NR4A family as markers and mediators of B cell tolerance across autoimmune diseases: from antigen discovery to treatment
When activated by infection or vaccination, B cells can produce antibodies against foreign invaders. “Self-reactive” B cells can produce autoantibodies, which can mistakenly tag cells in the body as foreign, thereby triggering the immune system to attack. Dr. Zikherman and colleagues previously showed that a small group of molecules—members of the NR4A family—are expressed at high levels in self-reactive B cells. She and her team of co-investigators will take advantage of high NR4A expression in self-reactive B cells to identify such cells in people with type 1 diabetes, multiple sclerosis, and systemic lupus erythematous. The investigative team will couple this with a novel high-throughput phage-display platform to screen samples from people in order to identify specific autoantigens and autoantibodies. The goal of this work is to define targets and genetic programs that guide disease-causing B cells to promote autoimmunity, to identify new disease biomarkers, and to develop new therapeutic approaches to eliminate such B cells selectively.
B cells are an important cell type in our immune system’s normal response to infection and they protect us by producing specialized molecules called antibodies that attach to and clear microbes from the body. Many vaccines work by triggering this critical defense mechanism. B cells also cooperate with other cells of the immune system to eliminate infections from the body. Autoimmune disease can develop when B cells and other immune cells inappropriately attack the body’s own tissues such as insulin-producing cells in the pancreas in patients with type 1 diabetes (T1D), or the insulating sheath that surrounds neurons in patients with multiple sclerosis (MS). In recent years, clinical trials have demonstrated that depleting B cells is an effective treatment for several different autoimmune diseases, including MS and systemic lupus erythematosus (SLE), and can delay onset of T1D. However, individual B cells and the antibodies that they produce recognize a vast range of different structures. Only a small population of “self-reactive” B cells and the so-called “autoantibodies” that they produce are thought to directly contribute to the development of autoimmune disease, while other B cells are important to protect against infection. Selectively eliminating the population of B cells that recognize the body’s own tissues would allow clinicians to maximize therapeutic efficacy while minimizing the risk of infection produced by complete and non-specific B cell depletion. Moreover, identifying such B cells and the specific tissue targets recognized by autoantibodies in different autoimmune diseases could allow us to better understand the causes of autoimmunity, and also to more accurately predict the clinical course and even the treatment responses of individual patients. However, identifying these rare disease-causing B cell populations and the types of autoantibodies that they produce is technically challenging, especially when the tissue targets that they recognize are largely unknown. Here we take a new approach to overcome this obstacle.