Follicular dendritic cells (FDCs) are recognized as critical stromal components of the secondary lymphoid tissues that retain antigen and immune complexes, but also respond to environmental stimuli and provide soluble factors, including BAFF, that impact late B cell differentiation. We hypothesize that FDCs may also be important for the retention of self-antigens such that the transient or episodic presence of a self-antigen can be captured. We propose that retention of autoantigens by FDCs may provide an important function in the continual elimination of autoreactive B cells as they complete late maturation in the spleen as "transitional" B cells. Selection events at this stage of development are not well understood and contrast with those described for early B cell maturation in the bone marrow. In this proposal, we introduce a new mouse model of B cell tolerance based upon the conditional expression of a membrane-bound self-antigen on FDCs. We provide the first direct evidence for FDCs as having a role in peripheral B cell tolerance. In the proposed work, we will: (i) Characterize the late B cell development block imposed by FDC-bound self-antigen. (ii) Use forced expression of microRNAs that are differential expressed in transitional and mature B cells to identify genes that are important for tolerance susceptibility of T1 cells.

Public Health Relevance

In the proposed work, we address peripheral tolerance at the transitional stage of B cell development corresponding to the recent B cell immigrants to the spleen. We provide evidence that follicular dendritic cells of the spleen are important in the elimination of self-reactive transitional B cells, thus defining a novel checkpoint in peripheralB cell tolerance. These findings and the model we developed with be of direct relevance to understanding defects in peripheral tolerance that are noted to occur in systemic lupus erythematosus and likely other antibody-dependent autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI098304-02
Application #
8431334
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Ferguson, Stacy E
Project Start
2012-03-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
2
Fiscal Year
2013
Total Cost
$243,750
Indirect Cost
$118,750
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Yau, Irene W; Cato, Matthew H; Jellusova, Julia et al. (2013) Censoring of self-reactive B cells by follicular dendritic cell-displayed self-antigen. J Immunol 191:1082-90