B-Cell Activation and Tolerance Mediated by B-Cell Receptor, Toll-Like Receptor, and Survival Signal Crosstalk in SLE Pathogenesis
Abstract
We previously found that B cell receptor (BCR)-delivered TLR9 agonists initiate a response involving proliferation followed by abrupt cell death; furthermore, responding cells are rescued by survival cytokines. We posited this as a normal immune response-limiting mechanism that, if thwarted, may lead to persistence of self-reactive antibody-secreting cells. In this proposal we sought to characterize the pathways leading to post-proliferative death and rescue, and to determine how different forms of rescue lead to alternative differentiation outcomes. During the first year we showed that in the context of BCR-delivered TLR9 signals, IL-21 promotes and IL-4 opposes the T-bet+CD11c+ B cell fate. In the second and third years, we extended these findings to show that IFN-gamma also promotes the Tbet+ fate, and that B cells with this phenotype are antigen-experienced cells that emerge in normal responses to viral infections as well as in autoimmune scenarios. During a six-month no-coast extension, we completed signaling pathway analyses and analyzed B cells from additional SLE patients. We have forwarded a theoretical framework to explain the link between these activation requisites and humoral autoimmunity.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2018
- Accession Number
- AD1058218
Entities
People
- Jean L. Scholz
- Michael P Cancro
Organizations
- University of Pennsylvania