Epigenetic regulation of pathogenic B cells in SLE

B cells are the cells that make antibodies. Some of them make autoantibodies , which target own tissue for immune response. In healthy people, those cells that make autoantibodies are destroyed. But in lupus and other autoimmune disorders they are not, so the autoantibodies they make interfere with the body’s own tissues. Dr. Sanz studies how and why they are able to thrive in people with lupus. He has found that even at a very early phase in their development, these B cells already have lupus-specific genetic changes that allow them to continue growing when they should be destroyed. This is especially true in African Americans with severe lupus. Dr. Sanz plans to use the Distinguished Innovator Award to further probe the genetic pathways that allow these misguided B cells to mature in lupus patients. This work should help researchers develop more personalized therapies and will build on Dr. Sanz’s earlier research in which he showed that a drug that eliminates B cells can be effective in treating lupus.

What this study means for people with lupus:

“Determining how B cells that make autoantibodies thrive in lupus patients, and in different ethnic and clinical subsets of patients, will help us devise more personalized and effective therapeutics,” said Dr. Sanz.

SLE is a disease of B cell hyperactivity with generation of multiple autoantibodies that mediate tissue damage through diverse mechanisms. Physiologically, the danger of a pro-autoimmune B cell compartment is avoided by efficient enforcement of B cell tolerance and purging or inactivation of autoreactive B cells of pathogenic potential. Accordingly, the establishment of a mature pro-autoimmune B cell compartment is a critical step in SLE pathogenesis. While the presence of this compartment is well recognized, the mechanisms leading to its establishment and its subsequent activation remain poorly understood. Taking advantage of our description of the key cellular players in the peripheral B cell compartment of SLE patients, we have begun to unravel the molecular networks underpinning the dysregulation of Lupus B cells. In particular, we have demonstrated that resting naïve B cells are already imprinted with a disease-related epigenetic program that primes these cells to vigorously differentiate into effector B cells through an extrafollicular pathway, particularly in African American patients with severe SLE. In this project, we will apply state-of-the-art single cell technology and computational tools to elucidate the molecular underpinnings of abnormal B cell development and activation in SLE, through 3 specific aims: Aim 1. To define the regulome underlying the development of SLE pro-autoimmune B cells Aim 2. To understand the epigenetic regulation of disease-specific autoreactive mature B cells Aim 3. To understand effector B cell pathways in SLE Understanding the specific molecular programs responsible for B cell dysregulation in SLE will be central to developing new classification, prognostic and therapeutic approaches. Moreover, understanding how different ethnic and clinical groups differ in these programs will allow for focused interventions targeted to the appropriate molecular defects within each group, thereby leading to safer and more effective approaches. Specifically, a precise understanding of epigenetic modification will open the door to the use of epigenetic modifiers that could be used to either induce disease remission or more likely and at least equally desirable, to maintain remission and change disease course after B cell depletion and/or prevent disease progression in at-risk patients. Finally, the results expected from our studies should greatly contribute to our ability to define SLE heterogeneity at a cellular and molecular level.