Autoimmune Disease Breakthrough Gained by Identification of 30 Errant Genes

A report in the January issue of Nature magazine announces that one more step in understanding what may cause the body to attack itself in its war against autoimmune disease has been discovered by researchers at the Massachusetts Institute of Technology's Whitehead Institute, says the Autoimmune Related Diseases Association (AARDA), a national nonprofit patient advocacy organization.
Newswise — A report in the January issue of Nature magazine announces that one more step in understanding what may cause the body to attack itself in its war against autoimmune disease has been discovered by researchers at the Massachusetts Institute of Technology's Whitehead Institute, says the Autoimmune Related Diseases Association (AARDA), a national nonprofit patient advocacy organization.What happens in certain cases to cause the body's immune system to go wild with an over reaction when it encounters invading viruses or bacteria, thus resulting in one or more autoimmune diseases--such as rheumatoid arthritis, lupus, multiple sclerosis, thyroid disease (Graves', Hashimoto's), juvenile (type 1) diabetes?
Researchers Richard Young and Alexander Marson, an M.D./Ph.D. student working in Young's laboratory, have reported discovering 30 genes that go awry in autoimmune diseases. According to Young, the regulatory T cells (called “T regs”) that normally control the immune system may have genetic defects. In that case, the T regs protective powers are weakened.
The "brain" of the T regs is a protein called Foxp3. It can send the message to increase or decrease the production of other genes. Dr. Marson, study lead author, said, "We identified a set of roughly 30 genes that are clearly regulated by Foxp3 and, surprisingly, a lot of them are suppressed by Foxp3." Mutation in more of the genes, PTPN22, is associated with a number of autoimmune disorders. It is speculated that altering the Foxp3 gene might be one way to reach a cure of autoimmune diseases.
Two significant implications have emerged from this research. Marson commented, "One is that we've identified this core set of genes that are probably likely to play key roles in preventing autoimmune more disease." He added, "The second implication, which is maybe more long-term, is that we hope that identifying these targets will allow us to screen for drugs to mimic the function of Foxp3 and, thus, treat autoimmune disease."
Autoimmune disease pioneer Noel R. Rose, M.D., Director of the Johns Hopkins Center for Autoimmune Disease Research, says that treating autoimmune disorders will require enhancing either the number or effectiveness of regulatory T cells. He remarked that the MIT study is "certainly important in trying to understand how these regulatory T cells work." He cautions, "Whether this will have important functional implications, only time will tell."
Commenting on the study results, Virginia Ladd, AARDA president and executive director, observes, “The discovery adds weight to the reason why autoimmune diseases should be considered a disease category similar to the way that cancer is viewed rather than as singular diseases.” She adds, “It also lends proof to the genetic connection among these diseases and an understanding as to why these diseases run in families.”
Ms. Ladd points out that the public is unaware of the genetic connection among various autoimmune diseases, and patients are seldom queried by healthcare professionals regarding the family history in autoimmune disease. AARDA is pressing for federal legislation that would bring more awareness to autoimmune diseases and the fact that collectively they affect millions of Americans.
The American Autoimmune Related Diseases Association is the only national organization dedicated to addressing the problem of autoimmunity, the major cause of chronic illness. For more information, please visit AARDA’s Web site at http://www.aarda.org or call 586-776-5903 or 888-856-9433.

Scientists Spot Key Autoimmune Disease Genes

MONDAY, Jan. 22 (HealthDay News) -- The identification by U.S. scientists of genes thought to be key to autoimmune disorders could be a big step toward new treatments for these illnesses, which include lupus, rheumatoid arthritis and type 1 diabetes.
Cells called regulatory T-cells are supposed to help keep the immune system in check, but in autoimmune disease, these mechanisms can fail.
Now, researchers reporting this week in the journal Nature have identified a set of genes closely linked to regulatory T-cell function. The finding could have important implications for research into autoimmune disease and even cancer, experts say.
"This is certainly important in trying to understand how these regulatory T-cells work," said Dr. Noel Rose, director of the Johns Hopkins Center for Autoimmune Disease Research in Baltimore. "Whether this will have important functional implications, only time will tell," said Rose, who was not involved in the study.
Though it is meant to shield our bodies from all pathogens foreign and domestic, the immune system can be frustratingly temperamental. For example, when presented with cancer, the system basically shrugs. In other cases, the cell's defense department can sometimes go into overdrive, leading to autoimmune disorders like systemic lupus erythematosus and Graves' disease, where the body attacks its own cells.
Both of these situations are linked to the immune system's fundamental purpose: to distinguish the body's own cells (and related entities) from foreign invaders. So, cancer cells are ignored by the immune system because they are determined to be the body's own cells. Autoimmune disorders arise when the immune system gets confused and attacks healthy tissues.
In this study, researchers from Harvard Medical School, the Dana-Farber Cancer Institute, the Massachusetts Institute of Technology, and the Whitehead Institute for Biomedical Research focused on genes that help direct these processes via regulatory T-cells.
They focused on a protein that is found only in regulatory T-cells, called Foxp3. Foxp3 is a transcription factor -- that is, it dials up or down the production of other genes. Its significance in controlling the immune system is underscored by the fact that people with mutant Foxp3 genes develop IPEX, a syndrome marked by massive autoimmune disorders and early mortality.
Using sophisticated gene microarray technology, the team scanned the entire T-cell genome. "We identified a set of roughly 30 genes that are clearly regulated by Foxp3 and, surprisingly, a lot of them are suppressed by Foxp3," said study lead author Alexander Marson, a graduate student at Harvard Medical School and MIT.

