The anatomy of autoimmune disease

What do diabetes, Crohn’s disease, psoriasis, and multiple sclerosis have in common? From the outside, not much: they affect different organs and have vastly different symptoms. But each is an autoimmune disease, and new research, identifying genes and cell types responsible for such diseases, reveals just how much they have in common.

“What we showed is that, to some extent, autoimmune disease is one fundamental entity with many variations,” says David A. Hafler, M.D., chair and the William S. and Lois Stiles Edgerly Professor of Neurology, professor of immunobiology, and a senior author of the paper.

In all autoimmune diseases, the body’s immune system gangs up on a person’s own cells. If the immune system attacks skin cells, the redness and itching of psoriasis can result; if it attacks pancreas cells, type 1 diabetes; if it turns against cells lining the intestines, ulcerative colitis or Crohn’s disease. As a whole, autoimmune diseases—which affect an estimated 50 million Americans—are tricky to treat, and their causes are poorly understood.

Previous research on individual autoimmune diseases have used genome wide association studies (GWAS) to narrow down which areas of DNA within the human genome are linked to disease. But the areas of the genome identified in GWAS can contain many genes.

Hafler and his colleagues at the Broad Institute of MIT and Harvard wanted to home in on specific genes linked to autoimmune diseases. To do so, they analyzed 39 previous GWAS studies, spanning 21 different diseases, using new software and data analysis techniques. Says Hafler, “We went from a large region of DNA that’s implicated in a disease to the precise gene change that’s likely responsible. I call this a post-GWAS understanding of disease.”

By mapping certain molecular features within these areas, the team discovered that many autoimmune diseases aren’t caused by variations in genes that encode proteins, but by changes to “enhancers,” elements in the DNA that can turn on nearby genes. If an enhancer is altered, a whole slew of genes it controls can be flipped on or off at once. In the case of many autoimmune diseases, the scientists reported February 19 in the journal Nature, the affected enhancers go on to affect immune genes. And, they found, many genes overlapped between diseases—affecting both Crohn’s disease and rheumatoid arthritis, for example.

But the team didn’t stop with the identification of genes and enhancers associated with the autoimmune diseases. Next, they studied which cell types each genetic change was active in. “If you have a genetic change in a region where the DNA is tightly wound up, that change is unlikely to make a difference to that particular cell,” Hafler explains. But in other cells, the DNA containing the genetic variant could be more “open” and thus accessible for DNA transcription, suggesting that the variant is influencing the cells’ function.

Some findings were expected: the DNA regions linked to ulcerative colitis, for instance, were activated in immune cells and mucosal cells lining the digestive system. But others were more surprising—the genetic variants associated with multiple sclerosis seemed to be inactive in brain cells, only making a difference in immune cells themselves.

“What this work does is provide, for the first time, a landscape as to how genetic variants are causing autoimmune disease,” Hafler says. “That landscape—the molecular events and cell types involved—is a critical step in understanding disease.”

While that step of pinpointing important genes and cell types requires more refinement to more fully reveal the cause of autoimmune diseases, it does pave the way toward drugs that can block the immune system from its unwarranted attack, Hafler says. It also shows just how effective new techniques can be at moving from GWAS results to specific genetic changes that cause disease. And that, he says, is useful for studying not only autoimmune disease, but everything from heart disease and Alzheimer’s to cancer.