Childhood Idiopathic Nephrotic Syndrome is Characterized by Antigen-Experienced B-Cell Responses and Diminished Immunoregulation that are Differentially Targeted by Distinct Immunosuppressive Treatments

Thursday, June 23, 2022

1:50 PM – 2:05 PM PT

Location: Salons 5/6

Authors: Tho-Alfakar Al-Aubodah, BSc (Presenting Author) - Research Institute of the McGill University Health Centre; Lamine Aoudjit, n/a (Co-Author) - Research Institute of the McGill University Health Centre; Giuseppe Pascale, n/a (Co-Author) - Research Institute of the McGill University Health Centre; Maneka Perinpanayagam, PhD (Co-Author) - University of Calgary; David Langlais, PhD (Co-Author) - McGill Genome Centre; Martin Bitzan, MD (Co-Author) - Research Institute of the McGill University Health Centre; Susan Samuel, MD, MSc (Co-Author) - University of Calgary; Ciriaco Piccirillo, PhD (Co-Author) - Research Institute of the McGill University Health Centre; Tomoko Takano, MD, PhD (Co-Author) - Research Institute of the McGill University Health Centre

Presenting Author(s)

TA

Tho-Alfakar Al-Aubodah, BSc

PhD Candidate
Research Institute of the McGill University Health Centre
Westmount, Quebec, Canada

Chair(s)

Jason Cyster, PhD

Professor
University of California, San Francisco
SAN FRANCISCO, California, United States

Idiopathic nephrotic syndrome (INS) is the most common chronic glomerular disorder in children featuring frequent relapses of heavy proteinuria. Effacement of podocyte foot processes – the major determinants of glomerular filtration – is the definitive and often sole histopathological manifestation of INS. Nevertheless, a T-cell-dependent etiology is suspected given the efficacy of broadly immunosuppressive drugs (glucocorticoids, GC) and T-cell-targeting agents at inducing remission, albeit with significant toxicity. Recently, the search for GC-sparing treatment alternatives identified the B-cell-depleting biologic rituximab (RTX) as a potent inducer of long-term remission and thereby positioned B-cells as the probable culprits of INS. Since the immune processes leading to podocyte effacement and the mechanisms by which GC and RTX mediate remission are unknown, we sought to characterize T- and B-cells in pediatric INS using single cell RNA-sequencing (scRNAseq) and high-parameter flow cytometry. Comparisons of patient and healthy PBMC by scRNAseq (N=4/group) and flow (N=10/group) revealed a T-cell-dependent antigen-experienced B-cell phenotype and a broadly activated T-cell phenotype with diminished regulatory T- (T_REG) cell frequencies during INS onset/relapse. GC treatments specifically reduced plasma cell proliferation and rescued T_REG-cell abundance, whereas RTX treatment provided long-term ablation of most antigen-experienced memory B-cells in both longitudinal (N=7) and cross-sectional (N >10/group) flow-based investigations. Accordingly, the eventual resurgence of memory B-cells following RTX treatment correlated with proteinuric relapses. Overall, we demonstrate that pediatric INS features a T-cell-dependent antigen-driven B-cell response and a T_REG-cell defect that are differentially targeted by GC and RTX, thus emphasizing the importance of adaptive immunity in INS.