Three potent proteins of the immune system, evolved to purge us of intestinalparasites, now often launch misguided attacks in our airways, triggering thecongestion of asthma that leaves millions gasping for air.
By studying the genetic machinery that controls production of these immunesoldiers called cytokines, a team of scientists has demonstrated a potentialstrategy to silence their misfiring and quell the asthma response.
In back-to-back papers in April and May, researchers at UC San Francisco andthe Lawrence Berkeley National Laboratory (LBL) report that a stretch of DNAcontrolling all three cytokine genes is so similar in humans and mice that themouse DNA can activate the three human genes inserted in a mouse.
The researchers showed too that the activity of all three genes can be atleast partially blocked, suggesting that a single drug could be used to attackasthma at its genetic source. Such a drug could be reliably tested in mice,their study shows.
"The primary aim of our research has been to demonstrate that if non-codingregions of DNA (stretches containing no genes) have been conserved in speciesseparated by many millions of years, they probably perform vital functions,"said Richard Locksley, MD, investigator in the Howard Hughes Medical Instituteand professor of medicine and microbiology/ immunology at UCSF.
"But in choosing a DNA region that modulates the genes for the cytokines IL-4,5 and 13, we are dealing with genes that are dramatically expressed in asthmaand other allergic diseases. Our experiments show that all three genes areregulated by the same non-coding DNA region, and interruption of this controlaffects all three genes at once. By blocking the activity of this region, weshould be able to block the expression of all three genes."
Many drugs are now being designed to interfere with activity of a single geneor the protein coded by that gene, but developing a drug to treat a diseasecaused by at least three genes could be far more difficult, Locksley said.Targeting a region of the genome that controls expression of the three genes atonce may offer a solution.
The demonstration that the human genes for IL-4, 5 and 13 can be faithfullyexpressed in mice under the regulation of the mouse DNA is being published inthe May issue of the Journal of Immunology. Lead author is Dee A. Lacy, MD,PhD, research associate in the Howard Hughes Medical Institute at UCSF; seniorauthor is Richard Locksley. Scientists at LBL collaborated on the research andthe paper.
The publication comes a few weeks after the team, led by the LBL scientists,identified the high degree of similarity between the mouse and human stretchesof DNA that regulate expression of the genes. These findings were published inthe April 7 issue of the journal Science.
Over the past decade a powerful principle has emerged that genes shared byevolutionarily distant species are likely to play major roles for the organismsand may provide a window to understand basic genetic mechanisms. The researchby the UCSF/LBL team extends that principle to the non-gene portions of thegenome.
"If evolution conserved a sequence over the 70 to90 million years since miceand humans diverged, it likely has a function," says geneticist Kelly Frazer,PhD, senior scientist at LBL's Life Sciences Division, senior author on theScience paper and co-author on the immunology paper. "Whether its function isto determine the structure of a protein coded for by a gene or to regulate geneexpression, we should be able to identify these sequences though mouse-to-humansequence comparisons."
In the research reported in the Journal of Immunology, the scientists insertedhuman chromosome segment 5q31which contains the genes for the three humaninterleukins (Ils) into the chromosome of a mouse that includes that species'versions of these genes.
"Remarkably," they report, "these human Ils were expressed faithfully in CD4+ Tcells in vitro and in vivo. These data support the existence of conservedregulatory elements near the cytokine cluster itself that enables theactivation and/or stable expression of the type 2 cytokine genes in a cell-andlineage-specific manner."
The resulting transgenic mouse strains showed normal lymph system development,the researchers reported. However, the mice did develop fewer mouseIL-4-producing cells, suggesting competition exists between the mouse and humancytokines genes for expression in the transgenic mice.
The fact that including an "extra" human copy of the genes cuts down onexpression of the mouse copies suggests to Locksley that some "rate-limitingfactor is scanning the DNA stretches to find these genes."
"The hope is that studies of this mechanism may guide new therapeuticstrategies to shut down expression of these genes associated with allergicdiseases and asthma," Locksley says.
Infections by hookworms and other parasites induce a potent response fromcytokines Il-4 and IL-13, the researchers write. Hookworms are a major worldparasite, infecting nearly a billion people. The half-inch worms commonly boreinto the body through bare feet and make their way to the gut where theyreproduce. A female can produce more than 20,000 eggs per day. The interleukinsregulate the intestinal immune response to the worms, and combine toorchestrate smooth muscle contraction, production of mucus and attack by immunecells that together lead to expulsion of the worms, Locksley explains.
Intestinal worms infect essentially all infants and children in developingcountries, Locksley says, and some scientists believe this type of immuneresponse can become misdirected, no longer playing the role it probably evolvedto play but focusing instead on viruses and allergens inhaled in therespiratory tract.
"The marked increase in asthma in developed countries may represent the pricewe pay for shoes and concrete, which have eliminated the usual pathogen targetand the timing during which this type of immune response would normally becomedirected to the gut," Locksley says.
Co-authors with Lacy, Locksley and Frazer on the Journal of Immunology paper,and collaborators on the research, are Zhi-En Wang, MD, research specialist inthe Howard Hughes Medical Institute (HHMI) at UCSF; Clifford J. McArthur,research specialist at UCSF; Derek J. Symula, PhD, research scientist at LBL;and Edward M. Rubin, MD, PhD, senior scientist at LBL.
The research was funded by the National Institutes of Health and the HowardHughes Medical Institute.
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