Single-cell transcriptomics reveals the immune mechanisms by which tonsillectomy improves clinical outcomes of recurrent Immuoglobulin A nephropathy after kidney transplant

Abstract

Immunoglobulin A nephropathy recurrence (IgANR) is a major cause of graft function loss in renal transplant patients with IgA nephropathy. Tonsillectomy has been recognized as an effective treatment for IgANR, but the cellular and molecular effects underlying its efficacy remain poorly understood. We aimed to identify the cell types and gene expression profiles in tonsillar tissue and peripheral blood mononuclear cells (PBMCs) to investigate the effectiveness of tonsillectomy in IgANR treatment. Flow cytometry and single-cell mRNA sequencing were performed to comprehensively characterize the cell types of 29 patients with IgANR. Additionally, we analyzed a tonsillar tissue sample and three PBMC samples to gain further insights. Single-cell transcriptome analysis revealed significant changes in gene expression following tonsillectomy in patients with IgANR. Conventional cytometry and transcriptome analysis revealed that B cells played a crucial role in IgANR treatment using tonsillectomy. Notably, the downregulation of IGHA1 expression, memory B cell inactivation, and alterations in related pathways led to a reduction in galactose-deficient IgA1 (Gd-IgA1), which plays a crucial role in IgA nephropathy. The phosphatidylinositol-3-kinase (PI3k)-Akt pathway was significantly downregulated in peripheral B cells, and peripheral B cells in patients with IgANR who underwent tonsillectomy demonstrated downregulated expression of T cell leukemia/lymphoma 1 A (TCL1A), an Akt coactivator. As a result, it is possible that TCL1A plays a major role in the mediation of this therapeutic effect. Tonsillectomy aids in the treatment of IgANR by guiding B cell phenotypes, inducing functional changes, and regulating the immune response, thereby reducing Gd-IgA1 levels and improving clinical outcomes.