subset of these HLA genes that codes a protein sequence called “shared epitope” represents the most significant genetic risk factor for rheumatoid arthritis. However, until now, the reason for this strong link has been unclear.
This team of researchers has turned the tables on a familiar belief in the RA research arena…namely, that the association between particular HLA genes and autoimmune diseases is a result of mistakenly identifying body tissues as foreign—making the body the target of the immune system and setting off an attack on self-tissues, which results in disease.
The study shows, for the first time, how this subset of HLA genes causes arthritis—by activating inflammation-causing cells, as well as bone-destroying cells (known as osteoclasts). This leads to severe arthritis and bone erosion.
“We showed how the shared epitope is directly triggering osteoclasts, the very cells that are responsible for joint destruction in people with the disease, ” says Dr. Holoshitz. “Understanding these mechanisms at play could be a significant piece of future drug development. Because we now know the molecular mechanism that activates arthritis-causing cells, we have the potential to block that pathway with simple chemical compounds that could be used to treat rheumatoid arthritis and other diseases.”
Dr. Holoshitz told OTW, “The risk for RA is affected by both genetic and non-genetic factors. The genetic part involves several genes, amongst which the shared epitope (SE) is the most significant one. Our findings indicate that the SE activates immune cells and osteoclasts that, together, facilitate joint inflammation/bone destruction. So, why not ALL individuals carrying genes that code the SE develop RA? This is because there has to be another, non-genetic event, most likely environmental (such as exposure to tobacco, or air pollution), which triggers disease onset.”
As for future research, Dr. Holoshitz told OTW, “We are now determining the generality of these findings in other HLA-associated diseases; characterizing the molecular events that the SE triggers in osteoclast; and deciphering the structure-function characteristics of the interaction between the SE and its receptor on cell surface. The latter effort, we hope, will help us design small molecules, which could interfere in the SE effect and might be further developed as drugs.”
He added, “Osteoclasts play a role in bone health and many bone diseases that pertain to orthopedic surgeons. They participate in determining bone strength and bone repair. The discovered mechanism could therefore apply to many orthopedic bone diseases. It is early to know, but theoretically, it could also be that the SE may affect postsurgical outcomes.”
