Cellular mechanism discovery could lead to new treatments for rheumatoid arthritis, multiple sclerosis and Crohn's disease

A major finding by researchers at the La Jolla Institute for Allergy & Immunology (LIAI) has identified a previously unknown cellular mechanism that acts as an off switch for immune system function.

The discovery could lead to the future development of new treatments for autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and Crohn's disease.

In autoimmune diseases, the immune system, which normally wards off invading viruses and bacteria, instead mistakenly attacks normal body tissues, leading to illness. "By understanding this cellular process for turning off immune system activity, we are hopeful this will lead to new treatments that will stop unwanted immune responses, such as those which occur in autoimmune diseases," said LIAI scientist Carl Ware, Ph.D., who co-led the study with LIAI researcher Chris Benedict, Ph.D. The research team also involved scientists from Rush Medical Center and Northwestern University in Chicago and Washington University in St. Louis.

The findings will be published September 13 in the Proceedings of the National Academy of Sciences (PNAS) in a paper entitled, "Evolutionarily Divergent Herpesviruses Modulate T cell activation by Targeting the Herpesvirus Entry Mediator (HVEM) Cosignaling Pathway."

Jennifer Gommerman, Ph.D., and Tania Watts, Ph.D., of the University of Toronto's Department of Immunology, who co-wrote a PNAS commentary on the paper scheduled for online publication this week, called the findings a significant advancement. "This discovery underscores the importance of this pathway in immune regulation and advances our knowledge of how to develop effective treatments for certain illnesses."

In the study, the team of scientists looked at two members of the herpes family of viruses, cytomegalovirus and herpes simplex virus, because of their ability to lay dormant in the immune system without causing disease. "These viruses teach us how to manipulate the immune system," Dr. Ware said. "We found that these two very different viruses were attacking the same communication pathway in the immune system." By disrupting that pathway, the viruses were keeping T lymphocytes - which are white blood cells that fight disease - from communicating with other cells in the immune system. "It's kind of like jamming a phone system," Dr. Ware explained. "If communication gets cut off, messages won't get through and nothing is going to get done."

Central in the viruses' ability to manipulate immune system communication was a cellular protein called the Herpesvirus Entry Mediator (HVEM), which the scientists found effectively worked as an "off and on switch" for immune responses. Several cellular proteins -- members of the tumor necrosis factor (TNF) family -- interact with HVEM to enable this immune system communication switch. HVEM is part of a larger TNF family of molecules involved in a wide variety of important immune system functions. The finding is the latest from Dr. Ware's laboratory involving TNF receptors, which he has been studying for more than 20 years. Drugs targeted at the TNF family are prominent treatments against some autoimmune diseases, including rheumatoid arthritis, psoriasis and Crohn's disease.

Mitchell Kronenberg, Ph.D., LIAI President and Scientific Director, said the team's findings are regarded as very exciting by the scientific community. "This research could one day lead to the development of drugs that mimic the action of HVEM," he said. "That could give medical science a new method for reducing or even stopping the inflammation associated with rheumatoid arthritis and other autoimmune diseases."

The findings also have implications beyond autoimmune disease, including possible application in treatments for infectious diseases and cancer. "An important part of our findings is that HVEM can not only switch off immune system response but it can also switch it on," Dr. Ware said. "This may be valuable in fighting infectious disease, where the body needs a stronger immune response. It also could aid in prompting immune cells to attack cancerous cells."

In addition to Ware and Benedict, other researchers participating in the study from the La Jolla Institute for Allergy & Immunology were Timothy Cheung, Ian Humphreys, Karen Potter, Paula Norris, Heather Shumway, Bonnie Tran, Ginelle Patterson, Rochelle Jean-Jacques and Miri Yoon. In Chicago, researchers participating were Patricia Spear from Northwestern University and Nell Lurain from Rush Medical Center, and in St. Louis, Kenneth Murphy from Washington University. The research was supported in part by grants from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.