OKLAHOMA CITY—In a study recently published in The Journal of Experimental Medicine, scientists from the Oklahoma Medical Research Foundation (OMRF) found that rogue immune cells lay in the bodies of healthy people, but unlike people who suffer from autoimmune diseases, the cells appear to be inactive. According to the scientists, the study—the first natural human account of an autoreactive B cell tolerated population—could lead to the development of methods to "turn off" these dangerous cells in autoimmune patients.
Previous research in mouse models has shown that autoimmune antibodies and the cells that produce them, autoimmune B cells, play a significant role in disease. Although 20 years worth of accumulated data has provided valuable insight into the mechanisms in which a healthy system abrogates or inactivates potential dangerous B cells, the OMRF scientists hypothesized that its human B cell population would be tolerated or inactivated much in the same way they were in mouse models.
Using a proprietary system to extract particular B cells subsets from the body, the research team then sorted the subsets into single cells and extracted their antibody proteins. These antibody proteins were recombinantly amplified and used to test for autoreactive potential against many of the autoantigens, such as nuclear and cytoplasmic antigens, that are indicated in autoimmune diseases. These cells were also sorted and tested for signs of inactivation through stimulation, measuring downstream effectors such as calcium flux and phosphate accumulation.
The research team found that that in healthy adults, rogue immune cells account for 2.5 percent of immune cells. The dormant rogue immune cells don't cause problems in healthy adults, but given the right stimulus in laboratory experiments, they become activated.
The finding could lead to the development of new ways to prevent and treat autoimmune conditions such as rheumatoid arthritis, lupus and type 1 diabetes, which in total affect up to 24 million Americans, says J. Andrew Duty, Ph.D., lead author of the study.
"I think I was personally surprised most by how similar these cells looked to their 'normal' counterpart (or the naive B cell) outside of their autoreactive potential and one other key distinguishing factor, that they had reduced IgM expression," Duty says. "We studied their outward 'phenotype' by evaluating many other surface proteins and found that they looked most similarly to the naive cell, which indicates that these cells are mature B cells and not an immature B cell that has escaped from the bone marrow or spleen. This really hit home for me that the biological nature of anergy was something real and not a product of manipulated mouse systems."
Correlating and verifying the work that has been done in mice "makes a huge leap in our understanding by providing the first natural human account of an autoreactive B cell tolerated population," Duty says, noting that in addition to the study being a human account, it is a natural account as the mouse studies were almost all done in artificial systems in which self-reactive B cells were introduced into the system. But Duty notes that there are always limitations to testing on humans.
"We studied these cells in normal healthy donors. Thus, it will be important to establish what this population looks like in autoimmune patients, and to correlate this population with disease onset and severity," Duty says. "It will also be valuable to continue to study the exact mechanisms to how these cells are inactivated normally by the body. Further research needs to be done to understand how a normal system controls or tolerates its potentially dangerous immune cells."
The study, Functional anergy in a subpopulation of naive B cells from healthy humans that express autoreactive immunoglobulin receptors, was published in the Dec. 22, 2008 edition of The Journal of Experimental Medicine and was funded by a National Institutes of Health grant.
Previous research in mouse models has shown that autoimmune antibodies and the cells that produce them, autoimmune B cells, play a significant role in disease. Although 20 years worth of accumulated data has provided valuable insight into the mechanisms in which a healthy system abrogates or inactivates potential dangerous B cells, the OMRF scientists hypothesized that its human B cell population would be tolerated or inactivated much in the same way they were in mouse models.
Using a proprietary system to extract particular B cells subsets from the body, the research team then sorted the subsets into single cells and extracted their antibody proteins. These antibody proteins were recombinantly amplified and used to test for autoreactive potential against many of the autoantigens, such as nuclear and cytoplasmic antigens, that are indicated in autoimmune diseases. These cells were also sorted and tested for signs of inactivation through stimulation, measuring downstream effectors such as calcium flux and phosphate accumulation.
The research team found that that in healthy adults, rogue immune cells account for 2.5 percent of immune cells. The dormant rogue immune cells don't cause problems in healthy adults, but given the right stimulus in laboratory experiments, they become activated.
The finding could lead to the development of new ways to prevent and treat autoimmune conditions such as rheumatoid arthritis, lupus and type 1 diabetes, which in total affect up to 24 million Americans, says J. Andrew Duty, Ph.D., lead author of the study.
"I think I was personally surprised most by how similar these cells looked to their 'normal' counterpart (or the naive B cell) outside of their autoreactive potential and one other key distinguishing factor, that they had reduced IgM expression," Duty says. "We studied their outward 'phenotype' by evaluating many other surface proteins and found that they looked most similarly to the naive cell, which indicates that these cells are mature B cells and not an immature B cell that has escaped from the bone marrow or spleen. This really hit home for me that the biological nature of anergy was something real and not a product of manipulated mouse systems."
Correlating and verifying the work that has been done in mice "makes a huge leap in our understanding by providing the first natural human account of an autoreactive B cell tolerated population," Duty says, noting that in addition to the study being a human account, it is a natural account as the mouse studies were almost all done in artificial systems in which self-reactive B cells were introduced into the system. But Duty notes that there are always limitations to testing on humans.
"We studied these cells in normal healthy donors. Thus, it will be important to establish what this population looks like in autoimmune patients, and to correlate this population with disease onset and severity," Duty says. "It will also be valuable to continue to study the exact mechanisms to how these cells are inactivated normally by the body. Further research needs to be done to understand how a normal system controls or tolerates its potentially dangerous immune cells."
The study, Functional anergy in a subpopulation of naive B cells from healthy humans that express autoreactive immunoglobulin receptors, was published in the Dec. 22, 2008 edition of The Journal of Experimental Medicine and was funded by a National Institutes of Health grant.
