Featured Research

from universities, journals, and other organizations

Novel Route To Lupus-Like Disease In Mice

February 2, 2001
Howard Hughes Medical Institute
Researchers have knocked out a gene that codes for an enzyme involved in modifying sugar molecules on the surface of cells, producing a disorder in mice that resembles the human disease, systemic lupus erythematosus.

Researchers have knocked out a gene that codes for an enzyme involved in modifying sugar molecules on the surface of cells, producing a disorder in mice that resembles the human disease, systemic lupus erythematosus.

Related Articles

Their finding represents the first time that an autoimmune disease has been linked to defects in cell-surface carbohydrate chains called glycans. According to the researchers, their work suggests that faulty glycan construction may play a role in the onset of human autoimmune diseases such as lupus. Autoimmune disorders, which are caused when the body's immune system attacks its own tissues, affect about five percent of people worldwide.

The researchers, led by Howard Hughes Medical Institute investigator Jamey D. Marth at the University of California, San Diego, published their findings in the January 30, 2001, issue of Proceedings of the National Academy of Sciences.

"Until now, it's been known only by association that various autoimmune syndromes are shadowed by changes in glycosylation," said Marth. He cited, for example, that antibodies that recognize glycans are a central part of the immune system's ability to "see" foreign invaders. "However, it wasn't known whether changes in glycosylation cause autoimmune disorders," said Marth.

Past efforts to model systemic autoimmune diseases in animals—by genetically altering white blood cells, for example—have not completely mirrored the human disorder. "In contrast, human autoimmune disease is often a long-term or chronic affliction and does not appear to be associated with similarly overactive lymphocytes," Marth said. "Patients may live many years with the disease and some do rather well, but the disease waxes and wanes. And in human lupus, intrinsic defects in the immune system, such as the presence of dysfunctional lymphocytes, do not appear."

To determine whether defects in glycosylation play a role in autoimmune responses, Marth and his colleagues knocked out the gene in mice that produces a -mannosidase II, an enzyme that prunes mannose sugars from growing glycan chains on cell surfaces. Pruning enables more complex growth by glycosylation—in much the same way that pruning a tree alters its growth pattern. Without the enzyme, the cells show abnormal surface glycan formation. In earlier studies with mice, Marth and his colleagues had observed abnormalities that suggested the enzyme might be involved in an autoimmune reaction.

While the resulting knockout mice did not show acute symptoms of immune disorder as they aged, they did develop inflamed and scarred kidneys and autoreactive antibodies indicative of lupus-like abnormalities seen in the human disease. "The disease produced in these mice was chronic and long term, waxing and waning," said Marth. "And it doesn’t appear to be due to defects intrinsic to lymphocyte development or activation, as these parameters were normal.

"As in humans with these disorders, these animals have a varied life span," said Marth. "They can live the human equivalent of sixty to seventy years, although their kidney function falters and some of them die much younger due to kidney failure."

Also intriguing, said Marth, was that the production of glycans in some tissues appeared to proceed via a pathway that did not require the a -mannosidase II enzyme. Exploring the differing pathways in the different tissues should give further insight into the role and machinery of glycosylation, he said. The clinical implications of the discovery of the effects of knocking out the a -mannosidase II gene are unclear, said Marth.

"We don’t know if there are examples of human systemic autoimmune disease and lupus out there that may be due to mutations in this gene," he said. "But what particularly concerns us is that there are currently very few clinical diagnostic tests for carbohydrate-based disease. It’s only been in the last five years that such syndromes have been discovered. And those were found serendipitously by a test for alcoholism that detects abnormal glycosylation in the liver due to alcohol intake," he said.

Marth emphasized that the role of glycosylation defects in producing autoimmune disease will not be known until clinics begin routine testing for such disorders—especially in the 50 percent of children who show symptoms of unknown inherited metabolic diseases.

Additional studies are needed to understand how knocking out a -mannosidase II produces an autoimmune disease, he said. The abnormal glycans might directly trigger the immune system, or they might indirectly cause cell malfunction and death, that overactivate the immune system, creating chronic inflammation, said Marth.

Also, he noted, compounds that inhibit a -mannosidase II have shown therapeutic effect as an anti-cancer drug. "In animal studies, these compounds have inhibited tumor growth and metastasis," said Marth. "These findings raise the possibility that inhibiting the enzyme might modulate the immune-autoimmune threshold, perhaps resetting the rheostat enough to induce the immune system to suppress tumor growth," he said.

Story Source:

The above story is based on materials provided by Howard Hughes Medical Institute. Note: Materials may be edited for content and length.

Cite This Page:

Howard Hughes Medical Institute. "Novel Route To Lupus-Like Disease In Mice." ScienceDaily. ScienceDaily, 2 February 2001. <www.sciencedaily.com/releases/2001/02/010202074144.htm>.
Howard Hughes Medical Institute. (2001, February 2). Novel Route To Lupus-Like Disease In Mice. ScienceDaily. Retrieved January 28, 2015 from www.sciencedaily.com/releases/2001/02/010202074144.htm
Howard Hughes Medical Institute. "Novel Route To Lupus-Like Disease In Mice." ScienceDaily. www.sciencedaily.com/releases/2001/02/010202074144.htm (accessed January 28, 2015).

Share This

More From ScienceDaily

More Health & Medicine News

Wednesday, January 28, 2015

Featured Research

from universities, journals, and other organizations

Featured Videos

from AP, Reuters, AFP, and other news services

Poultry Culled in Taiwan to Thwart Bird Flu

Poultry Culled in Taiwan to Thwart Bird Flu

Reuters - News Video Online (Jan. 28, 2015) Taiwan culls over a million poultry in efforts to halt various strains of avian flu. Julie Noce reports. Video provided by Reuters
Powered by NewsLook.com
Shark Bite Victim Making Amazing Recovery

Shark Bite Victim Making Amazing Recovery

AP (Jan. 27, 2015) A Texas woman who lost more than five pounds of flesh to a shark in the Bahamas earlier this month could be released from a Florida hospital soon. Experts believe she was bitten by a bull shark while snorkeling. (Jan. 27) Video provided by AP
Powered by NewsLook.com
Shoveling Snow: How to Prevent Back Injuries

Shoveling Snow: How to Prevent Back Injuries

Washington Post (Jan. 26, 2015) What&apos;s the proper technique for shoveling snow? A physical therapist offers specific tips for protecting your back while you dig out this winter. Video provided by Washington Post
Powered by NewsLook.com
Ebola Mistakes Should Serve a Lesson Says WHO

Ebola Mistakes Should Serve a Lesson Says WHO

AFP (Jan. 25, 2015) The World Health Organization&apos;s chief on Sunday admitted the UN agency had been caught napping on Ebola, saying it should serve a lesson to avoid similar mistakes in future. Duration: 00:55 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.


Breaking News:

Strange & Offbeat Stories

Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News


Free Subscriptions

Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile

Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?

Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins