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Accession Number:
AD1058218
Title:
B-Cell Activation and Tolerance Mediated by B-Cell Receptor, Toll-Like Receptor, and Survival Signal Crosstalk in SLE Pathogenesis
Corporate Author:
University of Pennsylvania Philadelphia United States
Report Date:
2018-05-01
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-betCD11c 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.
Descriptive Note:
Technical Report,15 Aug 2014,14 Feb 2018
Pages:
0090
Distribution Statement:
Approved For Public Release;
File Size:
8.99MB
