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Updated: Jun 14, 2026
In Vitro Differentiation Model of Human Normal Memory B Cells to Long-lived Plasma Cells
Published on: January 20, 2019
Longitudinal profiling reveals immune dynamics and distinct plasma cell signatures during B-cell depletion in
Hyo Jae Kim1, Min-Gang Kim2, Seongryong Kim3
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, South Korea; Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, South Korea.
Objectives:
IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder characterised by tissue infiltration of IgG4+ plasma cells, yet the precise roles of B cells remain unclear. This study aimed to characterise the longitudinal immune dynamics in IgG4-RD during B-cell depletion therapy to identify pathogenic cell subsets and specific biomarkers associated with relapse.
Methods:
We performed a longitudinal multiomics analysis on 119 peripheral blood samples from patients with IgG4-RD undergoing rituximab treatment, spanning active, remission, and relapse phases. Integrated single-cell transcriptomics, B-cell receptor (BCR) sequencing, and serum proteomics were performed on matched blood and tissue samples from submandibular gland and lymph nodes, with Sjögren's syndrome and healthy individuals as controls.
Results:
We identified a previously unrecognised, disease-specific IgG4+ plasma cell subset characterised by aberrant expression of the neuropeptide NMU and highly skewed IGHV1-69 usage. Circulating follicular helper T cells (CD4+Tfh) displayed signatures consistent with chronic antigen stimulation and type 2 immunity. Furthermore, markedly expanded double-negative T cells (dnT) highly expressed IL10, suggesting their involvement in immune regulation and isotype class switching. Longitudinal analysis following B-cell depletion emphasised the reconstitution dynamics of pathogenic plasma cells, furthermore highlighting the concurrent shifts in CD4+Tfh and dnT that mirrored disease remission and relapse, and underscored the amelioration of proinflammatory immune profiles.
Conclusions:
NMU-expressing IGHV1-69+ plasma cells represent a pathogenic effector population driving IgG4-RD recurrence. These findings establish a mechanistic framework for B-cell depletion and identify specific cellular and molecular biomarkers to improve disease monitoring and relapse prediction in clinical practice.
