Our laboratory investigates the basic mechanisms of B cell tolerance and translates these findings for intervention in autoimmune diseases.
Humoral immunity is highly effective for host defense because the B cell repertoire has an enormous potential for generating immune receptors. The “dark side” of this diverse immune repertoire resides in the generation of B cells whose receptors react with self antigens (i.e. are autoreactive). Accordingly, we seek to understand the mechanisms that prevent the emergence of potentially toxic B cell clones and antibodies.
Such mechanisms are broadly termed “immune tolerance” and every immune response must first negotiate checkpoints of immune tolerance before effective host defense can be generated. In autoimmune diseases, however, these checkpoints fail and autoagressive clones emerge. An important example of this process is the appearance of antibodies to insulin that predict autoimmune destruction of pancreatic beta cells leading to type 1 diabetes.
To understand this critical breach in immune tolerance, we developed NOD mice that harbor anti-insulin Ig transgenes. These mice permit us to track the fate and function of insulin binding B cells that are obscure in the normal repertoire.
Using these mice we identified flaws in checkpoints that permit emergence of anti-insulin B cells from the bone marrow. Further, we find that anergic B cells may retain functional properties that effect T cell activation in the periphery.
The role of autoantigen specific B cells in antigen presentation, islet invasion, and CD4 T cell function is being examined. In addition, we have discovered that some B cells invading islets express receptors that bind antigens other than insulin. We are currently capturing these receptors and using them to identify novel beta cell antigens that are targets in T1D.
Images from left to right:
- H&E Stain Showing Lymphocytes Infiltrating an Islet Immunofluorescent Staining of B Lymphocytes (Red) and T Lymphocytes (Green) Invading an Islet to Form Tertiary Lymphoid Structures
- Immunofluorescent Staining of B Lymphocytes (Red) and T Lymphocytes (Green) Invading an Islet to Form Tertiary Lymphoid Structures
- Key Contact Sites for Antibody Binding on Insulin
- Lymphocytes Invade the Pancreas
- Increased Marginal Zone B Cells in Mice Harboring Anti-Insulin 125Tg