Why anyone develops an autoimmune disease is one of the central puzzles in immunology. Scientists recognize that genetic and environmental factors play a role, "but how these two interact to cause autoimmunity is still a mystery," says Yaron Tomer, a professor of medicine at the University of Cincinnati.

The mystery unfolds with this observation: Even in autoimmune diseases considered to have a strong genetic component, the concordance rate in identical twins is often relatively low. For example, the concordance for monozygotic twins with multiple sclerosis is around 30%, for rheumatoid arthritis (RA) between 12% and 30%, and for systemic lupus erythematosus (SLE) between 24% and 69%. Such numbers leave plenty of room for environmental factors that can trigger these diseases.

Unfortunately, according to Tomer, it isn't easy to sort out the genetics from the environment. "Each one is complex in its own right," he says. In the 1980s, many researchers focused on the environment, especially on the involvement of infectious agents in autoimmunity, he recalls. However, "once the genetic revolution started in the mid-1990s, making identification of complex-disease genes feasible, genetic studies became the preferred approach to dissecting the etiology of autoimmunity." Few scientists are studying both the genetics and environment together because it's very complex, Tomer says.

Frederick Miller, chief of the environmental autoimmunity group at the National Institutes of Health agrees. "We know of a number of genetic-risk factors for different autoimmune diseases," he says, "but we are sure of many fewer environmental-risk factors, and the number of true gene-environment interactions that we know of is very few indeed."

The gene hunters have found several susceptibility genes. High on the list are the genes that code for the human leukocyte antigens (HLA) - the major histocompatibility complex (MHC) proteins on cell surfaces that allow the body to identify self from non-self. One of the strongest associations between an HLA polymorphism and an autoimmune disease appears in ankylosing spondylitis, an inflammatory disease of the vertebral joints. Individuals who carry the HLA-B27 allele are 90 times more likely to develop the disease compared to those with another HLA-B allele.

Immune-regulatory genes are also key players in autoimmunity. Polymorphisms of the cytotoxic T-lymphocyte-associated protein-4 ( CTLA-4 ) gene, which downregulates T cells to prevent exaggerated responses to infection, are clearly associated with thyroid autoimmunity, type I diabetes, RA and a number of other autoimmune diseases. Other sequences - including genes that encode cytokines, cytokine receptors, T-cell receptors, and immunoglobulins - are less strongly linked to autoimmunity than some of the MHC polymorphisms, but they are undoubtedly important.

So what kind of environmental hits might trigger autoimmunity in the genetically predisposed? A lineup of environmental suspects usually includes infectious agents, drugs, ultraviolet light, cigarette smoke, solvents, and pesticides. But there's a sundry assortment of other chemicals and environmental intangibles, such as psychosocial stress, that are also considered to be possible risks.

The classic example of an environmentally triggered autoimmune disorder is gluten-sensitive enteropathy, or celiac disease. The condition is elicited by eating wheat gluten and related cereal proteins, which induce an inflammatory response in the small intestine that typically results in abdominal pain, weight loss, and weakness. The patient's woes abate when these proteins are eliminated from the diet.

Gluten sensitivity is closely linked to two HLA genes that are expressed in antigen-presenting cells. It turns out that 90% of the patients with celiac disease have the HLA-DQ2 antigen, and most of the remainder carry the HLA-DQ8 antigen. These molecules present specific gluten peptides to T cells in the small intestine, which initiates a chain of events, including the formation of autoantibodies that damage the tissues of the bowel. Scientists are still sorting out all the molecular mechanisms involved in celiac disease.

There are some other examples of gene-environment connections (see sidebars), but few show such a tight coupling between a gene and a specific environmental factor. In most instances, a number of factors must conspire to cause an autoimmune disease. In that respect, autoimmunity has been likened to cancer.

"There is no single event that makes a cell become cancerous," says Virginia Rider, a researcher who studies the etiology of SLE at Pittsburgh State University in Kansas. "A cell often experiences a number of genetic and environmental ‘hits' before it's no longer capable of regulating its own reproduction. It may be the same with autoimmunity," she says.

The scientists who search for these hits readily admit that their work is just beginning. "I don't expect any immediate breakthroughs," says Miller. "I suspect it will be incremental as new approaches and technologies are developed."

By most accounts, the search for gene-environment interactions in autoimmunity is a relatively neglected area of research. "There have been too few national efforts to coordinate registries or information, so that groups can pool their resources," says Miller.

Miller also thinks that most of the limited resources have gone into studying the genetic side of autoimmunity. "We need to put more effort into the environmental side to really develop the technologies, the collaborations, and the national and international efforts to achieve the power to do these studies properly," he says. The new NIH "Genes and Environment Initiative" to support research on genetic contributions and gene-environment interactions in common disease is a start in this direction, according to Miller.

Even so, part of the problem is that research in autoimmune diseases is generally under-funded considering their incidence and cost to society, according to Virginia Ladd, director of the American Autoimmune Related Diseases Association (AARDA), a national health agency that promotes research, education, and awareness of autoimmune diseases. "Up until the last decade, autoimmune diseases were not looked at collectively," she says. "With few exceptions the autoimmune diseases are relatively rare, so it's been hard to do environmental studies on them," she adds.

So what's the payoff for studying gene-environment interactions? Ultimately, they may be the key to prevention of autoimmune disease, according to Noel Rose, director of the Johns Hopkins Center for Autoimmune Disease Research. "The reason I'm so oriented toward the environmental side is that we might prevent these diseases by identifying the people who are genetically susceptible and then making sure they don't come in contact with the environmental agent," he says.

Rheumatic heart disease, caused by repeated streptococcal infections in young people, serves as one example. Today, when a child becomes ill with rheumatic fever, physicians prescribe antibiotics, which prevent recurrences of the infection. Consequently, rheumatic heart disease rarely develops. That's at least one instance of autoimmunity that can be prevented by a better understanding of the environmental trigger.