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The CD19 signalling molecule is elevated in NOD mice and controls type 1 diabetes development.


AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.

Type Journal
Authors Ziegler, A. I.; Le Page, M. A.; Maxwell, M. J.; Stolp, J.; Guo, H.; Jayasimhan, A.; Hibbs, M. L.; Santamaria, P.; Miller, J. F.; Plebanski, M.; Silveira, P. A.; Slattery, R. M.;
Garvan Authors Dr Jessica Stolp
Published Date 2013-09-08 00:00:00
Published Volume 56
Published Issue 12
Published Pages 2659-2668
Status Published