By snipping out and analyzing tiny samples of patients' tonsils,scientists have identified a key cellular checkpoint that is somehowbypassed in lupus patients, where harmful immune cells that normallyare squelched by the body are mistakenly granted access.
The in-depth look at tissue from a person's tonsils, a techniqueseldom used to study the immune system, has provided doctors with keyinformation about just what goes wrong in patients with lupus to causetheir immune systems to attack themselves, causing symptoms like jointpain, fatigue, and other complications like kidney failure.
The paper detailing the work by immunologists andrheumatologists at the University of Rochester Medical Center will bein the November issue of the Journal of Clinical Investigation. Thepaper became available online Oct. 6.
"Tonsils are very informative," said Ignacio Sanz, M.D.,professor of Medicine, Microbiology & Immunology, and chief of theDivision of Clinical Immunology and Rheumatology, who led the study."Peripheral blood doesn't have the organization you need to reallyunderstand the immune system. The tonsils give us a window into theimmune system that we didn't have before."
The tonsils are made up of lymphoid tissue and help the bodyfight off infection. But unlike the spleen, a major organ that plays akey role in the immune system, doctors can take a small biopsy of thetonsils, getting a look at structures that are present there but not inthe blood, which is studied more commonly.
Sanz's team focused on lymph structures in the tonsils known asgerminal centers, where teeming masses of immune cells known as B cellsand T cells glom together and swap crucial information about invaderslike bacteria and viruses. Such ongoing education is crucial to ourimmune system -- it's how our cells are trained to recognize enemieslike 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 owntissues.
"Our immune system needs redundancy and adaptability torecognize and fight the antigens it needs to fight," said Sanz. "Butthe price we pay is a fair amount of auto-reactivity. Because of that,we need very good systems to discriminate and control auto-reactive Bcells."
It's those systems, trained to recognize and then eliminateerrant cells, which fail in lupus. Somehow, rogue cells -- in thisstudy, 9G4 B cells -- slip through the body's defenses. Doctors haveknown that in people with lupus, antibodies from such cells make up amuch greater percentage of the person's immune system than in healthypeople. In this study the team found that lupus patients have as manyas 10 times the number of such cells as healthy people in the germinalcenters, 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 medicineand another author of the paper. "Normally those cells are censored orregulated by a number of mechanisms. We've known in lupus that thesecells get through, but what we haven't known before is at what pointthe regulation is defective."
The finding shows that the cells have already somehow slippedpast multiple checkpoints in the immune system and have enmeshedthemselves in a sophisticated segment of the immune system. As part ofthe immune system's training program for new immune cells, the germinalcenter is one of the last opportunities the body has for recognizingand kicking out rogue cells. Once a B cell passes muster at a germinalcenter, it becomes an established part of the immune system and has thepower to churn out and train rank-and-file antibodies on what to attackand what to avoid.
It's a little bit like a terrorist who rises through the ranksof the CIA despite the CIA's best efforts to weed out infiltrators. Ifthe mole actually becomes a teacher and molds new recruits who go on toattack the country, the CIA would have a major problem on its hands,trying to control one of its own working directly counter to itsobjectives. That's the way it is when the immune system meets up withcells not filtered out correctly in lupus patients.
In addition to Sanz and Anolik, who treat hundreds of lupuspatients, other authors of the paper include otolaryngologist PaulDutcher, M.D.; technician Jennifer Barnard; former post-doctoralresearcher Amedeo Cappione III, Ph.D., now at Guava Technologies; andformer graduate student Aimee Pugh-Bernard, Ph.D., now at the NationalJewish Medical and Research Center. Gregg Silverman from the Universityof California at San Diego also worked with the team.
The study was funded by theNational Institute of Arthritis and Musculoskeletal and Skin Diseases,the Lupus Foundation of America, and the Autoimmunity Center ofExcellence funded by the National Institutes of Health.
Materials provided by University of Rochester Medical Center. Note: Content may be edited for style and length.
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