Pozovskiy, R. | Search bioRxiv

bioRxiv2026

Mechanistic insights into B-cell activation and autoreactivity regulation in active SLE and remission.

ObjectiveTo define cellular and molecular mechanisms distinguishing active systemic lupus erythematosus (SLE) from remission by profiling autoreactive antinuclear antigen- positive (ANA+) and non-autoreactive B cells subsets in three cohorts: active disease (SLE-A), long-term, drug free remission (SLE-R), and healthy controls (HC). MethodsPeripheral blood B cells were phenotyped by flow cytometry, including ANA reactivity. Single-cell RNA sequencing (scRNA-seq) was performed on sorted ANA+ and ANA- subsets. ResultsSeven transcriptomic B cell clusters were resolved: quiescent (Naive 1, Marginal Zone B cells [MZB], IgG Memory 1) and activated (Age-Associated B cells [ABCs], Naive 2, IgM Memory, IgG Memory 2). SLE-A showed expansion of activated clusters, MZB contraction, and a higher IgG:IgM B cell ratio. SLE-R exhibited an "immunological reset," distinct from healthy homeostasis, with reduced ABCs and IgG Memory 2, persistence of Naive 2, and partial restoration of MZB and Naive 1. Interferon- (IFNa) signaling was elevated across clusters in SLE-A (SLE-A > SLE-R > HC), whereas TNF signaling was enriched in activated clusters across cohorts, with minimal differences between SLE-R and SLE-A. IFNa and TNF scores were inversely correlated. B cells predominantly expressed TNFR2, suggesting immunomodulatory TNF effects in remission. ANA+ cells in HC and SLE-R showed enriched Fc{gamma}RIIb inhibitory and IL-4/STAT6 signaling, suggesting reinstated regulatory control. DiscussionCompared to SLE-A, SLE-R was characterized by partial reversion to HC homeostasis with residual activation. These findings delineate immunologic features of remission and suggest therapeutic opportunities, including modulation of TNFR2, Fc{gamma}RIIb, and IL-4 to help sustain remission. What is already known on this topicSome patients with SLE achieve complete clinical remission without treatment, referred as immune reset; the mechanisms that underlie this state have not been well characterized. Healthy individuals and patients with Systemic Lupus Erythematosus (SLE) normally harbor similar frequencies of autoreactive B cells; the checkpoints that regulate activation of these cells are not fully defined. What this study addsB cells, stratified by their reactivity to nuclear antigens (ANA), from active SLE (SLE-A), drug-free remission (SLE-R), and healthy controls (HC) were analyzed using single cell sequencing and flow cytometry. We identified B cells states associated with disease activity; SLE-R displayed a distinct profile that differed from SLE-A and HC. TNF signaling was present in activated B cell subsets in SLE-A and SLE-R. This persistence in SLE-R may reflect an immunomodulatory function of TNF on TNFR2, which is expressed on B cells. ANA+ cells in SLE-R and HC were enriched for inhibitory Fc{gamma}RIIb and IL-4/STAT6 programs. How this study might affect research, practice or policyThe signatures identified help define the "immunological reset" state in patients with SLE-R. We also identified pathways, such as type I IFN, TNFR2, Fc{gamma}RIIb, IL-4/STAT6 as potential targets for maintaining remission.

immunology↗

bioRxiv2023

Restoring adiponectin via rosiglitazone ameliorates tissue wasting in mice with lung cancer.

The cancer associated cachexia syndrome (CACS) is a systemic metabolic disorder resulting in loss of body weight due to skeletal muscle and adipose tissues atrophy. CACS is particularly prominent in lung cancer patients, where it contributes to poor quality of life and excess mortality. Using the Kras/Lkb1 (KL) mouse model, we found that CACS is associated with white adipose tissue (WAT) dysfunction that directly affects skeletal muscle homeostasis. WAT transcriptomes showed evidence of reduced adipogenesis, and, in agreement, we found low levels of circulating adiponectin. To preserve adipogenesis and restore adiponectin levels, we treated mice with the PPAR-{gamma} agonist, rosiglitazone. Rosiglitazone treatment increased serum adiponectin levels, delayed weight loss, and preserved skeletal muscle and adipose tissue mass, as compared to vehicle-treated mice. The preservation of muscle mass with rosiglitazone was associated with increases in AMPK and AKT activity. Similarly, activation of the adiponectin receptors in muscle cells increased AMPK activity, anabolic signaling, and protein synthesis. Our data suggest that PPAR-{gamma} agonists may be a useful adjuvant therapy to preserve tissue mass in lung cancer. Key points- The PPAR-{gamma} agonist, rosiglitazone, restores circulating adiponectin levels in mice with lung cancer. - Rosiglitazone preserves skeletal muscle and adipose tissue mass in mice with lung cancer. - The preservation of muscle mass with rosiglitazone is associated with increases in AMPK and AKT activity. - Stimulation of adiponectin signaling increases AMPK activity, anabolic signaling, and protein synthesis in muscle cell culture.

cancer biology↗