Autoimmune diseases are the second highest cause of chronic illness and the number one cause of morbidity in women in the United States. At least 100 chronic autoimmune diseases have been described that affect over 50 million Americans. As a class of disease, the annual health care burden for autoimmunity is estimated at over $100 billion. Most autoimmune diseases have limited treatment options and cannot be cured. One commonality to all autoimmune disease is the breakdown in immunological tolerance that lets the body's own immune system attack its tissues. While many tolerance mechanisms exist, a role for CD4+Foxp3+ T regulatory cells (Treg) in keeping self-immune responses in check is likely an essential tolerance mechanism for all autoimmune diseases. Thus Treg are considered a strong therapeutic target for the treatment of autoimmunity. To date there are no FDA approved adoptive Treg immunotherapies. Thus alternative approaches must be developed to harness the therapeutic power of Treg. To that end, we have discovered a new mature B cell subset that plays an essential role in the maintenance of Treg homeostasis. Using experimental autoimmune encephalomyelitis (EAE), the mouse model of the human central nervous system autoimmune disease multiple sclerosis, we have shown that in the absence of B cells, mice cannot recover from the signs of disease and Treg numbers are significantly reduced. Upon reconstitution of B cells, Treg numbers significantly increased and the mice recovered from EAE. These data demonstrate that a population of regulatory B cells (Breg) exists that attenuate inflammation indirectly through Treg. Because of their IgDlow/- phenotype, we have named them them B cell IgD Low or BDL. We will test the hypothesis: Single cell transcriptomic analysis on mouse BDL will define a distinct cell cluster with a phenotypic and regulatory gene expression profile that can be used to identify and track hBDL.
Inflammatory diseases if uncontrolled can cause severe tissue damage and even death. We have recently discovered a novel regulatory B cell subset (Breg) that attenuates the severity of inflammatory diseases by maintenance of CD4+Foxp3+ regulatory T cell numbers. This application will further characterize their phenotype and function in both mouse and human.
