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Gene expression profiles of peripheral blood mononuclear cells (PBMC) from children with active idiopathic nephrotic syndrome (INS) and healthy controls (HC) [RTXrel_vs_RTXrem]

ABSTRACT: An autoimmune B cell origin for childhood idiopathic nephrotic syndrome (INS) is predicted based on the efficacy of rituximab (RTX) at maintaining long-term remission from proteinuria. Knowledge regarding the nature of the culprit B cell response is very limited. In particular, no transcriptomics work has been performed to evaluate the B cell response in INS. Here, we performed single-cell RNA-sequencing (scRNAseq) on B cells isolated from peripheral blood mononuclear cells (PBMC) collected from four children with INS during the B cell recovery phase of a previous RTX treamtent while in remission or relapse (paired relapse-remisison samples). We show that the post-RTX B cell landscape is overwhelmingly antigen-inexperienced with minimal transcriptomic differences between relapse and remission. However, post-RTX relapses were associated with an early resurgence of an extrafollicular B cell population expressing genes associated with marginal zone B cells (MZB1, CD24, IGHM, CD1C, TNFRSF13B, GPR183). Together, our study provides evidence for an extrafollicular origin for humoral immunity in active INS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE233276 | GEO | 2023/10/29

REPOSITORIES: GEO

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Project description:Rituximab (RTX) is widely used as a first-line therapeutic strategy in B cell-mediated autoimmune diseases. However, a large proportion of patients either do not respond to the treatment or relapse during B cell reconstitution. Primary immune thrombocytopenia (ITP) is a prototypic B cell mediated autoimmune disease in which pathogenic antibodies directed against the platelet membrane glycoprotein IIb-IIIa (GPIIbIIIa) lead to platelet destruction by macrophages in the spleen. In ITP, RTX-mediated B-cell depletion leads to an immediate clinical response in 50% of patients but 80% of patients will subsequently relapse in the next following months. Patients failing to respond or relapsing after RTX treatment are splenectomized when alternative therapies are inefficient or unavailable. Therapeutic splenectomy, resulting in a durable platelet response in 60-70 % of ITP patients, offers a unique access to study the autoimmune response in the spleen. To understand the cellular basis of disease's relapse in secondary lymphoid organs in humans, memory B cells were sorted and analyzed by scRNAseq from the spleen of three different groups of splenectomized ITP patients: 1) Patients that achieved a complete response after a course of RTX and relapsed during B-cell reconstitution (hereafter referred to as “RTX relapse” patients), 2) patients with primary failure of RTX, i.e. who did not respond to treatment at the time of B-cell depletion (“RTX failure” patients), 3) patients with active ITP that were not treated with RTX (“ITP” patients). All were compared with sorted splenic memory B cells from organ donors with no immune disease who died from stroke or head trauma, hereafter referred to as healthy donors (“HD” patients). We also included in this analysis splenic memory B cells from children with sickle cell disease that underwent splenectomy and are known to have a high frequency of B cell activation secondary to classical childhood infections and vaccinations, reflected by an increased number of GC. Single-cell mRNA sequencing was performed according to an adapted version of the SORT-seq protocol (Muraro et al., 2016, Cell Systems 3, 385–394), with cDNA libraries generation, sequencing and reads alignment performed at Single Cell Discoveries (Utrecht, Netherlands).

Dataset Information

Gene expression profiles of peripheral blood mononuclear cells (PBMC) from children with active idiopathic nephrotic syndrome (INS) and healthy controls (HC) [RTXrel_vs_RTXrem]

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