Metabolic Target Identification in Age-Associated B Cells
Abstract
B cells are cells of the immune system that make antibodies. Antibodies are proteins that target invading pathogens for destruction. The immune system of a healthy person is self-tolerant; in other words, the immune system normally does not attack the cells and organs of one’s own body. However, in lupus and other autoimmune diseases, self-tolerance breaks down, and B cells make antibodies to one or more components of self. These autoantibodies contribute to disease symptoms. Nobody knows how self-tolerance is breached in autoimmune individuals, or why people with disease continue to produce these pathogenic antibodies. We recently discovered a tolerance checkpoint that raises a barrier to B cells responding to one type of self-molecule. We found ways that the checkpoint could be circumvented, leading directly to a type of B cell that is strongly associated with lupus called T-bet-positive age-associated B cells (Tbet+ ABCs). The tolerance checkpoint can be envisioned as a network of molecules that are in a resting state inside a mature B cell. When the B cell is activated by encounter with a component of self, one of two things can happen: the cell divides briefly and then dies; or the cell survives, and eventually becomes a Tbet+ ABC that can give rise to antibody producing cells. We have so far identified several key molecules in this network that influence this death-versus-survival fate. Now our objective is to characterize the metabolic architecture that underlies formation and survival of ABCs. Until recently, metabolism was thought to only play a housekeeping role that was similar in all cell types. Research of the past decade has shown that instead, different metabolic processes play very different roles, even within the same cell lineage. The studies proposed here are designed to delineate the metabolic pathways that support and promote the development of Tbet+ ABCs. The overarching objective is to identify candidate molecules within these pathways that could be targeted to reduce or eliminate Tbet+ ABCs, thereby preventing their contribution to the build-up of pathogenic autoantibodies. The ultimate applicability of the work is in the development of new and more precisely targeted therapies to mitigate or prevent some symptoms of lupus, thereby improving patient quality of life. The time to a patient- related outcome is measured in years for several reasons; for example, candidate target molecules identified here would first require validation in cultured human cells and in live animal models of health and lupus.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310264
Entities
People
- Michael P Cancro
Organizations
- United States Army
- University of Pennsylvania