Autoimmunity: finding common ground

Among researchers who study the adaptive immune system, generally speaking, you’re a T cell person or a B cell person. Kevan Herold, M.D., professor of immunobiology and medicine, studies T cells, so called because they mature in the thymus. Herold’s colleague, Eric Meffre, Ph.D., associate professor of immunobiology, studies B cells, which mature in bone marrow. T cells play a central role in the immune responses mounted by cells themselves; the primary job of B cells, in contrast, is to produce antibodies that target specific pathogens. Both play key roles in immunity, but Herold, an expert on type 1 diabetes, recalls that when he was doing postgraduate work at the University of Chicago in the 1980s, “the T cell people were in one building, and the B cell people were in another building,” he says. “And we never talked to them.”

Thanks to Herold, at Yale, things are moving in the opposite direction. He is a driving force behind the School of Medicine’s recent designation as an Autoimmunity Center of Excellence (ACE) by the National Institutes of Health (NIH), an achievement that Yale scientists see as a catalyst for a new burst of collaborative work on the dysfunctions of the immune system that underlie diverse diseases such as diabetes, lupus, and multiple sclerosis.

“We’re extremely strong in basic immunology, and our immunobiology department is one of the best in the country,” says Robert J. Alpern, M.D., dean and Ensign Professor of Medicine. “What we have focused on in the last five years is to take advantage of our best basic science and use that as a nidus to spin off translational research. And the new emphasis on autoimmunity is an example of that.”

Autoimmune diseases vary greatly in symptoms, but in all cases the underlying cause is the failure of the immune system to recognize one’s own normal cells and tissues as “self”; rather, the immune system mistakes these benign cells and tissues as foreign, and attacks them, causing inflammation and cell death. Because these diseases affect a wide range of organ systems, about 70 Yale Medical Group physicians in diverse specialties treat some form of autoimmune disease. However, the underlying mechanisms in apparently quite different diseases, such as diabetes and multiple sclerosis (MS), are remarkably similar—a fact that has great implications for further research (see sidebar). Yale’s ACE will, Herold hopes, stimulate collaborative research and pave the way for a greater understanding of common mechanisms of and potential treatments for autoimmune diseases.

The ACE program is a collaborative effort between the National Institute of Allergy and Infectious Diseases, the lead institution funding ACE; the Office of Research on Women’s Health; and the National Institute of Diabetes and Digestive and Kidney Diseases, all agencies of the NIH. In late 2009, Herold and Insoo Kang, M.D., associate professor of medicine, applied for and received the grant that established Yale’s ACE, now one of nine such centers in the U.S., which conduct collaborative research among themselves under the auspices of a national steering committee. The ACE grant, which is renewable at five-year intervals, enables the Yale scientists to participate in clinical trials and to initiate trials at Yale. Yale’s ACE will be a center in a trial of a new immunologic in Sjögren’s syndrome—an autoimmune disease of the tear ducts and salivary glands—for instance. And “we are looking into trials for scleroderma,” says Herold.

It is an auspicious time for a melding of efforts in autoimmunity at Yale, says Herold, who came to the School of Medicine three years ago to direct the autoimmunity research in the Department of Immunobiology’s Human and Translational Immunology (HTI) program. HTI, directed by Jordan S. Pober, M.D., Ph.D., professor of immunobiology, dermatology, and pathology, aims to move advances in basic immunology into a clinical setting.

“It was very clear to me, when I came here, that scattered across the campus there were outstanding people doing translational work in autoimmunity,” says Herold, who explores why overactive immune T cells mistakenly destroy the insulin-producing beta cells in the pancreas, causing type 1 diabetes. “But there hadn’t really been an outlet” for translation into clinical trials that would “enable the investigators to get more in depth into the clinically relevant immunologic questions,” he says. “Hopefully this center will do it.”

Crucial to these efforts is the arrival in 2009 of David A. Hafler, M.D., chair of the medical school’s Department of Neurology and Gilbert H. Glaser Professor. Hafler, also chief of neurology at Yale-New Haven Hospital (YNHH), came to Yale from Harvard Medical School, bringing a wealth of expertise in MS. Hafler is a leader in the effort to define the molecular basis and causes of MS, and he was among the first to apply the technique of T cell cloning to human disease, identifying the targets of activated immune cells in MS patients.

But in keeping with Yale’s focus on the commonalities of autoimmune diseases, Hafler has also done extensive research on the mechanisms of type 1 diabetes, and currently has an NIH-funded grant to study that disease. “If you look at the genetics of autoimmune disease, there’s a striking commonality of genetic variants. Presumably there is also an underlying similarity in terms of the immune system,” Hafler says. “We don’t truly understand the pathogenesis of any of these diseases at the level that we want to, but they have a commonality in terms of treatment. Some treatments are different, some are very similar, and some are paradoxical,” he says, citing as an example anti-TNF, which improves rheumatoid arthritis symptoms but seems to worsen MS. “These curious paradoxes give us great insight into these diseases. It’s not a luxury—it’s almost a requirement—to look to the mainstream science of immunology to explain these things.”

Meffre, who joined the immunobiology faculty in 2008 and whose research is focused on B cell tolerance (the extent to which these immune cells are reactive or nonreactive to self), has uncovered similar functional abnormalities in B lymphocytes from patients with type 1 diabetes, rheumatoid arthritis, and lupus. For Meffre, the ACE grant has already led to increased collaboration with other Yale scientists. As part of one ace project, for instance, a former colleague in Paris sends Meffre samples from Sjögren’s syndrome patients, which he analyzes for B cell function. But Meffre also shares these samples with Kang, who studies T cells. “There’s a lot of overlap in our research,” Meffre says.

A push for contiguous laboratory space is another aspect of Yale’s new collaborative research in autoimmunity. Though the particulars are yet to be determined, a group of principal investigators is slated to move this year into a single interdisciplinary autoimmunity lab dedicated exclusively to human studies. The new centralized laboratory space will also house scientists working in transplant and tumor immunology and in neurology.

“This new center for research on human autoimmunity,” Herold says, “will be a very exciting place.”