Immune tolerance in autoimmune and inflammatory diseases
The Kendall lab studies the role of B lymphocytes in Type 1 diabetes (T1D). Our long-term goal is to selectively block the survival and function of autoreactive B lymphocytes in this disease, while leaving normal cells available to fight infection. To do this, we study both autoreactive cellular activities in inflamed tissue, and B lymphocyte signaling events that allow the emergence and pathogenic function of autoreactive cells.
B lymphocytes promote T1D by acting as essential antigen-presenting cells to autoreactive T cells. Those T cells then mediate the destruction of pancreatic islets, resulting in loss of insulin-production, with downstream hyperglycemia and diabetes development. Inflamed pancreatic islets contain both T and B lymphocytes, organized into tertiary lymphoid structures (TLS). We use the nonobese diabetic (NOD) mouse to investigate the identity and function of these islet-invading B lymphocytes. We have discovered that B lymphocytes in diseased pancreas have a polyclonal repertoire overall, but are oligoclonal in each islet. The B cell repertoire is distinct from that in draining pancreatic lymph nodes, indicating a selective process in the inflamed tissue. The B cell receptors (BCRs) in these islets show evidence of somatic hypermutation (SHM), suggestive of T-B cellular interactions. We have also found that the B lymphocyte chemoattractant CXCL13 supports T-B cellular organization in the TLS. Surprisingly, TLS organization in this setting proves to be unnecessary for the selection of the B lymphocyte repertoire into the target tissue, for SHM of BCRs, or for diabetes development. Therefore, while TLS in nonimmune tissues appear morphologically similar to secondary lymphoid tissues, they may differ in important ways, including B lymphocyte antigenic selection, repertoire maturation, and the chemotactic factors underlying cellular recruitment and organization. Additional experiments have shown that autoreactive B cells infiltrate the islets, while nonautoreactive B cells do not, resulting in T-cell insulitis that does not cause diabetes. A future goal is to understand the factors that govern the trafficking and selection of these B lymphocytes into inflamed islets, and to develop methods of blocking islet infiltration.
A second line of investigation regards the contribution of B lymphocyte signaling to autoreactivity in T1D. Brutonâ€™s tyrosine kinase (BTK) contributes to the propogation of signals from the BCR, leading to downstream calcium flux and nuclear translocation of transcription factors, including NFÎºB. BTK is a multidomained cytosolic tec kinase that serves as an adaptor, as well as a kinase, molecule. It is critical to B lymphocyte, but not T lymphocyte function. We have discovered that BTK supports T1D in the NOD model. Genetic depletion of BTK from NOD mice resulted in significant disease protection (83% healthy, vs. 31% of BTK-sufficient littermates), even though 90% of the B lymphocyte population in these mice survived. Disease-protection was abrogated by introduction of a transgenic anti-insulin BCR that forces the emergence of autoreactive B cells. We are now working to characterize the specific mechanisms underlying disease protection in this model, and to test the ability of specific BTK-inhibitors to prevent and reverse T1D.