Spotlight on Research 2010

January 2010 (historical)

Intracellular Receptors Play a Role in Lupus and May Hold Clues to Treatment

Researchers supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have found new evidence concerning the role of the body’s innate immune system in lupus. Their findings, published in the Proceedings of the National Academy of Sciences, could eventually lead to ways to block the components of the immune system that initiate or perpetuate the disease.

The innate immune system, or non-specific immune system, is our first line of defense against invading microorganisms and is responsible for initially recognizing and removing these potentially dangerous pathogens. Under normal circumstances, the innate immune system is able to distinguish foreign microorganisms from components of our own bodies and, when necessary, trigger the adaptive, or specific, immune system to fight the invaders by producing antibodies against them. But in some people, a flaw in the process leads to the development of autoantibodies, proteins directed against the body’s own components.

For years, researchers have known that people with lupus produce antibodies to their own DNA and research has suggested that a class of receptors, called toll-like receptors (TLRs), located on and within the body’s cells, plays a role in the development of these autoantibodies. However, which of these TLRs were involved — and how — was not clear.

The new study by NIAMS-supported researchers at Scripps Research Institute and the University of California at San Diego in La Jolla, Calif., points to a group of TLRs, referred to as endosomal TLRs (eTLRs), expressed in intracellular compartments called endosomes.

The eTLRs work by recognizing the DNA and RNA released into a cell by an invading organism. This primes the adaptive immune system to produce antibodies against the organism. But in certain circumstances — for example, in a person with a genetic predisposition — the eTLRs recognize the body’s own DNA and RNA, activating an autoimmune response.

To confirm the role of these eTLRs in the production of antibodies that create an autoimmune response, scientists led by Dwight Kono, M.D., professor of immunology at Scripps Research Institute in La Jolla, Calif., studied mice lacking a protein called Unc93b1, which influences the behavior of eTLRs. They found that in two different lupus-prone mouse strains, the absence of Unc93b1 blocked the production of the harmful antibodies. Even when lupus-prone mice were given a substance that normally enhances disease, they could generate only a small amount of the antibodies, and not enough for disease. However, the lupus-prone mice were able to create antibodies to infectious agents, showing that blocking eTLRs might not lower normal immune responses in these mice.

These findings suggest that eTLRs might act as an Achilles’ heel in susceptible individuals, creating a way for the body’s own protective mechanisms to mistakenly attack its own cells. Their findings also suggest that it may be possible to block eTLRs that cause autoimmunity without interfering with the protection from infection that other TLRs provide. The researchers hope to continue their research in mice with the hopes of eventually finding applications for treating lupus in people.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services’ National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.

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Reference: Kono DH, Haraldsson MK, Lawson BR, Pollard KM, Koh YT, Du X, Arnold CN, Baccala R, Silverman GJ, Beutler BA, Theofilopoulos AN. Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus. Proc Natl Acad Sci USA. 2009 Jul 21;106(29):12061-6.