NEJM editorial on significance and limitations of new lupus gene expression researchJanuary 21, 2008Some 1.5 million Americans, most of them women, suffer from lupus, a disease where the person's immune system attacks the body's own tissue. This week marks a significant step forward in understanding how the disease works with the online publication of four new studies identifying genes involved in this often debilitating chronic disease. Mary K.Crow, M.D., associate chief of the division of Rheumatology and director of Rheumatology research at Hospital for Special Surgery in New York, has written an editorial in The New England Journal of Medicine to accompany the papers. One study appears in The New England Journal of Medicine and the other three appear in Nature Genetics, all to be published online on Jan. 20. In her editorial, Dr. Crow talks about the importance of the studies and the questions they leave unanswered, along with insights on next steps in lupus research. "Overall, these papers confirm what investigators have been finding over the past decades," says Dr. Crow, the co-director of the Mary Kirkland Center for Lupus Research and director of the Autoimmunity and Inflammation Research Program at Hospital for Special Surgery. "They show that many aspects of the immune system are involved in the development of the disease, but they also provide a new level of detail regarding the specific molecular pathways that contribute."
The new research looks at how variations in a single DNA base pair, called single nucleotide polymorphisms (SNP), can be used to identify genetic variations among individuals that are associated with a diagnosis of lupus. In some cases, the SNPs call attention to important genes but have no apparent functional importance themselves. In other cases, the variations might actually change the protein product so that it functions differently in lupus patients and healthy individuals. For example, in one specific gene the frequency of an "A" nucleotide in people with lupus might be significantly greater than in healthy individuals without the disease. This small variation may alter the expression or function of the protein encoded by that gene in a way that contributes to the disease. Two of the studies are comprehensive reports of genomewide analyses looking for these types of small changes, specifically for those that appear more frequently in lupus patients and could predispose them to the disease. A third study also used a total genome analysis but focuses on those SNPs that are predicted to change the amino acid sequence of the protein product, meaning there is a greater chance the resulting protein's expression, role or activity is changed. The fourth study centers around one gene in particular, called ITGAM. "These genetic studies are the first step in getting a detailed understanding of the molecular pathways that underlie lupus," says Dr. Crow. The results help direct researchers to the genes, molecules and cells that are directly involved in the disease so that they can eventually identify exactly which pathways they can target therapeutically. Dr. Crow was particularly intrigued by the research on ITGAM, whose association with lupus was supported by three of the new studies. The protein encoded by ITGAM is found on the immune system's white blood cells that are recruited to blood vessels when it is activated. Some of the characteristic clinical features of lupus involve changes in blood vessels, including alterations in the kidneys, eyes, skin and the premature atherosclerosis that is common in lupus patients. The ITGAM protein, which is an adhesion molecule, helps leukocytes adhere to the cells lining blood vessels. The new genetic analysis of ITGAM variations associated with the disease predicts that it may promote vascular inflammation. "The role of the target tissue, such as the blood vessels, had been prominent in early lupus research," says Dr. Crow, "but in the past 25 to 30 years the focus has been primarily on the immune system. The new research on ITGAM, I think, will help redirect the attention of the scientific community back to this aspect of the disease." While the immune system, as the attacker, is of central importance in disease pathogenesis, it is also necessary to look at the response of the tissues they are attacking, Dr. Crow explains. Dr. Crow also praised the impressive collaborative effort that was required to complete the reported studies. For one of the studies, the International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN) coordinated the planning and organization of a large genotyping and data analysis effort that involved contributions from more than 150 participants. While some investigator groups have the patient numbers and financial support to provide important new genetics data independently, the success of the SLEGEN study supports broad collaboration, with credit shared among the many essential contributors, as a model that could be followed in investigation of the genetic factors in other complex diseases. However, three of the four studies, including both large genomewide association studies, are also missing a critical component - they don't take into account the populations of people that have the highest morbidity and mortality from the disease. "In the major studies, all of the subjects were of European descent," says Dr. Crow, "but lupus is most severe in people with African, Asian and Hispanic backgrounds. We need to confirm that these same genes are involved in all of our patient populations and identify any distinct genes that might be involved in those populations at greatest risk for poor outcomes." Hospital for Special Surgery has been a leader for more than forty years in research into the underlying mechanisms of lupus and was the nation's first National Institutes of Health-sponsored Specialized Center of Research in lupus. The Mary Kirkland Center for Lupus Research at HSS combines novel research with patient programs to provide the best care for its lupus patients. Dr. Crow has studied the immunologic mechanisms responsible for lupus for many years. Her recent research has looked at the role of a family of molecules, the interferons, in lupus, their association with disease activity and the mechanisms of type I interferon production. Her recent findings from studies of lupus families have shown that increased interferon-alpha levels are a heritable risk factor for lupus. Hospital for Special Surgery | |||||||||||||||||||||
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Related Lupus Current Events and Lupus News Articles Wistar researchers invigorate 'exhausted' immune cells In battles against chronic infections, the body's key immune cells often become exhausted and ineffective. Researchers at The Wistar Institute have found a way to restore vigor to these killer T cells by blocking a key receptor on their surface, findings that may advance the development of new therapies for diseases such as HIV, hepatitis B and C, and cancer. Key protein molecule linked to diverse human chronic inflammatory diseases Liwu Li, associate professor of biological sciences at Virginia Tech, has revealed a common connection between the cellular innate immunity network and human chronic inflammatory diseases, including atherosclerosis, Type 2 Diabetes, and neurodegenerative diseases. Accumulated bits of a cell's own DNA can trigger autoimmune disease A security system wired within every cell to detect the presence of rogue viral DNA can sometimes go awry, triggering an autoimmune response to single-stranded bits of the cell's own DNA, according to a report in the August 22nd issue of the journal Cell, a Cell Press publication. UT Pathologists Believe They Have Pinpointed Achilles Heel of HIV Human Immunodeficiency Virus (HIV) researchers at The University of Texas Medical School at Houston believe they have uncovered the Achilles heel in the armor of the virus that continues to kill millions. 'Multi-target' immune therapy improves outcomes of severe lupus nephritis A new treatment using a combination of drugs targeting different parts of the immune system improves the recovery rate for patients with severe lupus involving the kidneys, according to a report in the October Journal of the American Society of Nephrology (JASN). Specific location of the TRAF1/C5 gene associated with multiple autoimmune diseases The TRAF1/C5 locus on chromosome 9 has been revealed to play a role in multiple autoimmune diseases including type 1 diabetes and systemic lupus erythematosus (SLE). Ovarian function and fertility preserved in women with severe systemic lupus erythematosus Ovarian function can be preserved and disease activity controlled in women with severe systemic lupus erythematosus (SLE) when treated with a 6-month course of cyclophosphamide (CYC), a chemotherapy drug, followed by the immunosuppressant mycophenolate mofetil (MMF). Lupus more severe in patients with Southern European ancestry ystemic lupus erythematosus (SLE) patients with a higher percentage of ancestry from southern Europe have more severe disease manifestations, according to new research presented today at EULAR 2008, the Annual Congress of the European League Against Rheumatism in Paris, France. 'HiCy' drug regimen reverses ms symptoms in selected patients A short-term, very-high dose regimen of the immune-suppressing drug cyclophosphamide seems to slow progression of multiple sclerosis (MS) in most of a small group of patients studied and may even restore neurological function lost to the disease, Johns Hopkins researchers report. Abnormal 'editing' of gene messages may be a cause of lupus Researchers at Wake Forest University have uncovered evidence that the abnormal "editing" of gene messages in a type of white blood cell may be behind the development of lupus. More Lupus Current Events and Lupus News Articles |
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