More MS news articles for Oct 2001

Autoimmune diseases could share common genetic etiology

An emerging understanding of this link may lead to important therapeutic advances in diseases such as rheumatoid arthritis, MS and lupus.

Oct. 8, 2001
By Mark Moran,
AMNews correspondent.

From rheumatoid arthritis to multiple sclerosis, lupus and inflammatory bowel syndrome, genetic research is proving that autoimmune diseases may be "all in the family."

By now, physicians are used to hearing that the Human Genome Project has yielded more complexity than simplicity when it comes to understanding most human disease. But experts say that when it comes to autoimmune disease, genetic research is demonstrating a remarkable commonality -- a shared genetic etiology that may clarify the basic pathophysiology of a host of diverse conditions and lead to real therapeutic advances against more than one.

Daniel Kastner, MD, PhD, chief of the genetics and genomics branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, says this genetic commonality points the way toward a unifying understanding of the autoimmune diseases -- a view that they are an abnormal inflammatory response to infectious agents or other environmental insults that might be otherwise innocuous to people not carrying a specific combination of genes. And that may someday be good news for doctors treating conditions that have markedly different clinical presentations but still may run in families.

"If there are common pathogenic mechanisms, it means that if you target one you may have a salutary effect on other conditions," Dr. Kastner says. "So our job may be a little bit easier in terms of coming up with efficacious therapeutic targets."

The most recent evidence for genetic commonality in autoimmune disease emerged from a genome-wide study of 257 families with 301 sibling pairs who have rheumatoid arthritis. That study revealed linkages to mutations occurring in broad regions of several chromosomes already linked to other autoimmune diseases: systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis and ankylosing spondylitis. Among those regions is a dense complex of genes known as the HLA complex, some of which are known to be involved in immune response.

Peter Gregersen, MD, a lead author of the study, says the findings contribute to an emerging consensus that rheumatoid arthritis is an autoimmune disorder and that it shares a common genetic heritage with other autoimmune conditions.

"It is not at all random that these same regions keep coming up," says Dr. Gregersen, director of the center for genomics and human genetics at the North Shore Long Island Jewish Research Institute, New York. "If you had to put your money down, you would say there is some resemblance in the mechanism of all these diseases, which is reinforced by the fact that these diseases may run in families."

Dr. Gregersen is leading another multisite study seeking to enroll large aggregations of families with multiple autoimmune disorders.

That study hopes to investigate the underlying genetics of eight core diseases: rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus, multiple sclerosis, autoimmune thyroid disease, type I diabetes, psoriasis and inflammatory bowel disease.

"We hope to figure out how these genes interact to cause juvenile diabetes in one person and rheumatoid arthritis in another, yet with some underlying commonality," Dr. Gregersen says.

While much work remains to identify the exact locations of those genes, the broad genetic commonality across autoimmune conditions already has implications for treating physicians, Dr. Kastner says.

"The take-home message for doctors from these common susceptibility genes is that they will have to look in the families of their rheumatoid arthritis patients for other conditions as well," he says. "In terms of screening, one has to think not just that a relative might have rheumatoid arthritis, but also multiple sclerosis or lupus. There are common themes across these different conditions."

Rheumatoid arthritis and most other autoimmune diseases continue to be regarded as "complex" conditions, involving a host of genetic mutations in complicated interaction with any number of environmental factors.

Yet the complexity of these disorders is yielding to a new understanding of how the mutations may have evolved over time in response to infectious agents in the environment.

Evolutionary role for single mutations
Dr. Kastner notes that the recent work on rheumatoid arthritis grew out of previous work looking at the genetics of several "monogenic" autoimmune diseases -- conditions which, unlike RA or lupus, can be traced to a single genetic mutation.

Such conditions include familial Mediterranean fever, an inflammatory disease common in Jewish, Arab and Italian populations, which Dr. Kastner's laboratory mapped in 1997 to a specific gene on chromosome 16. Others are familial Hibernian fever, first described in Irish families but now recognized in many ethnic groups, and Muckle-Wells syndrome, an inherited condition predisposing individuals to periodic fevers and deafness.

The common denominator is that the single genetic mutation may result in an inflammatory response to an event -- such as exposure to an infectious agent -- that would be innocuous in persons not carrying the mutation. And the conditions follow a distinctive familial pattern, with siblings of patients having a 25% to 50% chance of also having the disease.

"In the single gene diseases you have a clear pattern of inheritance," Dr. Kastner says. "You see the disease being passed from parent to child."

But for rheumatoid arthritis, lupus and other complex autoimmune diseases, the picture is more complicated. Depending on the family, an identical twin of a patient with rheumatoid arthritis may have only a 15% to 30% risk of also having the disease. "That tells you right away there are other factors involved," he says. "The mode of inheritance is probably caused by several genes interacting with one another and environmental influences."

That has led to an intriguing hypothesis: Some of the genetic mutations involved in complex autoimmune disease -- when they appear by themselves -- may actually have evolved to be protective against infectious agents.

But when two or more mutations occur in the right combination with exposure to infection or other environmental event, the result may be the distinctive pathophysiologic pattern of autoimmune disease, an abnormal inflammatory response leading to an attack on the body's own defenses.

Dr. Gregersen says the theory has a lot going for it. "One has to explain the fact that the HLA gene, for instance, is incredibly common," he says. "It must be there for a reason, and most of the time it's probably doing some good. But in the setting of other predisposing genes, chance events, and environmental exposure, you get disease."



Multiple Autoimmune Disease Genetics Consortium, supported by the National Institutes of Health ( )