Cracking the immune system’s code

Through the lens of his first microscope, a young David A. Hafler, M.D., witnessed white blood cells rushing to attack unwelcome viruses and bacteria. “How could that not be interesting to a child?” he said recently.

Hafler wasted no time acquainting himself with the intricate ecosystem that makes up human blood. At age 10, unable to find an immunologist in the phonebook, he showed up alone for an appointment with a hematologist in his Teaneck, N.J., neighborhood. A skeptical receptionist asked his mother’s whereabouts. Undeterred, Hafler managed a one-on-one conversation with the physician and went home with a hematology textbook.

As an undergraduate chemistry major at Emory University in Atlanta, Hafler continued to follow his passion for immunology. A mentor there, Dale McFarlin, M.D., introduced him to multiple sclerosis (MS)—in which a person’s own immune system attacks the protective myelin sheaths covering his or her nerves.

At that time, the autoimmune disease’s cause and workings remained largely mysterious. “When I started in 1970, there was absolutely nothing for MS patients. They were in wheelchairs,” Hafler says.

Over the next decade, he earned his medical degree from the University of Miami School of Medicine, completed a neurology residency at what was then called Cornell Medical Center/New York Hospital, and worked in the lab of Henry G. Kunkel, M.D., at The Rockefeller University, before joining the Harvard Medical School faculty in 1984.

In 2009 Hafler joined the School of Medicine as chair of the Department of Neurology and neurologist-in-chief at Yale New Haven Hospital. By then he had helped contribute paradigm-altering ideas to the field. For example, in the 1980s, Hafler and colleagues found that MS activates the body’s entire immune system, just like HIV. Working with another group, Hafler conducted research suggesting that MS patients maintain a higher number of T cells, which in turn seem to react to a particular region of a protein that makes up nerve-covering myelin.

This untangling of the major mechanisms of action within MS has allowed Hafler, now the William S. and Lois Stiles Edgerly Professor of Neurology and professor of immunobiology, to tackle ever-intricate aspects of the disease. In 2013, he and colleagues suggested in Nature that increased levels of salt contribute to higher levels of a particular type of T cell, which led mice to develop a disease called autoimmune encephalomyelitis, the mouse equivalent of MS.

In November, Hafler and colleagues published a study in The Journal of Clinical Investigation that details how a high-salt diet likely impairs the ability of T regulatory cells—a subtype of T cell that guards against autoimmune reactions in the body—to function well. Thousands of years ago “we lived in Sub-Saharan Africa on 200 mg of salt [per day],” Hafler says. “Today the average American eats five grams of salt daily.” He recently began a Phase I clinical trial to monitor the effects in humans of switching from a very low-salt diet to a high-salt one.

MS patients today can choose from among 12 medications to keep their chronic disease in check. Despite years of research that has led to better care for patients, Hafler says he has “one big experiment left to do.” He wants to identify the epigenetic factors—environmentally caused, heritable modifications to the way cells read DNA—that could be responsible for the development of MS in the first place.