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UCSD Researchers Identify Gene Linked To Lupus-Like Disease In Mice

Date:
January 30, 2001
Source:
University Of California, San Diego School Of Medicine
Summary:
Researchers at the University of California, San Diego School of Medicine have identified a gene in mice that causes an autoimmune disease remarkably similar to human systemic lupus erythematous (SLE, or lupus), an incurable and potentially fatal multi-organ disease that turns victims’ immune systems against them.

Researchers at the University of California, San Diego School of Medicine have identified a gene in mice that causes an autoimmune disease remarkably similar to human systemic lupus erythematous (SLE, or lupus), an incurable and potentially fatal multi-organ disease that turns victims’ immune systems against them.

According to the Lupus Foundation of America, SLE affects nearly 1 million people in the United States. Ninety percent of the patients are women, with a high percentage African-Americans and Hispanics. Characterized by an immune system gone wild, SLE damages organs such as kidneys, liver, brain, heart, spleen, joints, and lungs.

In the Jan. 30 issue of Proceedings of the National Academy of Sciences, the UCSD investigators report that an SLE-like systemic autoimmune disease in mice is caused by a genetic mutation in an enzyme called alpha-mannosidase II. The enzyme is key to the formation of cell-surface carbohydrate structures called N-glycans, which are involved in the immune response recognition of self verses non-self.

When functioning normally, the human immune system circulates white blood cells called lymphocytes throughout the body, looking for and destroying invading pathogens such as bacteria, viruses and toxins. Autoimmune diseases such as arthritis, multiple sclerosis and SLE occur in about 5% of the population when a person’s own immune system fails to recognize cells of the body and attacks normal organs and tissue.

In spite of the prevalence of autoimmune disease, the inherited genetic susceptibilities and causes are not known. In SLE patients, for example, the lymphocytes appear normal, and yet the victims’ tissues and organs are ravaged by an attacking immune system.

Over the years, researchers have noted a correlation between changes in N-glycans, or carbohydrate structure, and the presence of autoimmune disease, according to UCSD cellular and molecular medicine professor Jamey D. Marth, Ph.D., who is the senior author of the PNAS paper and a Howard Hughes Medical Institute associate investigator.

Also a member of UCSD’s Glycobiology Research and Training Center, Marth has long been interested in the role that cell-surface carbohydrates, or glycans, play in disease. He notes that “only in the last five years have many of the genes that control glycan or carbohydrate production and diversification on the cell surface become identified and cloned. This entire area of study, called glycobiology, is an emerging area of biomedical research.”

Knowing that glycan structures may play a role in the immune response and can provide recognition of the body’s own cells, Marth and his team wanted to know if abnormal N-glycans played a role in causing an autoimmune response. They chose to study the N-glycan pathway by focusing on the role of the alpha-mannosidase II enzyme, one of the starting points in N-glycan variation.

The researchers also studied two molecular pathways that normally overlap in N-glycan production. They found in mice deficient in the alpha-mannosidase II enzyme that the enzyme participates in one of the pathways that leads to normal N-glycan formation, but doesn’t affect the alternate pathway.

After breeding mice without the enzyme, the researchers analyzed the tissue and organ systems. They found both significantly reduced levels of N-glycans and abnormally shaped N-glycans that are responsible for the SLE-like autoimmune response. Although lymphocyte development was normal, the mice were found to have excessive levels of antibodies, kidney inflammation and extensive scarring, excess protein and blood cells in their urine, and an increase in mortality connected with dying tissue and cysts in the kidneys. In addition, other tissues also were damaged, although not to the same extent as the kidneys.

“This is an entirely new manner by which autoimmune disease can occur, by a gene controlling carbohydrate formation,” Marth says, adding that, “these findings provide new insights into understanding autoimmune disease and suggest new diagnostic tests for possible causes of human SLE.”

In addition to Marth, authors of the PNAS paper are UCSD researchers Daniel Chui, BSc., research associate; research technicians Gayathri Sellakumar, BSc; Ryan S. Green, BSc; Tammie McQuistan, BSc; and Kurt W. Marek, BSc; plus Mark Sutton-Smith, Ph.D.; Howard R. Morris, Ph.D.; and Anne Dell, Ph.D., members of the Department of Biochemistry, Imperial College of Science, Technology & Medicine in London, England.

The research was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute in collaboration with Biotechnology and Biological Sciences Research Council and Wellcome Trust.


Story Source:

The above story is based on materials provided by University Of California, San Diego School Of Medicine. Note: Materials may be edited for content and length.


Cite This Page:

University Of California, San Diego School Of Medicine. "UCSD Researchers Identify Gene Linked To Lupus-Like Disease In Mice." ScienceDaily. ScienceDaily, 30 January 2001. <www.sciencedaily.com/releases/2001/01/010130071959.htm>.
University Of California, San Diego School Of Medicine. (2001, January 30). UCSD Researchers Identify Gene Linked To Lupus-Like Disease In Mice. ScienceDaily. Retrieved August 1, 2014 from www.sciencedaily.com/releases/2001/01/010130071959.htm
University Of California, San Diego School Of Medicine. "UCSD Researchers Identify Gene Linked To Lupus-Like Disease In Mice." ScienceDaily. www.sciencedaily.com/releases/2001/01/010130071959.htm (accessed August 1, 2014).

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