Oct. 7, 2005 By snipping out and analyzing tiny samples of patients' tonsils, scientists have identified a key cellular checkpoint that is somehow bypassed in lupus patients, where harmful immune cells that normally are squelched by the body are mistakenly granted access.
The in-depth look at tissue from a person's tonsils, a technique seldom used to study the immune system, has provided doctors with key information about just what goes wrong in patients with lupus to cause their immune systems to attack themselves, causing symptoms like joint pain, fatigue, and other complications like kidney failure.
The paper detailing the work by immunologists and rheumatologists at the University of Rochester Medical Center will be in the November issue of the Journal of Clinical Investigation. The paper became available online Oct. 6.
"Tonsils are very informative," said Ignacio Sanz, M.D., professor of Medicine, Microbiology & Immunology, and chief of the Division of Clinical Immunology and Rheumatology, who led the study. "Peripheral blood doesn't have the organization you need to really understand the immune system. The tonsils give us a window into the immune system that we didn't have before."
The tonsils are made up of lymphoid tissue and help the body fight off infection. But unlike the spleen, a major organ that plays a key role in the immune system, doctors can take a small biopsy of the tonsils, getting a look at structures that are present there but not in the blood, which is studied more commonly.
Sanz's team focused on lymph structures in the tonsils known as germinal centers, where teeming masses of immune cells known as B cells and T cells glom together and swap crucial information about invaders like bacteria and viruses. Such ongoing education is crucial to our immune system -- it's how our cells are trained to recognize enemies like colds and flu, and where they learn not to attack our own bodies. Unfortunately, in diseases like lupus, diabetes, rheumatoid arthritis, and multiple sclerosis, our cells don't always learn the difference, and some immune cells become "auto-reactive" and attack our own tissues.
"Our immune system needs redundancy and adaptability to recognize and fight the antigens it needs to fight," said Sanz. "But the price we pay is a fair amount of auto-reactivity. Because of that, we need very good systems to discriminate and control auto-reactive B cells."
It's those systems, trained to recognize and then eliminate errant cells, which fail in lupus. Somehow, rogue cells -- in this study, 9G4 B cells -- slip through the body's defenses. Doctors have known that in people with lupus, antibodies from such cells make up a much greater percentage of the person's immune system than in healthy people. In this study the team found that lupus patients have as many as 10 times the number of such cells as healthy people in the germinal centers, sophisticated processing centers of the immune system.
"Auto-reactive B cells are generated by the body every day," said colleague Jennifer Anolik, M.D., assistant professor of medicine and another author of the paper. "Normally those cells are censored or regulated by a number of mechanisms. We've known in lupus that these cells get through, but what we haven't known before is at what point the regulation is defective."
The finding shows that the cells have already somehow slipped past multiple checkpoints in the immune system and have enmeshed themselves in a sophisticated segment of the immune system. As part of the immune system's training program for new immune cells, the germinal center is one of the last opportunities the body has for recognizing and kicking out rogue cells. Once a B cell passes muster at a germinal center, it becomes an established part of the immune system and has the power to churn out and train rank-and-file antibodies on what to attack and what to avoid.
It's a little bit like a terrorist who rises through the ranks of the CIA despite the CIA's best efforts to weed out infiltrators. If the mole actually becomes a teacher and molds new recruits who go on to attack the country, the CIA would have a major problem on its hands, trying to control one of its own working directly counter to its objectives. That's the way it is when the immune system meets up with cells not filtered out correctly in lupus patients.
In addition to Sanz and Anolik, who treat hundreds of lupus patients, other authors of the paper include otolaryngologist Paul Dutcher, M.D.; technician Jennifer Barnard; former post-doctoral researcher Amedeo Cappione III, Ph.D., now at Guava Technologies; and former graduate student Aimee Pugh-Bernard, Ph.D., now at the National Jewish Medical and Research Center. Gregg Silverman from the University of California at San Diego also worked with the team.
The study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Lupus Foundation of America, and the Autoimmunity Center of Excellence funded by the National Institutes of Health.
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