Stage 1 type 1 diabetes memory B lymphocytes transcriptionally differ from healthy controls and harbor insulin-binding specificities

Lindsay E Bass; Wyatt J McDonnell; Christina T Brannon; Nilesh P Kumar; Simon A Mallal; Ivelin S Georgiev; James W Thomas; Daniel J Moore; Rachel H Bonami

doi:10.1093/immhor/vlaf053

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Stage 1 type 1 diabetes memory B lymphocytes transcriptionally differ from healthy controls and harbor insulin-binding specificities

Journal article

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Stage 1 type 1 diabetes memory B lymphocytes transcriptionally differ from healthy controls and harbor insulin-binding specificities

Lindsay E Bass, Wyatt J McDonnell, Christina T Brannon, Nilesh P Kumar, Simon A Mallal, Ivelin S Georgiev, James W Thomas, Daniel J Moore and Rachel H Bonami

ImmunoHorizons, Vol.9(11), vlaf053

2025

DOI: https://doi.org/10.1093/immhor/vlaf053

PMID: 41259806

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Abstract

Adult

Antigens, CD19 - metabolism

Autoantibodies - immunology

Autoantigens - immunology

B-Lymphocytes - immunology

Case-Control Studies

Diabetes Mellitus, Type 1 - genetics

Diabetes Mellitus, Type 1 - immunology

Female

Humans

Immunologic Memory

Insulin - immunology

Insulin - metabolism

Male

Memory B Cells - immunology

Memory B Cells - metabolism

Receptors, Antigen, B-Cell - genetics

Receptors, Antigen, B-Cell - immunology

Receptors, Antigen, B-Cell - metabolism

Autoreactive B cell activity defines the earliest detectable stage (Stage 1) of type 1 diabetes (T1D) but is incompletely understood, particularly for B cells reactive against the key T1D autoantigen, insulin. To test whether Stage 1 T1D B cells are transcriptionally rewired compared to healthy individuals, we performed single-cell transcriptional, phenotypic, and immune repertoire profiling of CD19+ cells isolated from the peripheral blood of Stage 1 T1D individuals, identified via Type 1 Diabetes TrialNet as being positive for ≥ 2/5 islet autoantibodies, and healthy controls. Stage 1 T1D memory B cells upregulated n = 122 genes compared to healthy controls, including genes involved in actin cytoskeleton rearrangement, B cell receptor (BCR) signaling, and antigen presentation, and exhibited reduced BCR somatic hypermutation, particularly in atypical-like memory B cells. Clonally expanded B cells in the atypical-like memory subset of Stage 1 T1D individuals exhibited avidity driven insulin-binding specificities, without polyreactivity to HEp-2 cell autoantigens. Insulin-binding B cells showed non-significant upregulation of genes involved in key B cell functions. Our findings highlight transcriptional and BCR-repertoire differences in Stage 1 T1D B cells with potential for optimization as future screening tools to identify rare, autoreactive B cells and biomarkers of T1D progression.

Details

Title: Stage 1 type 1 diabetes memory B lymphocytes transcriptionally differ from healthy controls and harbor insulin-binding specificities
Authors/Creators: Lindsay E Bass - Vanderbilt University
Wyatt J McDonnell - Vanderbilt University Medical Center
Christina T Brannon - Department of Medicine, Division of Rheumatology and Immunology, VUMC, Nashville, TN 37232, United States
Nilesh P Kumar - Vanderbilt University
Simon A Mallal - Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia 6150, Australia
Ivelin S Georgiev - Vanderbilt Center for Antibody Therapeutics, VUMC, Nashville, TN 37232, United States
James W Thomas - Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN 37232, United States
Daniel J Moore - Vanderbilt University
Rachel H Bonami - Vanderbilt University
Publication Details: ImmunoHorizons, Vol.9(11), vlaf053
Publisher: Oxford University Press on behalf of The American Association of Immunologists.
Grant note: P30 DK020593 / NIDDK NIH HHS U01 DK085461 / NIH HHS U01 DK103266 / NIH HHS UL1 TR000445 / NCATS NIH HHS U01 DK061042 / NIH HHS R01 AI152693 / NIAID NIH HHS U01 DK103266 / NIDDK NIH HHS U01 DK103282 / NIDDK NIH HHS U01 DK106994 / NIDDK NIH HHS F31 DK141224 / NIDDK NIH HHS
Identifiers: 991005831948707891
Murdoch Affiliation: Institute for Immunology and Infectious Diseases
Language: English
Resource Type: Journal article

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