Naive B Cells Retain Interferon Signature in Inactive Lupus

Key Takeaways

• Circulating resting naive B cells from adults with active or inactive systemic lupus erythematosus (SLE), primarily women of Black ancestry, showed interferon-associated differences from healthy controls.
• Inactive SLE was associated with enrichment of IL-12, TNF-α/NF-κB, and CD40-related gene sets in resting naive B cells, not demonstrated functional pathway activation.
• Shared interferon-related chromatin accessibility coexisted with activity-associated regulatory patterns, while transcription factors were computationally implicated rather than directly shown to bind.

When systemic lupus erythematosus (SLE) activity is low, do circulating resting naive B cells retain molecular alterations that distinguish the disease from health? Periods of low activity and flares also raise the question of which alterations vary with activity. Investigators compared disease states across resting naive and transitional B-cell populations to examine both questions.

A recent study compared peripheral-blood B cells from healthy controls and adults with inactive or active SLE. Participants were adult women, primarily of Black ancestry. One cohort underwent flow-cytometric characterization; an additional cohort provided sorted cells for RNA sequencing (RNA-seq): 17 healthy controls, 15 participants with inactive SLE, and 12 with active SLE. Investigators profiled resting naive B cells and T1/T2 transitional B cells separately.

Inactive disease was defined as SELENA-SLEDAI ≤4 and active disease as SELENA-SLEDAI ≥5. RNA-seq supported differential-expression and gene-set analyses in both cell populations. Assay for transposase-accessible chromatin with sequencing (ATAC-seq) examined a subset of the RNA-seq samples. Differential-accessibility testing, binding-motif enrichment, and integrated network inference assessed regulatory patterns without directly measuring transcription-factor binding.

Interferon-α response gene expression distinguished both SLE activity states from controls, with no significant active-versus-inactive difference in the specified gene-set comparison. Across the SLE cell-type and activity groupings, 25 upregulated differentially expressed genes (DEGs) formed a shared interferon-response pattern; other active-associated genes were shared by resting naive and transitional cells. In inactive SLE resting naive cells, gene sets related to interleukin-12 (IL-12), tumor necrosis factor alpha (TNF-α)/nuclear factor kappa B (NF-κB), CD40, and interleukin-10 (IL-10) responses were enriched in the reported comparisons. Direct active-versus-inactive analyses also implicated CD40 and interleukin-4 (IL-4) responses. These expression patterns did not establish functional signaling. Shared accessible chromatin included interferon-linked regions near IFI44/IFI44L, while other regions were activity-associated. One-third of active-SLE resting naive-cell differentially accessible regions (DARs) overlapped inactive-SLE DARs at a twofold accessibility-change threshold. Computational analyses implicated basic helix-loop-helix (bHLH) factors, E2A/E2-2, and MEF2 in inactive disease; active-associated regions had additional interferon regulatory factor (IRF)-family motif enrichment. T1/T2 cells also showed SLE-associated expression changes but less separation by activity.

These observational molecular comparisons in adult women predominantly of Black ancestry may not generalize to other populations. Time since the last flare varied widely among inactive RNA-seq participants; this was prior disease history, not prospective follow-up demonstrating flare prediction. Age and medications did not correlate with leading transcriptome components in the reported covariate analysis, and the leading ATAC-seq component tracked activity rather than assessed covariates. Those group-level results do not rule out effects of individual therapies. Neither chromatin accessibility nor enriched expression established causation, direct factor binding, or B-cell differentiation. The comparisons did not validate a clinical assay or treatment-monitoring endpoint or assess response to B-cell-targeting therapy.

Researchers interpreted resting naive B-cell programs as reflecting both SLE disease state and differences in activity. Their relevance to future B-cell-targeting research remains an open question, not an established clinical use.

Clinician Questions

Why doesn't IL-12 pathway gene enrichment establish IL-12 signaling in inactive SLE B cells?

In circulating resting naive B cells from adults with inactive SLE, IL-12 pathway gene sets share members with other response programs. TYK2 and JAK2, for example, also participate in interferon signaling, so enrichment of overlapping transcripts does not demonstrate that an IL-12 signaling event occurred.

Does accessible RSAD2 chromatin mean RSAD2 is expressed in resting naive B cells in SLE?

No. Accessible regions at the RSAD2 locus were identified in resting naive B cells from adults with active and inactive SLE, but RSAD2 expression was not detectable in the resting naive cells analyzed by RNA-seq. Chromatin accessibility and measurable RNA expression are different observations.

Recommended Reading

• For more on immune-targeted SLE treatment: Telitacicept Outperforms Belimumab in 24-Week Active SLE Cohort