Division of Rheumatology and Immunology
Department of Medicine
Our overarching goal is to identify mechanisms by which autoantigen-specific B lymphocytes breach immune tolerance barriers to drive autoimmune disease.
B lymphocytes in autoimmune disease: B lymphocytes are immune cells that attack pathogens like flu. Under the wrong circumstances, they can also target "self" proteins to cause autoimmune diseases. Autoantibodies signal this attack is happening, sometimes well before disease symptoms appear. Autoantibodies may directly cause tissue destruction, or they may simply serve as red flags of inappropriate autoreactive T cell-B cell interactions. Our primary research interest is to understand how self-reactive B lymphocytes expand in the repertoire to drive autoimmune disease.
Type 1 diabetes: Several autoantigens (self proteins) are targeted in type 1 diabetes, including insulin. Selective elimination of anti-insulin B lymphocytes prevents type 1 diabetes in a mouse model, highilghting this population of cells as an attractive therapeutic target. We are currently employing high-throughput approaches to interrogate this critical population of autoantigen-presenting cells in type 1 diabetes patients who are in the very early, pre-symptomatic stages of disease. Our long-term goal is to use innovative approaches to study and target this dangerous population of immune cells to hasten development of safe and effective therapies for this devastating disease.
B lymphocytes present insulin autoantigen to drive beta cell attack. Anti-insulin B lymphocytes internalize insulin autoantigen via the B cell receptor (BCR) and present insulin peptide to T cells (A). CD4 T cells produce inflammatory cytokines that promote CD8 T cell attack of beta cells. A small fraction of anti-insulin B lymphocytes differentiate to become antibody-secreting cells, either through T cell-dependent responses that drive somatic hypermutation and affinity maturation (B) or T cell-independent mechanisms (C). Autoantibody does not directly mediate beta cell destruction; rather, it signals T-B cell interaction.
“Hidden” anti-insulin B lymphocytes are detected with anti-insulin mAb. A) Schematic of insulin-binding monoclonal antibody (e.g. mAb123). Insulin autoantigen-occupied BCR are detected by mAb123. B-C) Flow cytometry of VH125Tg/NOD mice, gated on live B220+ IgMa+ lymphocytes. B) Labeled insulin fails to detect highly insulin-occupied B cells in the pancreas. C) mAb123 recognizes anti-insulin B cells that are otherwise obscured from detection due to high BCR occupancy with insulin in the pancreas.