Regulation of B cell Responses in SLE and Other Autoimmune Diseases

Emory University, Atlanta GA

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Abstract

Autoimmune disease represents a significant health problem. Over the decade, novel immune based therapies to treat autoimmune diseases, such as those used in systemic lupus erythematosus (SLE) have met considerable efficacy challenges. This suggests that there is considerable heterogeneity in the disease, which could occur at the genetic level, but also at the epigenetic level. Epigenetic processes, which include DNA methylation and posttranslational modification of histones, act on chromatin structure, regulating gene specific programs, the phenotypes, and potential actions of cells. Transcriptional and epigenetic analyses of multiple B cell subsets of patients with highly active disease displayed a cell-type specific multifactorial signature that was surprisingly present in naïve resting B cells (rN). The latter suggests that rN cells in SLE patients are primed to respond to autoimmune signals. While these findings presented the bases to begin to dissect SLE related pathways, further analyses of the same rN B cells in patients in remission/inactive disease showed substantial heterogeneity from each other and to the active disease signature. The full heterogeneity and epigenetic components of this signature are not yet known, and their definition may influence future care. Included within the inactive rN signature is an increase in anergic B cells, which are reduced in active SLE. The epigenetic programming of anergic B cells is also not fully understood in humans. To understand the heterogeneity in patients in remission and determine the programming of these cells, in Aim 1 we will apply a comprehensive single cell sequencing approach that utilizes barcoded cell surface markers, transcriptome analysis inclusive of VDJ repertoire, and chromatin accessibility. Type I interferons (IFN) are an important mediator of SLE, and cellular responses to IFN are present in all SLE molecular signatures. Anifrolumab, an IFN receptor inhibitor, is now used in the clinics with some success as is the BAFF inhibitor Belimumab, which impacts B cell maturation and naïve B cell survival. Because IFN and BAFF impact a number of pathways leading to autoimmunity, it is important to know if the B cells following these treatments have reset their epigenetic features to that of a healthy state. To answer this question, Aim 2 will focus on analyzing the transcriptomes and epigenomes of rN B cells in patients pre and post therapy with these biologics and compare them to healthy controls. To accomplish this, we have developed a robust experimental platform that utilizes small cell numbers for RNA, chromatin accessibility, and DNA methylation; and have optimized CUT&Tag for histone modifications from sorted cells. Together, these technologies will define the genes and pathways, as well as the transcription factor networks that control cell phenotypes and the efficacy of treatment regimens to allow resetting of the epigenome to a healthy state. We will dovetail our technologies with the Principal Project and because our technologies and approaches are universal, this program is ideally suited for partnerships across the ACE network and collaborative agenda.