Autoimmune disease results from the escape of (er defects In) normal control mechanisms and developmental pathways that maintain a healthy immune system. Despite the increase in autoimmune disease within our aging population, the mechanisms by which autoimmune cells are generated and how these cells are programmed are not well understood. We hypothesize that these abnormal events and programming are in part controlled by a unique epigenetic program that will be revealed in the DNA methylation and histone modification landscape that Is established within the genomes of autoimmune cells. Systemic lupus erythematosus (SLE) patients undergo relapsing episodes of disease. During autoimmune flares, specific B cell subsets dominate that are likely responsible for the disease flares. Aside from surface marker phenotyping, little Is known about the molecular programming and potential of these autoimmune B cells. As part of the Emory ACE, we will use whole genome strategies to derive and Integrate epigenetic and transcription profiles for autoimmune B cells purified frem SLE patients and determine the epigenetic landscape and programming of these cells and hew they are different from the B cells of healthy individuals. Preliminary data have identified candidate loci, including cell surface markers that are both differentially expressed and epigenetically regulated in SLE patient derived B cells. We will also follow SLE patients on Belimumab (anti-BAFF/BLyS) and Rituximab (Anti-CD20) to gain insight into how the B cell subsets and their epigenetic and transcriptional programming change following treatment. For the Collaborative Project, we hypothesize that epigenetic determinants for both B and T cells will play a role in etiology or sustainment of other autoimmune diseases. With this overall hypothesis in mind, we propose to collaborate with other centers to determine the transcriptomes and epigenomes of autoimmune and healthy control B and T cells that are the focus of their investigations. Because the technology and approaches are universal, this program is ideally suited for a collaborative program. We expect that the integration of our combined studies will provide insight into the development of autoimmunity, cellular programming, and immune dysfunction, and will identify biomarkers that could be used for diagnosis, monitoring disease progression, or as targets for novel therapies.

Public Health Relevance

Specific mechanisms by which autoimmune cells are generated and how autoimmune cells are eplgenetically programmed are not well understood. We hypothesize that autoimmunity is caused by abnormal epigenetic mechanisms and that understanding these mechanisms will lead to novel approaches to treat disease. This Collaborative Project is aimed at 1) understanding the epigenetic bases of systemic lupus erythematosus and 2) determining if other autoimmune diseases share a similar epigenetic program

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-PA-I (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
United States
Zip Code
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