NR4A Family as Markers and Mediators of B Cell Tolerance in SLE: From Antigen Discovery to Treatment
Abstract
Rationale: 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. In recent years, clinical trials have demonstrated that depleting B cells is an effective treatment for several different autoimmune diseases, including systemic lupus erythematosus (SLE). 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 nonspecific B cell depletion. Moreover, identifying such B cells and the specific tissue targets recognized by autoantibodies in SLE 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. Objective and Aims: We have previously shown that a small group of molecules called the NR4A family are expressed at high levels, specifically in self-reactive B cells that encounter and recognize the body’s own tissues. In this grant proposal: (1) we take advantage of the NR4A family to identify these disease-causing B cell populations in patients with SLE; and (2) we propose to couple this approach with a unique and well-validated screening pipeline that we developed for discovering novel autoantibodies and the identity of the tissue targets that they recognize. We do so by leveraging a biological “library” that displays all the different proteins that human cells are capable of producing. This approach will enable us to identify new types of autoantibodies that, paired with the well-characterized clinical data and detailed SLE disease activity from our patient cohorts, will significantly advance our ability to subtype patients based on clinical manifestations of disease and link this to disease outcomes. Furthermore, the ability to identify self-reactive B cells will allow us to determine the genetic program that regulates self-reactive B cells and how this may go awry in SLE. Successful completion of the proposed studies will provide new mechanistic insights into the pathobiology of SLE and pave the pave the way for novel diagnostic and therapeutic approaches to treat SLE. Patient Impact: Through the use of our unique and cutting edge strategies, we will be able to identify new autoantibodies in SLE and identify their tissue targets. This will provide new biomarkers of disease and specific-organ autoimmunity in SLE. Of particular import is our ability to apply this approach for CNS lupus–a poorly understood manifestation of SLE. We anticipate meaningful results within the timeline of this grant that will help clinicians to further subtype patients with lupus.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110979
Entities
People
- Julie Zikherman
Organizations
- United States Army
- University of California, San Francisco