Christophe O. Benoist, M.D., Ph.D., and Diane J. Mathis, Ph.D.

Since 1983, scientific partners Diane J. Mathis, Ph.D., and Christophe O. Benoist, M.D., Ph.D., have focused their research on the control of immune responses. In particular, they seek to understand why the immune system destroys the body’s own organs during autoimmune diseases like type 1 diabetes and rheumatoid arthritis. The Benoist/Mathis laboratory has used powerful and advanced techniques of molecular biology and genetics to study this problem.

In 1999, Drs. Benoist and Mathis came to Joslin to jointly head the Section on Immunology and Immunogenetics. Here, their laboratory continues to focus on understanding the genetic and cellular mechanisms that underlie autoimmune diseases.

Diseases such as diabetes result from the misdirected action of T lymphocytes, a type of white blood cell that normally protects from infections but can also turn against the body’s own organs. Regulatory cells and genes normally keep these T cells in check, but in autoimmune diseases these barriers are overrun. The main goal of the laboratory is to understand why these safeguards fail, and how they are affected by the genetic variations that predispose to autoimmunity.

In several instances, this work involves translating discoveries made in mice to applications for patients with diabetes. For example, using advanced DNA-chip techniques, the lab recently discovered that a particular subset of immune cells called natural killer (NK) cells plays a key role in the rapid destruction of pancreatic cells in diabetes-susceptible mice. These NK cells, which normally protect against viruses or tumors, are proving noxious in combination with autoimmune T cells. Blocking the NK cells strongly prevents diabetes in mice. In collaboration with colleagues at Joslin Clinic, researchers in the lab have uncovered suggestive variations in NK cells of people with diabetes.

Similarly, working with colleagues at Massachusetts General Hospital, several fellows in the lab discovered that autoimmune attack of the pancreas is accompanied by changes of blood flow in the islets, which can be imaged by external magnetic resonance imaging. These techniques are being translated to determine whether they can be used to detect autoimmune attack in at-risk patients, or to monitor the positive effect of treatments.

In 2002, the laboratory described the function of a protein, dubbed AIRE (autoimmune regulator), which is critical in helping immune cells learn to recognize and avoid attacking the far-flung organs and tissues of the body—pancreatic islet cells, for example. The protein appears to work in the thymus (a gland located above the heart), where new T lymphocytes learn to distinguish between self and foreign proteins.

Building on the work of other groups, researchers in the lab reported that the medullary epithelial cells (a small network of thymic cells) express hundreds of genes characteristic of organs throughout the body, such as the pancreas, brain or eye. Researchers believe that the thymus uses the proteins produced by these genes to teach the developing T cells which self-antigens they will encounter in the different organs and tissues of the body. Thus the thymus may be considered an immunological “self-shadow.” The discovery of this important mechanism for controlling autoimmunity could shed light on how the healthy immune system develops tolerance to its own proteins and how tolerance is lost, as it is in diabetes, multiple sclerosis and other autoimmune diseases.

This line of research contributes to an understanding of other autoimmune diseases. Drs. Benoit and Mathis reported on a surprising set of factors contributing to joint destruction during the development of rheumatoid arthritis in mice, and how a particular responsiveness of blood vessels around the joint may account for some of the manifestations of arthritis. In so doing, they are providing new insights into the mechanisms underlying the pathogenesis of this disease and are stimulating searches for new therapeutic agents.

Biographical Sketches
Drs. Mathis and Benoist head the Section on Immunology and Immunogenetics at Joslin, hold the William T. Young Chair in Diabetes Research and are Professors at Harvard Medical School. Dr. Mathis is also the Director of the Juvenile Diabetes Research Foundation (JDRF) Center on Immunological Tolerance in Type 1 Diabetes at Harvard Medical School. Dr. Mathis received her doctoral degree from the University of Rochester in 1977. She was a postdoctoral fellow at the Laboratoire de Génétique Moléculaire des Eucaryotes in Strasbourg, France, when she became associated with Dr. Benoist, who received his medical degree from the Université Paris VII and his doctoral degree from the Université Louis Pasteur in Strasbourg. They were both postdoctoral fellows at Stanford University Medical Center from 1981 to 1983, when they returned to France and established a laboratory at the Institut de Génétique et de Biologie Moléculaire et Cellulaire in Strasbourg.

The Mathis/Benoist laboratory moved to Joslin Diabetes Center in 1999. In 2003, Dr. Mathis was elected to membership in the prestigious National Academy of Sciences, and Dr. Benoist received this honor in 2005; Dr. Benoist is also a member of the French Académie des Sciences. They have won numerous awards including the Romancon Prize and the Foundation Athena Research Prize.

Selected References
Turvey SE, Swart E, Denis MC, Mahmood U, Benoist C, Weissleder R, Mathis D. Noninvasive imaging of pancreatic inflammation and its reversal in type 1 diabetes. J Clin Invest 115:2454-2461, 2005.

Zucchelli S, Holler P, Yamagata T, Roy M, Benoist C, Mathis D. Defective central tolerance induction in NOD mice: genomics and genetics. Immunity 22:385-396, 2005.

Poirot L, Benoist C, Mathis D. Natural killer cells distinguish innocuous and destructive forms of pancreatic islet autoimmunity. Proc Natl Acad Sci U S A 101:8102-8107, 2004.

Turley S, Poirot L, Hattori M, Benoist C, Mathis D. Physiological beta cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J Exp Med 198:1527-1537, 2003.

Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D. Projection of an immunological self shadow within the thymus by the aire protein. Science 298:1395-1401, 2002.

Matsumoto I, Maccioni M, Lee DM, Maurice M, Simmons B, Brenner M, Mathis D, Benoist C. How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease. Nat Immunol 3:360-365, 2002.