Autoimmune patients undergoing B cell depletion therapy (BCDT) with Rituximab can enter clinical remission for years, while others experience only transient relief (months). Although we do not understand why some patients respond well to BCDT and others do not, it is clear that B cells are pathogenic in a subset of patients. Clinical data show that BCDT can be efficacious without significantly reducing autoantibody titer, suggesting that B cells cause pathology via by another mechanism. Therefore, it is important to identify the Ab-independent functions of B cells and understand how B cells performing these functions contribute to pathology in autoimmune disease. However, these efforts have been hampered because we understand so little about the Ab-independent effector functions of B cells. Our data show that one potentially important effector function of B cells is to secrete cytokines. Indeed, we know that cytokines made specifically by B lineage cells regulate humoral and cellular immune responses in vivo. Based on these data, we hypothesize that cytokine-producing B cell effectors (Beff) likely contribute to immune responses to pathogens as well as autoantigens and that Beff cells can be either protective or damaging depending on the immune microenvironment and the cytokine secreted by the Beff cells. However, without until recently, it has been difficult to experimentally address this hypothesis, as we were not able to track cytokine-producing Beff cells in vivo. Importantly, we have now identified a novel subset of IFNy-producing Beff cells that develop in response to influenza infection and are inappropriately expanded in a mouse model of SLE (YaaFcyRllb-/- or Yaa.R2 mice). These data now provide us with the unique opportunity to address our original hypothesis. Therefore goals of this proposal are to (i) determine the factors that regulate the development of IFNy Beff cells in infectious and autoimmune settings and (ii) identify the functional role(s) of these cells in immune responses directed against pathogens and autoantigens.

Public Health Relevance

Approximately 3-5% of Americans suffer from autoimmune disease and effective treatments for many patients are lacking. One promising therapy for autoimmune disease is Rituximab, an antibody that depletes B cells from pro-B cells to plasmablasts. The goals of this proposal are to understand how B cells mediate pathology in autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI078907-04
Application #
8528454
Study Section
Special Emphasis Panel (ZAI1-PA-I)
Project Start
2013-08-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$400,101
Indirect Cost
$28,400
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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