Germinal centers (GCs) are unique microenvironment that has proliferative B cells undergoing class switching, somatic hypermutation, and affinity maturation. Although alternative pathways exist, GCs are the major source of long-lived antibody (Ab)-secreting plasma cells and memory B cells. Previous studies have demonstrated that SLE may develop as a result of enhanced GC activity. Spontaneous GC formation has been found in the lupus-prone mice. In addition, active lupus patients have abnormal GC reactions and increased plasma cells. Therefore, understanding signaling pathways that regulate the GC formation and GC B cell differentiation may identify novel targets for the successful intervention of SLE. The signal transducer and activator of transcription factor 3 (STAT3) signaling pathway is critical for human B cells to differentiate into Ab-secreting plasma cells. Dysregulation of STAT3 pathway has also been implicated in the development of SLE. However, the role of STAT3 in the GC B cell response has been controversial. A previous study has demonstrated that B cell-specific STAT3 deficient mice have lower T- dependent IgG response but display normal GC formation. Paradoxically, GC is the major source of both memory B cells and long-lived plasma cells. One caveat of this study is that they only examined GC response at day 12. Our preliminary studies demonstrated that B cell-specific STAT-3 KO mice had significantly decreased GC formation, GC B cells, and Tfh cells in the later phase (day 21) but not in the early time point (day 14). Furthermore, STAT3-deficient autoreactive B cells had defective autoAb responses and GC B cell differentiation upon immunization. We hypothesize that STAT3 signaling is essential for the maintenance of the GC formation and GC B cell differentiation.
Two Aims are proposed to address this hypothesis.
Aim 1 determines the mechanisms by which STAT3 signaling regulates the maintenance of the GC formation and GC B cell response using C?1-cre mice which specifically delete STAT3 in the GC B cells. We will also determine extracellular signals that stimulate STAT3 activation in GC B cells.
Aim 2 examines whether B cell intrinsic STAT3 signaling is required for autoAb production and disease progression in lupus-prone MRL/lpr mouse model. In addition, we will use anti-CD19 single chain variable fragment (scFv) miniAb to specifically deliver STAT3 siRNA into B cells in MRL/lpr mice. The therapeutic efficacy of this intervention will be determined. The overall goal of this proposal is to determine how STAT3 signaling regulates the GC formation and GC B cell response and whether ablation of STAT3 signaling specifically in autoreactive B cells provides benefit for lupus treatment.

Public Health Relevance

This study will determine the cellular and molecular mechanisms by which STAT3 signaling pathway regulates the germinal center formation and germinal center B cell response. The successful completion of this study may provide an innovative approach for autoimmune disease therapy such as systemic lupus erythematosus (SLE).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI124235-01A1
Application #
8967897
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Johnson, David R
Project Start
2015-09-01
Project End
2017-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
$189,617
Indirect Cost
$64,617
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40202