The molecular roots of inflammatory and autoimmune diseases such as asthma, arthritis, and multiple sclerosis ( MS ) have been discovered by a team of researchers led by The University of Texas M. D. Anderson Cancer Center.

In an article in the Nature Immunology, the researchers report finding a novel type of " T helper " cell they say is the culprit for initiating chronic inflammation and autoimmunity in a variety of body tissues. This newly described T cell - which they call inflammatory TH cells ( or Thi ) - produces interleukin 17 ( IL-17 ), a potent cytokine.

" We suspected that IL-17 is a player in autoimmune and inflammatory diseases, but we didn't understand where IL-17 came from before this finding," says the study's lead investigator, Chen Dong.

" Now we have discovered the source of IL-17 and also have solidly demonstrated that these are the crucial cells that regulate tissue inflammation in autoimmune disease and asthma," he says. " These findings suggest that shutting down the activity of these THi cells might stop chronic inflammatory diseases from developing in the first place."

He adds that while such drugs are years away from development and clinical trials, agents that block IL-17 could represent an effective treatment, based on these results.

Dong and four other M. D. Anderson researchers collaborated with scientists from the University of Washington, the Institute for Systems Biology in Seattle and Johns Hopkins School of Medicine.

While the findings have no immediate relevance to the field of oncology, it is known that cancer can arise from inflammatory processes.

Before this study, two different types of effector T helper cells had been known - type I ( TH1 ), linked to the body's response to microbial infection, and type 2 ( TH2 ), which plays a crucial function in production of B cell antibodies and also is associated with development of allergies.

Although TH1 and TH2 are known to produce powerful cytokines - such as interferon-gamma ( IFN-g ) and allergy-associated interleukin 4 ( IL-4 ), respectively - they are not inflammatory or associated with production of IL-17, which sets off an errant immune response that results in tissue inflammation.

Researchers could not understand the origins of such an inflammatory response in body tissues. The only clue they had was that excess IL-17 molecules are found in arthritic joints, in lungs swollen by asthma and in brain cells that lead to nerve degeneration and the onset of multiple sclerosis.
" But we didn't know which T cells were responsible for secreting IL-17," Dong says. To find out where IL-17 came from, the researchers designed a series of cell culture studies and mouse experiments.
In brief, they "educated" T helper cells to become IL-17 producing cells. They found that IL-17 is triggered by a unique set of signals that now define this new "lineage" of T helper cells. " They are completely different from TH1 and TH2 effector cells," says Dong. They then used a mouse model of multiple sclerosis and demonstrated that they could stop development of the disease with an antibody agent that blocked IL-17. Finally, they developed a transgenic mouse model of asthma and found that, by producing excessive IL-17 in the lung, they were able to produce asthmalike symptoms.

Dong says the researchers hypothesize that these newly discovered THi cells travel to selected body tissues and release IL-17. This action, in turn, stimulates expression of "chemokines," which results in a rush of inflammatory cells into the tissue. Thus a chronic inflammatory reaction is set up, he says.

Source: University of Texas M. D. Anderson Cancer Center, 2005


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