Single-cell RNA and BCR sequencing of age-associated B cells in mouse and human lupus
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE307415 | GEO | 2026/06/03
REPOSITORIES: GEO
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Project description:Age-Associated B Cells (ABCs) are a population of CD11c+ and/or CD11b+ B cells expanded in autoimmune lupus. To understand potential heterogeneity within ABCs and the relationship of ABCs to other splenic B cell subsets, we performed scRNA-seq with 5' V(D)J and CITE-seq cell surface features using the 10x Genomics Chromium platform on total splenic CD19+ B cells sorted from lupus-prone MRL/lpr. We found that ABC are a distinct transcriptional lineage that resolved into two related clusters. Analysis of BCR heavy chains identified clones present in both ABC and plasmablast compartments. Inferred lineage trees based on V gene somatic hypermutation suggested that self-renewing ABC feed into the plasmablast compartment repeatedly while continuing to themselves undergo mutation and expansion.
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Project description:Both multiple myeloma (MM) and systemic lupus erythematosus (SLE) are characterized with abnormal production of plasma cells. In both diseases, the process of B cells differentiate into plasmablast/plasma cell is disordered. Despite the continuous research on the development of prognostic factors and introduction of new agents, dysregulation of plasmablast/plasma cells in MM and SLE is still uncontrolled. Thus, it is necessary to explore the novel therapeutic target to plasmablast/plasma cells. Because of plasmablast-like, Mus musculus myeloma SP 2/0 cell line was selected to explore the novel therapeutic target to plasmablast/plasma cells. To explore the novel therapeutic target to plasmablast/plasma cells, we determined mRNA profiles in SP 2/0 cells compared to naive B cells by RNA-seq. RNA-seq was done with an Illumina HiSeq 2500 instrument at GENEWIZ, Suzhou, China.
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Project description:While circumstantial evidence supports enhanced TLR7 signaling as a mechanism of human systemic autoimmune disease, we have lacked the proof afforded by lupus-causing TLR7 gene variants. Here we describe human systemic lupus erythematosus (SLE) caused by TLR7 gain-of-function (GoF). We identified a de novo, novel, missense TLR7 Y264H variant in a child with severe lupus. The de novo TLR7 Y264H variant selectively increased sensing of guanosine and was sufficient to cause lupus when introduced in mice (kika mice). We performed RNA-seq of kika and wild type B cells cultured for 20 hours with anti-IgM and found a decreased tendency to apoptosis in kika B cells, including decreased expression of active Caspase 3 and also a small decrease in proliferation. Overall, these results suggest that hypersensitive TLR7 signaling allows the survival of B cells that are binding self-antigen through their surface BCR.
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Project description:We report here that ABCs exhibited a unique phenotype in aging and lupus model mice, where BCR signaling is constitutively activated, and surface BCRs are internalized. Autoreactive anergic B cells exclusively differentiated into ABCs in a BCR-dependent manner in vivo. Additionally, anergic B cells showed enhanced ABC differentiation in vitro compared to naive B cells. This was suppressed by Nr4a1 expression, possibly due to the inhibition of several signaling pathways, including BCR.
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Project description:This study aimed at defining the role of the B-cell adaptor protein BANK1 in the appearance of age-associated B cells (ABCs) in two SLE mouse models (TLR7.tg6 and Imiquimod-induced mice), crossed with Bank1-/- mice. The absence of Bank1 led to a significant reduction in ABC levels, also affecting other B cell populations. To gain deeper insights into their differentiation pathway and the impact of Bank1 on B cell populations, a single-cell transcriptome assay was performed. In the TLR7.tg6 model, we identified 10 clusters within B cells, including an ABC-specific cluster which was decreased in Bank1-deficient mice. In its absence, ABCs exhibited an anti-inflammatory gene expression profile, while being pro-inflammatory in Bank1-sufficient lupus mice. Trajectory analyses revealed that ABCs originated from marginal zone and memory-like B cells, ultimately acquiring transcriptional characteristics associated with atypical memory cells and long-lived plasma cells. Also, Bank1 deficiency normalized the presence of naïve B cells, which were nearly absent in lupus mice. Interestingly, Bank1 deficiency significantly reduced a distinct cluster containing IFN-responsive genes. These findings underscore the critical role of Bank1 in ABC development, impacting early B cell stages towards ABC differentiation, and the presence of IFN-stimulated gene-containing B cells, both populations determinant for autoimmunity.
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Project description:Age-associated B cells (ABCs) accumulate during infection, aging and autoimmunity, contributing to lupus pathogenesis. Here, we screened for transcription factors driving ABC formation and found Zeb2 was required for human and mouse ABC differentiation in-vitro. ABCs were reduced in ZEB2 haploinsufficient individuals and in mice lacking Zeb2 in B cells. In mice with TLR7-driven lupus, Zeb2 was essential for ABC formation and autoimmune pathology. Zeb2 binds to the +20kb intronic enhancer of Mef2b, repressing Mef2b-mediated germinal center B cell differentiation and promoting ABC formation. Zeb2 also targets genes important for ABC specification and function including Itgax. Zeb2-driven ABC differentiation required Jak-Stat signaling, and treatment with the Jak1/3 inhibitor tofacitinib reduced ABC accumulation in mice and autoimmune patients. Zeb2 thus emerges as a driver of B-cell autoimmunity.
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