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The machinery of immune systems

Joseph Craft, MD
Photo by Robert A. Lisak
Joseph Craft, MD

From a young age, Joseph Craft, MD, FW ’85, the Paul B. Beeson Professor of Medicine (Rheumatology) and professor of immunobiology, adopted a problem-solving approach to chores on his childhood 300-acre farm in rural North Carolina. If a piece of farm machinery shuddered to a stop in the middle of a cornfield, Craft inspected every piston, rod, and washer in the engine to diagnose the problem. If one of his calves fell ill, he needed to find out why. “You develop a curiosity about all kinds of things,” Craft said.

In college, Craft honed his curiosity in chemistry, which laid the groundwork for a career devoted to understanding the immune system—particularly antibodies. Antibodies are proteins formed to bind to and attack antigens—structures located on the surface of invading viruses, bacteria, and other foreign molecules that can trigger an immune response. Chemical interactions form an important part of the antigen-antibody relationship.

When Craft was a first-year medical student, he helped care for a patient with systemic lupus erythematosus (SLE), an autoimmune disease that has no cure as of 2020. Craft decided then that he wanted to understand immunology through lupus. “It was a very mysterious disease at the time,” Craft said. “It still is, but we know a lot more about how it works.”

Since he arrived at Yale in 1980, Craft’s immunology research has focused on how lupus develops, along with different aspects of the immune system’s response to foreign pathogens and vaccines. He directs the Investigative Medicine Program for physicians who earn a PhD while gaining experience in the lab or in-patient research. In 2004, he won Yale’s prestigious Charles W. Bohmfalk Prize for teaching in the basic sciences and is a fellow of the American Association for the Advancement of Science.

Yale Medicine Magazine discussed antibodies and inflammation with Craft, as well as follicular B helper T cells (TFH), which his laboratory also studies, and which could play a future role as a therapeutic target for lupus.

Lupus is an autoimmune disease. Briefly, what’s going on in the immune system when it develops? Our immune system produces antibodies, proteins that circulate in the blood, that protect us against infections. The cells that make antibodies are called B lymphocytes. When you get a flu vaccine, for example, the vaccine initiates production of antibodies by B lymphocytes, which lead to protection against flu infection. This is a well-regulated process, and vaccines are quite safe. In patients with lupus, however, the immune system is not regulated properly, and patients with lupus develop antibodies against DNA and RNA, which are in every cell. Antibodies directed against components of one’s own cells are called autoantibodies. Autoantibodies bind to the individual’s tissues, damaging organs, especially the skin, joints, and kidneys in lupus. As a consequence, the majority of patients with lupus have skin and joint inflammation, and about half of patients will have kidney disease.

How does inflammation figure into this? Autoimmunity is a response of the immune system against itself. If not properly regulated, autoimmune attacks lead to tissue inflammation and ultimately damage, if not properly treated.

How do follicular B helper T (TFH) cells figure into this process? We are trying to understand how TFH cells contribute to inflammation in lupus and what drives chronic inflammation. TFH cells largely function in your spleen and lymph nodes. B lymphocytes’ production of protective antibodies, after flu shots for example, absolutely requires help from a second T helper lymphocyte. The latter are called follicular helper T cells, as they reside in special areas of the spleen and lymph nodes, the follicles where B lymphocytes also reside. An analogy would be if you are lifting a sofa, you can lift one end, but you’ll need help with the other end. Now we are trying to understand the basic biology of TFH cells—how they function and survive, as well as how they help B lymphocytes make antibodies. We’ve identified how they are activated and new ways to characterize them. In lupus, T follicular helper cells are also required for production of tissue-damaging autoantibodies.

Would TFH cells be a good target for a potential new drug for lupus? We have shown that targeting TFH cells could help symptoms of lupus, but we are trying to determine which mechanism of TFH cells to target, and how to do this effectively and safely.

What stands out in your more than 30 years here at Yale? Yale is a special place to do research and care for patients because of the dedication, expertise, and intellect of the students, staff, and faculty. I’ve learned so much from these colleagues, shaping how I care for patients and do science. What is most impressive are the students and trainees. Their intellect, capacity for work, their curiosity—it’s just mind-boggling. One can’t help but make contributions in an environment like this.