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Proteins paired for destruction

Researchers discover that abnormal regulation of two cancer-fighting proteins may play a role in joint destruction in rheumatoid arthritis
Drs. Veronika Groh, Thomas Spies and Lee Nelson
Drs. Veronika Groh (left), Thomas Spies and Lee Nelson of the Clinical Research Division teamed up to discover that two immune-system proteins called NKG2D and MIC play an important role in the progression of rheumatoid arthritis, one of the most common types of autoimmune disease. Photo by Todd McNaught

A new Clinical Research Division study has found that two proteins that normally may stimulate immune responses against infections and cancer are also among the likely culprits behind the self-destructive immune response found in rheumatoid arthritis, one of the most common-and debilitating-autoimmune diseases.

Dr. Veronika Groh and colleagues discovered that aberrant regulation of a protein pair, known as NKG2D and MIC, may fuel a class of self-destructive immune-system cells that attack cartilage and bone. The findings help to explain why commonly prescribed anti-inflammatory medications provide incomplete relief for rheumatoid arthritis and ultimately could lead to the development of improved treatment strategies.

The study appears in the Aug. 5 issue of the Proceedings of the National Academy of Sciences. Co-authors include Drs. Lee Nelson and Thomas Spies, investigators in the Clinical Research Division; Anja Br?hl, former student in the Spies lab; and Dr. Hani El-Gabalawy of the University of Manitoba Arthritis Center.

Disease fighters of the immune system known as T cells and natural-killer cells are normally under tight control by stimulatory and inhibitory signals that communicate through receptors-including NKG2D-found on the cells' surfaces.

In healthy individuals, only diseased cells are targeted for destruction. But in patients with autoimmune disorders such as rheumatoid arthritis, multiple sclerosis and juvenile diabetes, scientists speculate that certain T cells are over-stimulated, which leads to an attack on healthy cells. In rheumatoid arthritis, the condition causes an inflammation of the lining of the joints, which leads to progressive destruction of cartilage and bone.

Previous work from the Spies lab has shown that NKG2D-bearing T cells and natural-killer cells hone in on other cells that are coated with MIC, a protein produced in response to viral or bacterial infection, tumor formation or other physiological stresses. The lock-and-key binding of the protein pair triggers a biological fire alarm that results in the destruction of the stressed or diseased cell.

What is unusual about the NKG2D receptor, Groh said, is that its function is not specifically opposed by an inhibitory receptor.

"For most receptors, scientists have identified pairs of stimulatory and inhibitory isoforms (receptors similar in form but with different functions)," she said. "But NKG2D doesn't have an apparent counterpart. Because of that, the NKG2D-MIC system, if misregulated in some way, is almost perfectly set up to lead to autoimmunity."

Several observations made in other laboratories led Groh and Spies to speculate that a breakdown in the NKG2D-MIC system might be the source of the self-destructive immune response associated with rheumatoid arthritis. Others had found that patients with the disease have an abundance of a subtype of T cells that appeared to be prone to react against the body's own tissue.

"That caught our attention," Groh said. "We wondered whether those cells would express NKG2D."

Rampant activation

Groh and Spies approached Nelson, who had a collection of blood samples from patients with rheumatoid arthritis that allowed them to test their hypothesis. The researchers found that in contrast to most T cells, the unusual subpopulation of T cells from the patient blood samples did produce NKG2D. Using synovial (joint) tissue samples provided by El-Gabalawy, they also discovered that MIC was aberrantly produced in synovial cells.

Normally, MIC activation of NKG2D-bearing cells doesn't occur for a sustained period. Over time, MIC protein is shed from the stressed cells, and the abundance of MIC in peripheral blood eventually dampens the NKG2D response. Yet although they detected excess shed MIC protein in the patient samples, the researchers found that NKG2D activation continued unabated.

A closer look at the patient samples revealed a possible reason for the rampant activation. The study confirmed that synovial cells produced an abundance of two types of cytokines, messenger molecules secreted by immune-system cells that can dampen or stimulate T-cell attack. In particular, the cells produced two cytokines known as IL-15 and TNF-a, which the authors found to stimulate NKG2D-bearing cells.

"IL-15 and TNF-a seem to counteract the down-modulation potential of the soluble MIC," Groh said. "As long as the synovial tissue produces these cytokines, NKG2D remains activated."

Groh said that although these findings don't explain the initial trigger for the onset of the autoimmune disease, they do help to explain how the sustained self-destruction is maintained.

Hope for treatment

The observation that IL-15 perpetuates activation of NKG2D also helps to clarify why some of the most promising new anti-inflammatory medications prescribed for rheumatoid arthritis are insufficiently effective. One such drug is Enbrel, developed by Immunex Corporation (now Amgen), which blocks the action of TNF-a but does not neutralize IL-15. Based on the results of the new study, the researchers speculate that drugs that inhibit both cytokines could offer additional relief for patients by allowing the shed MIC protein to diminish the NKG2D activation.

In addition, the finding that soluble MIC is shed from synovial cells into the circulation could provide the basis for the development of a new prognostic and/or disease-monitoring test for rheumatoid arthritis. Currently, no such test is available for the disease.

Misregulation of NKG2D and MIC may not be unique to rheumatoid arthritis. Researchers from other laboratories have found that several autoimmune disorders, including insulin-dependent diabetes, celiac disease and Wegener's granulomatosis, also are associated with the unusual population of T cells found in rheumatoid arthritis.

"Scientists are just starting to examine whether NKG2D and MIC are misregulated in other autoimmune diseases," Groh said. "There is preliminary evidence that MIC/NKG2D interactions are also critical for the progression of certain inflammatory bowel diseases. However, it remains an open question to what extent this phenomenon applies to other autoimmune diseases.

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