· Autoimmune properties of nucleus pulposus: an experimental study in pigs.

· Geiss A,
· Larsson K,
· Rydevik B,
· Takahashi I,
· Olmarker K.
Department of Orthopaedics, Sahlgrenska University Hospital, Goteborg University, Goteborg, Sweden.

STUDY DESIGN: Assessment of activated T and B cells in a subcutaneous chamber filled with autologous nucleus pulposus using flow cytometry and immunohistochemistry. OBJECTIVES: To examine if subcutaneously placed autologous nucleus pulposus may attract activated T and B cells in an animal model. SUMMARY OF BACKGROUND DATA: Nucleus pulposus has been suggested to trigger an autoimmune response if exposed to the immune system, for example, in association with disc herniation. T-cell activation represents a hallmark in the generation of an autoimmune response, subsequently leading to the differentiation of B cells, but a causal association between the exposure of nucleus pulposus to the systemic circulation and T and B cell activation is still lacking. METHODS: Autologous nucleus pulposus was harvested from the intervertebral disc of 9 pigs and placed subcutaneously in perforated titanium chambers. In order to control for the effect of the titanium chamber, an additional empty chamber was placed subcutaneously in each pig. After 7 days, the pigs were killed and the chambers were harvested. Flow cytometry and immunohistochemistry were used for analysis of T-helper cells (CD4+), cytotoxic T cells (CD8+), and B cells (Igkappa) in the chamber exudates and T cells (CD45RC) in the remaining blood clot tissue of the chamber. RESULTS: As compared with the empty chambers, the proportion of activated T cells (CD4+ and CD8+) was significantly higher in the exudate of the nucleus pulposus filled chamber. The proportion of activated B cells expressing immunoglobulin kappa (Igkappa) was also significantly elevated in the exudate of the nucleus pulposus chambers. The analysis of the remaining chamber tissue revealed a significantly higher amount of T cells (CD45RC) in the nucleus pulposus chambers than in the empty chambers. CONCLUSIONS: The present findings indicate that nucleus pulposus attracts activated T and B cells. However, since the cell population in the nucleus pulposus of young pigs may differ from that of adult humans, the obtained data may not be directly transferred to the human situation of a disc herniation. The observations in the present study may nevertheless explain some of the local tissue reactions occurring in association with disc herniation and nerve root involvement, thereby providing further insight into the pathophysiology of sciatica.

Regulatory T cells require WASp if they are to prevent self-destruction.

In humans, mutation of the gene encoding a protein known as WASp leads to susceptibility to infections and systemic autoimmunity. Most studies have focused on understanding the defects in T cell activation caused by the WASp deficiency, but researchers at the University of Washington in Seattle have now found that in mice and humans a population of T cells known as regulatory T cells (Treg), which keep other immune cells from attacking the body's own tissues and causing autoimmunity, are also impaired in the absence of WASp.
In the study, which appears online on January 11 in advance of publication in the February print issue of the Journal of Clinical Investigation, David Rawlings and colleagues show that like WASp-deficient humans, WASp-deficient mice develop systemic autoimmune disease. This was not due to a defect in the number of Treg that developed in the mice, but due to a defect in their ability to control autoimmunity. Consistent with this, the peripheral blood of a WASp-deficient patient in whom a spontaneous revertant mutation occurred had substantial numbers of WASp+ Treg. These cells were able to ameliorate this individual's recurrent episodes of autoimmune hemolytic anemia, indicating that a defect in Treg function is likely to contribute to the systemic autoimmunity from which individuals lacking WASp suffer.
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TITLE: Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis
AUTHOR CONTACT:David J. RawlingsUniversity of Washington School of Medicine, Seattle, Washington, USA.Phone: (206) 987-7450; Fax: (206) 987-7310; E-mail: drawling@u.washington.edu.
Jennifer SeymourMedia Relations ManagerChildren's Hospital and Regional Medical Center, Seattle, Washington, USA.Phone: (206) 987-5207; Fax: (206) 987-5215; E-mail: jennifer.seymour@seattlechildrens.org