Accession Number:

AD1058218

Title:

B-Cell Activation and Tolerance Mediated by B-Cell Receptor, Toll-Like Receptor, and Survival Signal Crosstalk in SLE Pathogenesis

Descriptive Note:

Technical Report,15 Aug 2014,14 Feb 2018

Corporate Author:

University of Pennsylvania Philadelphia United States

Personal Author(s):

Report Date:

2018-05-01

Pagination or Media Count:

90.0

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.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE