Ann Marshak-Rothstein, PhD
University of Massachusetts Medical School
Title: DNA- and RNA-associated autoantigens in the activation of human B cells
The Study and What It Means to Patients
"Support from the LRI will enable us to extend our analysis of the cell components recognized by TLRs in mice to TLR activation in human cell populations, and allow us to identify those patients most likely to respond to therapies directed at blocking specific TLRs.”
Dr. Marshak-Rothstein’s research group was the first to propose that the TLRs could have a primary role in lupus by turning on the immune system to attack the body. Recent animal studies found that one TLR, TLR7, has a harmful role, while another, TLR9, has the opposite effect helping to protect against lupus.
Building on that work, Dr. Marshak-Rothstein is developing a highly innovative experimental approach to pinpoint which specific TLR is mainly to blame for causing lupus in humans. This experimental approach also promises to reveal new targets for therapies that could prevent or arrest lupus.
Dr. Marshak-Rothstein noted, “Support from the LRI will enable us to extend our analysis of the cell components recognized by TLRs in mice to TLR activation in human cell populations, and allow us to identify those patients most likely to respond to therapies directed at blocking specific TLRs.”
Title: DNA- and RNA-associated autoantigens in the activation of human B cell
Members of the Toll-like receptor gene family have been clearly implicated in the development of systemic autoimmune diseases such as SLE. In vitro, RNA or RNA-associated autoantigens can activate TLR7-expressing cells, while DNA or DNA-associated autoantigens activate TLR9-expressing cells. However the specific contributions of TLR7 and TLR9 to the disease process in vivo is less clear; TLR7-deficient mice develop attenuated clinical disease and TLR9-deficient mice develop more severe disease.
We have identified inherent differences in the TLR9/DNA- and TLR7/RNA-driven responses of murine autoreactive B cells consistent with the in vivo phenotype. The goal of the current application is
to determine whether the TLR9/TLR7 dichotomy applies to human Bcells. A critical aspect of this project is to devise a physiologically relevant readout system that reflects both the BCR and TLR signaling components of autoreactive B cell activation and differentiation. Our strategy involves the development of bifunctional antibodies that will enable us to target physiologically relevant autoantigens to BCR-mediated endosome trafficking pathways in human B cells. The outcome of TLR7 vs TLR9 activation will be evaluated in vitro and in vivo.
These studies will further provide a high throughput system for testing TLR-based inhibitors and thereby identify appropriate TLR-based therapeutic targets.