B lymphocytes are central mediators of humoral immunity. Aberrant B cell function also contributes to multiple autoimmune diseases, including rheumatoid arthritis (RA). In addition, we and others have recently found that B cells also serve critical negative regulatory functions during adaptive CD4+ T cell responses that can dampen both cellular and humoral immune responses, and the development of autoimmunity. This unexpected observation is explained in part by the identification of a potent regulatory B cell subset that dramatically attenuates Th1 immune responses and autoimmunity in mice. This regulatory B cell subset is uniquely CD1d+CD5+, produces IL-10. and represents 1-2% of total spleen B cells in wild type mice and <1% of circulating human B cells. We call this subset B10 cells to emphasize that they are the predominant, if not exclusive, B cell population that produces IL-10 and to distinguish them from other regulatory subsets that may also exist. B10 cell numbers within tissues increase significantly in mice with autoimmunity and age. In this proposal, we hypothesize that antigen-specific regulatory B10 cells influence autoimmune disease in both mice and humans. We will test this hypothesis and examine B10 cell generation, function, and mechanisms of action using the mouse collagen-induced arthritis (CIA) model of RA and B cells from patients with RA. In four specific aims, the proposed studies will identify the extent that the B10 subset modulates immune responses during autoimmunity, determine whether B10 cells can be manipulated for therapeutic benefit, and identify and characterize this unique B cell subset in normal humans and patients with autoimmunity.
Specific Aim 1 will identify and characterize the B10 cell subset before, during and after CIA induction;
Specific Aim 2 will characterize B10 cell function during CIA;
Specific Aim 3 will develop an in vivo preclinical mouse model for B10 cell adoptive therapy;
and Specific Aim 4 will identify and characterize the B10 subset during human autoimmune disease. These overlapping studies will significantly expand our knowledge of how B10 cells regulate both normal and abnormal immune responses in both species.

Public Health Relevance

These studies will contribute to the multi-project Duke ACE objectives, which focus on the origins of autoreactive B cells and their regulation during autoimmune disease. Since B10 cells function as an important regulatory checkpoint for adjusting normal and abnormal immune responses, understanding their functions may provide mechanisms for modulating immune responses and the treating autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI056363-09
Application #
8375328
Study Section
Special Emphasis Panel (ZAI1-QV-I)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$244,191
Indirect Cost
$108,531
Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Su, Kuei-Ying; Watanabe, Akiko; Yeh, Chen-Hao et al. (2016) Efficient Culture of Human Naive and Memory B Cells for Use as APCs. J Immunol 197:4163-4176
Cui, Ang; Di Niro, Roberto; Vander Heiden, Jason A et al. (2016) A Model of Somatic Hypermutation Targeting in Mice Based on High-Throughput Ig Sequencing Data. J Immunol 197:3566-3574
Cao, Yonghao; Amezquita, Robert A; Kleinstein, Steven H et al. (2016) Autoreactive T Cells from Patients with Myasthenia Gravis Are Characterized by Elevated IL-17, IFN-γ, and GM-CSF and Diminished IL-10 Production. J Immunol 196:2075-84
Haddon, David James; Jarrell, Justin Ansel; Diep, Vivian K et al. (2015) Mapping epitopes of U1-70K autoantibodies at single-amino acid resolution. Autoimmunity 48:513-23
Kountikov, Evgueni I; Poe, Jonathan C; Maclver, Nancie J et al. (2015) A spontaneous deletion within the desmoglein 3 extracellular domain of mice results in hypomorphic protein expression, immunodeficiency, and a wasting disease phenotype. Am J Pathol 185:617-30
Hall 3rd, R P; Fairley, J; Woodley, D et al. (2015) A multicentre randomized trial of the treatment of patients with pemphigus vulgaris with infliximab and prednisone compared with prednisone alone. Br J Dermatol 172:760-8
Aranow, Cynthia; Kamen, Diane L; Dall'Era, Maria et al. (2015) Randomized, Double-Blind, Placebo-Controlled Trial of the Effect of Vitamin D3 on the Interferon Signature in Patients With Systemic Lupus Erythematosus. Arthritis Rheumatol 67:1848-57
Nair, Nitya; Mei, Henrik E; Chen, Shih-Yu et al. (2015) Mass cytometry as a platform for the discovery of cellular biomarkers to guide effective rheumatic disease therapy. Arthritis Res Ther 17:127
Ci, Xinxin; Kuraoka, Masayuki; Wang, Hongxia et al. (2015) TSC1 Promotes B Cell Maturation but Is Dispensable for Germinal Center Formation. PLoS One 10:e0127527
Labowsky, Michael; Lowenthal, Justin; Fahmy, Tarek M (2015) An in silico analysis of nanoparticle/cell diffusive transfer: application to nano-artificial antigen-presenting cell:T-cell interaction. Nanomedicine 11:1019-28

Showing the most recent 10 out of 141 publications