Format

Send to

Choose Destination
J Immunol. 2018 Aug 1;201(3):861-873. doi: 10.4049/jimmunol.1701717. Epub 2018 Jun 27.

Anti-Insulin B Cells Are Poised for Antigen Presentation in Type 1 Diabetes.

Author information

1
Division of Pediatric Endocrinology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232.
2
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232; and.
3
Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University, Nashville, TN 37232.
4
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232; and james.w.thomas@vumc.org.

Abstract

Early breaches in B cell tolerance are central to type 1 diabetes progression in mouse and man. Conventional BCR transgenic mouse models (VH125.Tg NOD) reveal the power of B cell specificity to drive disease as APCs. However, in conventional fixed IgM models, comprehensive assessment of B cell development is limited. To provide more accurate insight into the developmental and functional fates of anti-insulin B cells, we generated a new NOD model (VH125SDNOD) in which anti-insulin VDJH125 is targeted to the IgH chain locus to generate a small (1-2%) population of class switch-competent insulin-binding B cells. Tracking of this rare population in a polyclonal repertoire reveals that anti-insulin B cells are preferentially skewed into marginal zone and late transitional subsets known to have increased sensitivity to proinflammatory signals. Additionally, IL-10 production, characteristic of regulatory B cell subsets, is increased. In contrast to conventional models, class switch-competent anti-insulin B cells proliferate normally in response to mitogenic stimuli but remain functionally silent for insulin autoantibody production. Diabetes development is accelerated, which demonstrates the power of anti-insulin B cells to exacerbate disease without differentiation into Ab-forming or plasma cells. Autoreactive T cell responses in VH125SDNOD mice are not restricted to insulin autoantigens, as evidenced by increased IFN-γ production to a broad array of diabetes-associated epitopes. Together, these results independently validate the pathogenic role of anti-insulin B cells in type 1 diabetes, underscore their diverse developmental fates, and demonstrate the pathologic potential of coupling a critical β cell specificity to predominantly proinflammatory Ag-presenting B cell subsets.

PMID:
29950508
DOI:
10.4049/jimmunol.1701717
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center