Gene-altered mouse is model for rare autoimmune syndrome
By knocking out a single gene in mice, immunologists at Duke University Medical Center have mimicked a little-understood autoimmune disorder in humans. In the puzzling disorder, called Sjögrens syndrome, the persons tear and salivary glands are affected, causing dry eyes and mouth, as they are damaged by an attack of the persons own immune cells.
According to researchers, the achievement not only offers insight into Sjögrens syndrome, but into the general developmental machinery of the immune system. The immunologists, Yuan Zhuang, HongMei Li and MeiFang Dai, published their findings in the October 2004 issue of the journal Immunity. The work was sponsored by the National Institutes of Health and the Leukemia and Lymphoma Society.
In a preview of the article, immunologist Marjan Versnel wrote that the new mouse model "offers a wonderful opportunity to study in detail the relationship between the immune system and autoimmunity occurring in the context of only a single genetic lesion." Versnel is at Erasmus Medical Center in the Netherlands.
According to Zhuang, while Sjögrens syndrome is not well known, affecting up to 0.6 percent of the population. It manifests itself in middle age, mostly in women. "Most patients do not see a physician unless it becomes very serious or other problems arise, such as fatigue, arthritis, or inflammation of the lungs, kidneys or blood vessels," he said. Treatment for the disorder involves lubricant drops for the eyes and drugs that increase production of saliva.
"Basically nothing was known about the genetic basis of the disease," said Zhuang. "It was only known that the patients showed infiltration of lymphocytes into lachrymal and salivary glands and the production of certain autoantibodies." Lymphocytes are white blood cells -- T cells and B cells -- that are major components of the immune system. T cells are those that directly attack invaders such as bacteria and viruses, while B cells are the armament factories of the immune system, producing antibodies that recognize and attack such invaders.
While other genetically altered mouse models had been produced that showed similar symptoms, those animals showed other pathologies that do not mimic Sjögrens syndrome, said Zhuang. Also, they did not arise from a single genetic mutation, so it is difficult to determine the initial cause of the disease in these complex animal models, he said.
Zhuang and his colleagues did not set out to produce a mimic of Sjögrens syndrome in their studies. Rather they were exploring the role of a regulatory protein, called Id3, that previous studies in Zhuangs laboratory had revealed to be key to the development of lymphocytes. "In our basic studies, we suspected that if we developed animal models lacking the gene we would not only better understand its role in immune development, but see disease characteristics as well," said Zhuang. "We had no prior knowledge that we would produce such a precise model of Sjögrens syndrome."
Indeed, he said, the mice lacking the gene had all the characteristics of the disease, including reduced tear and saliva secretion and infiltration of lymphocytes into their tear and salivary glands. The animals also showed production of the antibodies that indicated the immune system was activated to attack the animals own tissues.
Also, the researchers found that they could induce symptoms of the syndrome in normal mice by transferring bone marrow cells from the genetically altered mice. Bone marrow is the source of immune cells that could cause the disorder. The researchers experiments with the Id3-deficient mice also revealed that T cells play a dominant and essential role in generating the pathology of the disorder.
According to Zhuang, development of the model will now enable the researchers to explore the complexities of the disease and the immune system in general. "This model really tells us that the biology of Id3 and the immune system is more complex than was suspected," he said. "For example, we need to understand why autoimmunity so specifically affects the lachrymal and salivary glands when the Id3 gene is very broadly expressed in many cell types."
Thus, the researchers are exploring the mechanism by which the Id3 mutation compromises early development of T cells and produces an autoimmune response. Importantly, said Zhuang, genetic analysis can be further applied to this animal model. For example, the defect in Id3 may cause different effects in different strains of mice with other genetic deficiencies -- offering even further opportunity for understanding the intricacies of immune system development.
Zhuang and his colleagues are also collaborating with medical center rheumatologists Drs. William St. Clair and Rob Geletka to determine whether Id3 deficiency plays a role in the disease in humans. They have begun to screen blood samples from patients with the disorder.
Dennis Meredith | EurekAlert!