The CD19 signalling molecule is elevated in NOD mice and controls type 1 diabetes development
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- Ziegler, A.I., Le Page, M.A., Maxwell, M.J. et al. Diabetologia (2013) 56: 2659. doi:10.1007/s00125-013-3038-2
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Type 1 diabetes is characterised by early peri-islet insulitis and insulin autoantibodies, followed by invasive insulitis and beta cell destruction. The immunological events that precipitate invasive insulitis are not well understood. We tested the hypothesis that B cells in diabetes-prone NOD mice drive invasive insulitis through elevated expression of CD19 and consequent enhanced uptake and presentation of beta cell membrane-bound antigens to islet invasive T cells.
CD19 expression and signalling pathways in B cells from NOD and control mice were compared. Expansion of CD8+ T cells specific for insulin and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) were compared in CD19-deficient and wild-type NOD mice and this was correlated with insulitis severity. The therapeutic potential of anti-CD19 treatment during the period of T cell activation was assessed for its ability to block invasive insulitis.
CD19 expression and signalling in B cells was increased in NOD mice. CD19 deficiency significantly diminished the expansion of CD8+ T cells with specificity for the membrane-bound beta cell antigen, IGRP. Conversely the reduction in CD8+ T cells with specificity for the soluble beta cell antigen, insulin, was relatively small and not significant.
Elevated CD19 on NOD B cells promotes presentation of the membrane-bound antigen, IGRP, mediating the expansion of autoreactive T cells specific for antigens integral to beta cells, which are critical for invasive insulitis and diabetes. Downregulating the CD19 signalling pathway in insulin autoantibody-positive individuals before the development of type 1 diabetes may prevent expansion of islet-invasive T cells and preserve beta cell mass.
KeywordsB cells CD19 signalling molecule Invasive insulitis Membrane-bound antigen NOD mice T cells Type 1 diabetes
B cell receptor
Hen egg lysozyme
Islet-specific glucose-6-phosphatase catalytic subunit-related protein
T cell receptor
Regulatory T cell