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Abstract Number: 963

Alterations of Memory and Naive B Cell Subsets Associate with Reduced IFNα and TNFRII in ANA+ Healthy Individuals

Aleksandra Bylinska1, Samantha Slight-Webb 1, Miles Smith 2, Susan R. Macwana 1, Nicolas Dominguez 1, Eliza F. Chakravarty 3, Joan T. Merrill 4, Judith James 3 and Joel Guthridge 3, 1Oklahoma Medical Research Foundation, Oklahoma City, OK, 2Oklahoma Medical Research Foundation, Oklahoma City, 3Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 4Okalahoma Medical Research Foundation, Oklahoma City, OK

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Antinuclear antibodies (ANA), B cells, Gene Expression and cytokines, Systemic lupus erythematosus (SLE)

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Session Information

Date: Monday, November 11, 2019

Title: B Cell Biology & Targets In Autoimmune & Inflammatory Disease Poster

Session Type: Poster Session (Monday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Loss of systemic self-tolerance leading to anti-nuclear autoantibody (ANAs) by B cells is a hallmark of SLE. However, up to 20% of healthy female individuals are also ANA+, and most will never develop clinical autoimmune disease. The B cell pathways involved in autoimmune progression and regulation of healthy ANA+ individuals is unknown.

Methods: Peripheral blood mononuclear cells (PBMCs) from African American ANA- (n=6), ANA+ healthy individuals (n=6) and SLE (n=6) subjects were sorted for CD3-CD19+ B cells by flow cytometry and RNA was isolated for next-generation sequencing. Differential gene expression, Weighted Gene Correlation Network Analysis and pathway analysis were used to identify differences in pathways and upstream regulators. scRNA-sequencing of B cells from PBMCs were used to determine frequencies and identify differential gene signatures in specific B cells subsets. Plasma soluble mediators were assessed by xMAP multiplex arrays and used for linear regression analyses.

Results: Pathway analysis of total B cells in ANA+ healthy individuals revealed unique pathway modules with elevated eigengene scores associated with p53 signaling (p=0.000275), TNFRII signaling (p=0.0000699), apoptosis (p=0.00399) and death receptor signaling (p=0.00902) compared to ANA- controls and SLE patients. Using scRNA-seq analysis, seven distinct B cell populations among all subjects were identified using a community detection algorithm and visualized using Uniform Manifold Approximation Projection. The proportion of total B cells within each cluster varied by disease status. A unique cluster of CD69low naïve B cells was more prevalent in ANA+ healthy subjects, memory B cells also trended higher in ANA+ healthy individuals, while SLE patients were characterized by higher frequencies of plasma cells and CD69high naïve B cells. Gene expression signatures of p53/TNFRII, apoptosis, and death receptor signaling were elevated in all B cell subsets of ANA+ healthy individuals (Figure 1A-B). In ANA+ healthy individuals, the elevated gene expression signatures in memory B cells correlated negatively with plasma IFNα (p=0.0027), IL-15 (p=0.011), IP-10 (p=0.027), IL-10 (0.025), TNFRII (p=0.029), and IL-23 (p=0.038) levels, and negatively in CD69low naïve B cells with IFNα (p=0.012) and TNFRII (p=0.045) levels (Figure 1C-F). SLE patients exhibited higher plasma levels of multiple cytokines including IFNα and associated mediators, TNFRII, IL-10, BLyS and Th1/2/17 associated mediators (p< 0.05).

Conclusion: ANA+ healthy individuals have enhanced gene expression in B cell pathways that drive apoptosis and cell cycle suppression, which may regulate autoreactive T cell activation, and proliferation, and subsequent clinical autoimmune pathogenesis. This provides clues into potential targets for prevention of clinical autoimmunity.

Figure 1. African American ANA+ B cell populations negatively correlate with pro-inflammatory cytokines.
A. Visualization of B cell subpopulations by UMAP of scRNA-seq data.
B. Proportion of cells from each disease classification in each B cell cluster reveals differences is constituent subpopulations.
C. Linear regression of plasma TNFRII fluorescent intensity -FI- with TNFRII/p53/apoptosis/death-receptor signaling – related gene module score for memory B cells -cluster B1-.
D. Linear regression of plasma IFNα fluorescent intensity -FI- with TNFRII/p53/apoptosis/death-receptor signaling – related gene module score for memory B cells -cluster B1-.
E. Linear regression of plasma TNFRII fluorescent intensity -FI- with TNFRII/p53/apoptosis/death-receptor signaling – related gene module score for naive B cells -cluster B4-.
F. Linear regression of plasma IFNα fluorescent intensity -FI- with TNFRII/p53/apoptosis/death-receptor signaling – related gene module score for naive B cells -cluster B4-.


Disclosure: A. Bylinska, None; S. Slight-Webb, None; M. Smith, None; S. Macwana, None; N. Dominguez, None; E. Chakravarty, None; J. Merrill, Abbvie, 5, Amgen, 5, Astellas, 5, AstraZeneca, 5, BMS, 2, 5, Celgene, 5, EMD Serono, 5, GSK, 2, 5, Idorsia, 5, ILTOO, 5, Immupharma, 5, Incyte, 5, Janssen, 5, Lilly, 5, Remegen, 5, Servier, 5, Xencor, Inc., 2; J. James, Abbvie, 5, Janssen, 5, Progentec, 2, Progentec Diagnostics, Inc., 2, Xencor, 2, Xencor, Inc., 2; J. Guthridge, DxTerity, 2.

To cite this abstract in AMA style:

Bylinska A, Slight-Webb S, Smith M, Macwana S, Dominguez N, Chakravarty E, Merrill J, James J, Guthridge J. Alterations of Memory and Naive B Cell Subsets Associate with Reduced IFNα and TNFRII in ANA+ Healthy Individuals [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/alterations-of-memory-and-naive-b-cell-subsets-associate-with-reduced-ifn%ce%b1-and-tnfrii-in-ana-healthy-individuals/. Accessed .
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