An important part of the quest for better treatments and, ultimately, a cure for systemic lupus erythematosus (SLE, or lupus) involves efforts to identify genes that predispose some people to lupus or affect the course of this autoimmune disease. Although the exact causes of lupus are still unknown, scientific evidence indicates that the disease is caused by a combination of genetic and environmental factors.
Unlike “simple” genetic diseases such as cystic fibrosis and Huntington’s disease, which are caused by a single defective gene, lupus involves complex interactions among several genes. Despite this complexity, ALR investigators and other researchers are making strides in understanding the role of genetic factors in lupus. A few recent advances are highlighted here. According to ALR Scientific Director John H. Klippel, MD, “these findings underscore the importance and rapid progress of genetic research in lupus.”
In a recent study, ALR investigators Jeffrey Ravetch, MD, PhD, of The Rockefeller University in New York, and Edward Wakeland, PhD, of the University of Texas Southwestern Medical Center in Dallas, joined forces to examine the interactions between genes responsible for causing lupus-like disease in mice. Dr. Wakeland has identified numerous genes that affect lupus development in mice. Dr. Ravetch’s work has focused on a lupus susceptibility gene called FcgRIIB. He found that mice that lack this gene, and thus do not produce the FcgRIIB protein, develop a lupus-like autoimmune disease. The FcgRIIB protein is known to play a critical role in preventing inappropriate immune responses that can lead to autoimmune disease, and preliminary evidence suggests that people with lupus may have low levels of this protein during periods of high disease activity.
Previous studies by Dr. Ravetch indicate that additional genetic factors act together with the FcgRIIB gene deficiency to cause lupus in mice. In a study published in the May 6, 2002 issue of the Journal of Experimental Medicine, Drs. Ravetch and Wakeland and their coworkers looked at how several genes previously shown to play a role in lupus affect the development and progression of lupus in mice deficient in FcgRIIB. They did this by crossbreeding mice lacking the FcgRIIB gene with mice that have other genetic factors known to influence lupus development, thereby producing new genetic combinations in the offspring.
The researchers found that, when combined with the FcgRIIB gene deficiency, some genes increase the severity of lupus while other genes lessen the severity of disease. By examining signs of disease such as kidney inflammation and the production of abnormal antibodies in mice with various gene combinations, the researchers gained a new understanding of the specific role that each gene plays in causing or modifying the course of disease. Because the mice used in this study mimic many aspects of the genetics of lupus in humans, this and future studies in this mouse model of lupus will help researchers understand how multiple genetic factors can act in concert to cause disease.
Evidence for the role of genetic factors in lupus susceptibility in people comes from studies showing that lupus runs in families. However, pinpointing specific genes that affect susceptibility to lupus in humans has been difficult because no single gene can by itself cause the disease, and the effects of any one gene on disease development are relatively small. This means that researchers doing genetic analyses need to study large numbers of families with lupus to identify individual disease genes.
To increase their chances of identifying genes involved in lupus susceptibility, a team of researchers including Swapan Nath, PhD, and John Harley, MD, PhD, of the Oklahoma Medical Research Foundation in Oklahoma City looked specifically at families with lupus in which at least one SLE patient had symptoms affecting the nervous system, such as seizures or psychotic behavior. Because nervous system symptoms occur in only a subset of people with lupus, the researchers reasoned that people in these families might be more likely to share genes involved in lupus susceptibility, especially genes that may predispose to nervous system symptoms of the disease.
The researchers conducted a detailed genetic analysis of DNA samples from families in which at least two people had lupus. Their results, published in the July issue of Human Genetics, indicate that a specific region on human chromosome 4 is associated with lupus susceptibility in people from families of European-American origin, but not of African-American origin. This association was much stronger in families in which at least one lupus patient had nervous system symptoms.
The findings of this study support the idea that grouping families with lupus according to certain shared characteristics of the disease increases the likelihood of identifying genes for lupus. They also add to evidence from an earlier study indicating that this region of chromosome 4 may be involved in lupus susceptibility. The researchers are now focusing on this area of the chromosome to pinpoint the specific gene that causes lupus susceptibility.
Researchers are also looking for differences in the activity of particular genes in people with lupus compared to healthy individuals, in hopes of gaining clues to the causes of disease. Increasing or decreasing the activity of individual genes in different cell types is one of the main ways in which the body regulates the myriad biological processes that keep us alive and healthy. When gene activity is altered inappropriately, a cell’s normal function may be affected in a manner that contributes to disease.
A recent study led by Peter Lipsky, MD, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Maryland, found that the activity of two genes, called RAG1 and RAG2, is increased in certain white blood cells in the bloodstream of people with active SLE. These white blood cells, known as B cells, are a key component of the immune system. Each B cell has the potential to produce a single type of antibody, and the RAG genes help determine the particular type of antibody that a B cell makes.
Normally, the antibodies produced by B cells help our immune system ward off “foreign” invaders such as bacteria or viruses. However, in people with lupus, some B cells produce abnormal antibodies that attack and damage the body’s own tissues. On the basis of their findings, published in the May issue of Arthritis and Rheumatism, Dr. Lipsky and his colleagues suggest that an increase in the activity of RAG1 and RAG2 genes in certain B cells may contribute to the aberrant antibody response in people with lupus.
What these studies mean for people with lupus: Identifying genes that play a role in lupus and learning what these genes do and how they interact is important for understanding the underlying causes of lupus. Information on the biological basis of lupus gleaned from genetic studies should enable the development of new treatments that target specific factors involved in the disease process, and may even lead to ways to prevent or cure lupus.
Autoimmune diseases such as lupus are caused by a failure in the immune system’s ability to distinguish between invading organisms and a person’s own tissues. As part of this aberrant immune response, B cells in the bloodstream produce abnormal antibodies (“autoantibodies”) that react against molecules from the body, such as DNA and certain proteins, including antibodies themselves.
In the April 11, 2002 issue of Nature, a research team led by Dr. Ann Marshak-Rothstein of Boston University School of Medicine reports that, in mice with systemic autoimmune disease, a “receptor” protein on the surface of B cells, known as TLR9, causes molecules from the body to be recognized by B cells as if they were molecules from disease-causing organisms. TLR9 is part of a family of receptor proteins known as Toll-like receptors (TLRs) that are designed to recognize and react to foreign molecules such as bacterial proteins or bacterial DNA. But in autoimmune disease, the new findings show, TLRs also react to molecules from the body, triggering autoantibody production by the B cell.
These findings “bring together a series of observations that we knew about in lupus but didn’t know how they were connected,” says ALR investigator Robert Carter, MD, of the University of Alabama at Birmingham. Specifically, they show that autoantibodies and DNA circulating in the bloodstream can combine to deliver a one-two punch that results in abnormal activation of B cells and further autoantibody production. The DNA and the different antibodies stick together as a complex. The antibodies bind to one type of receptor on the B cell, which helps the DNA come into contact with and bind to TLR9. Together, these steps help trigger autoantibody production.
What it means for people with lupus: These findings show how certain proteins and DNA circulating in the blood in people with lupus work together to cause disease, and suggest that TLR receptors on autoantibody-producing B cells may be a target for new lupus therapies. “If we can find ways of blocking the TLR receptors, we can probably find new ways to treat lupus,” Dr. Carter says. His ALR-funded research project focuses on another family of receptor proteins that is also involved in controlling the ability of B cells to produce antibodies in response to certain triggering substances. These receptors are activated by a protein from the body known as B lymphocyte stimulator (BLyS). Preliminary research by Dr. Carter and his colleagues indicates that elevated levels of BLyS may play a role in lupus.
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