HOUSTON - The molecular roots of inflammatory and autoimmune diseasessuch as asthma, arthritis, and multiple sclerosis (MS) have beendiscovered by a team of researchers led by The University of Texas M.D. Anderson Cancer Center. They say their findings may point to ways toeffectively treat these diseases - if not stop them before they start.
In a lead article in the November issue of Nature Immunology(released online on Oct. 2), the scientists report finding a novel typeof "T helper" cell they say is the culprit for initiating chronicinflammation and autoimmunity in a variety of body tissues. This newlydescribed T cell - which they call inflammatory TH cells (or THi) -produces interleukin 17 (IL-17), a potent cytokine that researchershave already linked to an immune system gone awry.
"We suspected that IL-17 is a player in autoimmune and inflammatorydiseases, but we didn't understand where IL-17 came from before thisfinding," says the study's lead investigator, Chen Dong, Ph.D., anassociate professor in the Department of Immunology.
"Now we have discovered the source of IL-17 and also have solidlydemonstrated that these are the crucial cells that regulate tissueinflammation in autoimmune disease and asthma," he says. "Thesefindings suggest that shutting down the activity of these THi cellsmight stop chronic inflammatory diseases from developing in the firstplace."
He adds that while such drugs are years away from development andclinical trials, agents that block IL-17 could represent an effectivetreatment, based on these results.
Dong and four other M. D. Anderson researchers collaborated withscientists from the University of Washington, the Institute for SystemsBiology in Seattle and Johns Hopkins School of Medicine.
While the findings have no immediate relevance to the field ofoncology, it is known that cancer can arise from inflammatoryprocesses. Further understanding of how the immune system functions,and how it can go awry, is important, Dong says.
T cells are white blood cells that play a variety of roles in theimmune system, including the identification of foreign molecules in thebody, such as bacteria and viruses, and the activation and deactivationof other immune cells.
T helper cells are specific T cells that have receptors that recognizeand bind to fragments (known as antigens) of the invaders that alreadyhave been displayed on the surface of other immune system cells. (TheseT helper cells are also called CD4 T cells since they express CD4molecules.) Once the antigen has been bound, these T helper cellsbecome activated, and they morph into "effector" cells which then boostan immune response by secreting "cytokine" molecules such asinterleukins and interferons.
Before this study, two such different types of effector Thelper cells had been known - type I (TH1), linked to the body'sresponse to microbial infection, and type 2 (TH2), which plays acrucial function in production of B cell antibodies and also isassociated with development of allergies.
Although TH1 and TH2 are known to produce powerful cytokines - such asinterferon-gamma (IFN-g) and allergy-associated interleukin 4 (IL-4),respectively - they are not inflammatory or associated with productionof IL-17, which sets off an errant immune response that results intissue inflammation.
Researchers could not understand the origins of such aninflammatory response in body tissues. The only clue they had was thatexcess IL-17 molecules are found in arthritic joints, in lungs swollenby asthma and in brain cells that lead to nerve degeneration and theonset of MS. "But we didn't know which T cells were responsible forsecreting IL-17," Dong says.To find out where IL-17 came from, the researchers designed a series ofcell culture studies and mouse experiments. In brief, they "educated" Thelper cells to become IL-17 producing cells. They found that IL-17 istriggered by a unique set of signals that now define this new "lineage"of T helper cells. "They are completely different from TH1 and TH2effector cells," says Dong.They then used a mouse model of MS and demonstrated that they couldstop development of the disease with an antibody agent that blockedIL-17. Finally, they developed a transgenic mouse model of asthma andfound that, by producing excessive IL-17 in the lung, they were able toproduce asthmalike symptoms.
Dong says the researchers hypothesize that these newlydiscovered THi cells travel to selected body tissues and release IL-17.This action, in turn, stimulates expression of "chemokines," whichresults in a rush of inflammatory cells into the tissue. Thus a chronicinflammatory reaction is set up, he says.
The scientists don't know what initially sets off activation of thenewly discovered T helper cell in diseases such as arthritis andasthma, Dong says. "We don't know why these dangerous helper T cellsare activated in the patients, but we now know how they function, andthat should take us a long way to understanding and treating these andother inflammatory and autoimmune diseases."
The study was funded by grants from the National Institutes of Health,the Arthritis Foundation, the Cancer Research Institute and M. D.Anderson Cancer Center.
Dong's co-authors include Heon Park, Ph.D., Zhaoxia Li, M.D., Ph.D.,and Ying Wang from the University of Washington; Leroy Hood, Ph.D., andQiang Tian, Ph.D., from the Institute for Systems Biology; Zhou Zhu,M.D., Ph.D., from Johns Hopkins School of Medicine; and Xuexian O.Yang, Ph.D., Seon Hee Chang, Ph.D., Roza Nurieva, Ph.D., and Yi-HongWang, M.D., from M. D. Anderson Cancer Center.
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