SLE is a systemic autoimmune disease characterized by profound B cell abnormalities and multiple autoantibody production. However, despite major advances in the field of human B cell biology, the precise antigenic and cellular mechanisms that underlie the activation, diversification and expansion of B cells in SLE remain poorly understood. Moreover, a precise understanding of the relative participation of different B cell subsets during acute disease exacerbations has been hampered by disease heterogeneity, imprecise B cell phenotyping and the lack of high-throughput technologies needed to define the antigenic forces driving the generation and selection of autoreactive B cells and serum autoantibodies. During the current ACE cycle we have established the tools required to address these questions including multi-dimensional flow cytometry;next generation sequencing (NGS);large scale single cell antibody generation;and bioinformatics platforms for the integrative analysis of high-density immunological, transcriptional and clinical data. Moreover, we have initiated collaborations with expert groups for the study of B cell and ASC epigenetics (Dr. Boss, Collaborative Agenda PI) and for the analysis of serum antibody proteomics (Dr. Cheung;CST). In this Principal Project of the Emory ACE U19, we proposed to build on these accomplishments to dissect the participation of B cell and ASC subsets through the following specific aims:
Aim 1. Participation and antigenic selection of different B cell compartments in SLE flares using repertoire analysis by NGS and single cell antibody production;
Aim 2. Relative contribution of short-lived and long-lived antibody secreting cells to the SLE serum autoantibody proteome;
and Aim 3. Epigenetic and transcriptional control of SLE B cells in conjunction with the Collaborative Project. The work proposed is highly synergistic with the Collaborative Agenda and the Pilot Project and has a high degree of innovation in terms of the questions asked and the experimental approach. The expect results should be of far-reaching significance for our understanding of the pathogenic mechanisms acting upon B cells in human autoimmunity and for the rationale design of safer and more effective therapies.

Public Health Relevance

This project will provide critical insight into the contribution of different B cells and antibody secreting cells to the autoantibody repertoire and disease process in human SLE. Together with the Collaborative Project, it will also study the epigenome and transcriptional program of autoimmune B cells

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI110483-01
Application #
8732941
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Type
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
St Clair, E William; Baer, Alan N; Wei, Chungwen et al. (2018) Clinical Efficacy and Safety of Baminercept, a Lymphotoxin ? Receptor Fusion Protein, in Primary Sjögren's Syndrome: Results From a Phase II Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol 70:1470-1480
Tipton, Christopher M; Hom, Jennifer R; Fucile, Christopher F et al. (2018) Understanding B-cell activation and autoantibody repertoire selection in systemic lupus erythematosus: A B-cell immunomics approach. Immunol Rev 284:120-131
Putterman, Chaim; Pisetsky, David S; Petri, Michelle et al. (2018) The SLE-key test serological signature: new insights into the course of lupus. Rheumatology (Oxford) 57:1632-1640
Upadhyay, Amit A; Kauffman, Robert C; Wolabaugh, Amber N et al. (2018) BALDR: a computational pipeline for paired heavy and light chain immunoglobulin reconstruction in single-cell RNA-seq data. Genome Med 10:20
Jenks, Scott A; Cashman, Kevin S; Zumaquero, Esther et al. (2018) Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus. Immunity 49:725-739.e6
Hamilton, Jennie A; Wu, Qi; Yang, PingAr et al. (2018) Cutting Edge: Intracellular IFN-? and Distinct Type I IFN Expression Patterns in Circulating Systemic Lupus Erythematosus B Cells. J Immunol 201:2203-2208
Barwick, Benjamin G; Scharer, Christopher D; Martinez, Ryan J et al. (2018) B cell activation and plasma cell differentiation are inhibited by de novo DNA methylation. Nat Commun 9:1900
Asare, A; Kanaparthi, S; Lim, N et al. (2017) B Cell Receptor Genes Associated With Tolerance Identify a Cohort of Immunosuppressed Patients With Improved Renal Allograft Graft Function. Am J Transplant 17:2627-2639
Fortner, Karen A; Bond, Jeffrey P; Austin, James W et al. (2017) The molecular signature of murine T cell homeostatic proliferation reveals both inflammatory and immune inhibition patterns. J Autoimmun 82:47-61
Sanz, Iñaki (2017) New Perspectives in Rheumatology: May You Live in Interesting Times: Challenges and Opportunities in Lupus Research. Arthritis Rheumatol 69:1552-1559

Showing the most recent 10 out of 33 publications