The cellular and molecular events underlying the generation of self-reactive antibodies in autoimmunity remain poorly understood. Notably, marginal zone (MZ) B cells are enriched for self-reactive B cells, and are known to generate antibody-secreting plasma cells exceptionally quickly compared to other B cells. This R21 project centers on understanding the molecular mechanisms through which MZ B cells generate plasma cells with accelerated kinetics, with a focus on defining extracellular cues and associated intracellular signaling pathways that prime MZ B cells for differentiation. The central hypothesis guiding this work is that the mTOR/mTORC1 kinase, an emerging biomarker in lupus and related autoimmune diseases, couples BAFF-receptor signaling and expression of relevant plasma cell genes to facilitate rapid induction of antibody synthesis. To test this hypothesis we will: 1) Define the role of mTOR/mTORC1 signaling in plasma cell priming, and 2) Explore the identity of extracellular inputs driving plasma cell priming in situ. These studies will enhance knowledge of the processes underlying the generation of all plasma cells including those secreting pathogenic self-reactive antibodies.

Public Health Relevance

Biochemical pathways controlling the earliest phases of plasma cell differentiation remain poorly understood. These studies will address the biochemical events that allow some B cells to generate plasma cells faster than others. The results will have direct implications for therapeutic strategies to combat antibody-mediated autoimmune diseases, or conversely to induce long-lived immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI133998-01
Application #
9403332
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Ferguson, Stacy E
Project Start
2017-06-01
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
Total Cost
$241,500
Indirect Cost
$91,500
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104