| First Author | Felton JL | Year | 2018 |
| Journal | J Immunol | Volume | 201 |
| Issue | 3 | Pages | 861-873 |
| PubMed ID | 29950508 | Mgi Jnum | J:264309 |
| Mgi Id | MGI:6195357 | Doi | 10.4049/jimmunol.1701717 |
| Citation | Felton JL, et al. (2018) Anti-Insulin B Cells Are Poised for Antigen Presentation in Type 1 Diabetes. J Immunol 201(3):861-873 |
| abstractText | 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 (VH125(SD)NOD) 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 VH125(SD)NOD mice are not restricted to insulin autoantigens, as evidenced by increased IFN-gamma 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 beta cell specificity to predominantly proinflammatory Ag-presenting B cell subsets. |
