Transcriptionally distinct atypical B cell populations contribute to insulin autoreactivity and show differential activation, isotype switching, and somatic hypermutation in early-stage type 1 diabetes individuals
- 1Vanderbilt Health
Abstract
Autoreactive B cells must escape immune tolerance mechanisms to drive autoimmune disease, potentially through alternative paths to memory and antibody-secreting cell formation. "Atypical" B cells represent one such alternative pathway and are expanded in several human autoimmune diseases. Atypical B cells display phenotypic heterogeneity, but how this connects with differences in transcriptional programming, isotype switching and somatic hypermutation is incompletely understood in type 1 diabetes (T1D). Screening efforts to detect T1D prior to clinical diabetes onset affords an opportunity to study B cells early in immunopathogenesis, in which they primarily function as antigen-presenting cells. Prior evidence points to atypical B cell populations as reservoirs for islet autoreactivity in human T1D. We therefore developed sorting strategies to enrich for atypical and other autoreactive-prone B cell populations from the peripheral blood of early-stage T1D individuals and performed single-cell RNA/BCR-sequencing. We identified four transcriptionally defined atypical B cell clusters, each showing differential upregulation of atypical B cell defining genes. Additional gene expression changes were noted in broadly transcriptionally similar, but phenotypically distinct atypical B cell populations, with differences noted in the average extent of isotype switching and somatic hypermutation. Some atypical B cell populations showed extensive clonal sharing with classical memory or plasmablast subsets, consistent with relationships amongst these subsets. B cells reactive against a key islet autoantigen, insulin, were enriched in select atypical B cell populations. These findings highlight specific atypical B cell populations and features with potential value as biomarkers of disease progression or response to immunotherapy in T1D, and potentially other autoimmune diseases.
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BibTeX
@misc{bass2026transcriptionally,
title = {{Transcriptionally distinct atypical B cell populations contribute to insulin autoreactivity and show differential activation, isotype switching, and somatic hypermutation in early-stage type 1 diabetes individuals}},
author = {L. E. Bass and L. M. Clark and B. Han and D. J. Moore and R. H. Bonami},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.754202},
url = {https://www.biorxiv.org/content/10.64898/2026.09.30.754202v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Transcriptionally distinct atypical B cell populations contribute to insulin autoreactivity and show differential activation, isotype switching, and somatic hypermutation in early-stage type 1 diabetes individuals
AU - L. E. Bass
AU - L. M. Clark
AU - B. Han
AU - D. J. Moore
AU - R. H. Bonami
PY - 2026
DA - 2026/09/30
PB - bioRxiv
DO - 10.64898/2026.09.30.754202
UR - https://www.biorxiv.org/content/10.64898/2026.09.30.754202v1
AB - Autoreactive B cells must escape immune tolerance mechanisms to drive autoimmune disease, potentially through alternative paths to memory and antibody-secreting cell formation. "Atypical" B cells represent one such alternative pathway and are expanded in several human autoimmune diseases. Atypical B cells display phenotypic heterogeneity, but how this connects with differences in transcriptional programming, isotype switching and somatic hypermutation is incompletely understood in type 1 diabetes (T1D). Screening efforts to detect T1D prior to clinical diabetes onset affords an opportunity to study B cells early in immunopathogenesis, in which they primarily function as antigen-presenting cells. Prior evidence points to atypical B cell populations as reservoirs for islet autoreactivity in human T1D. We therefore developed sorting strategies to enrich for atypical and other autoreactive-prone B cell populations from the peripheral blood of early-stage T1D individuals and performed single-cell RNA/BCR-sequencing. We identified four transcriptionally defined atypical B cell clusters, each showing differential upregulation of atypical B cell defining genes. Additional gene expression changes were noted in broadly transcriptionally similar, but phenotypically distinct atypical B cell populations, with differences noted in the average extent of isotype switching and somatic hypermutation. Some atypical B cell populations showed extensive clonal sharing with classical memory or plasmablast subsets, consistent with relationships amongst these subsets. B cells reactive against a key islet autoantigen, insulin, were enriched in select atypical B cell populations. These findings highlight specific atypical B cell populations and features with potential value as biomarkers of disease progression or response to immunotherapy in T1D, and potentially other autoimmune diseases.
ER -