title: The CD19 signalling molecule is elevated in NOD mice and controls type 1 diabetes development.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Immunology, Monash University, AMREP building, 89 Commercial Road, Melbourne, VIC, 3004, Australia.
authors.forename: Alexandra I
authors.initials: AI
authors.lastname: Ziegler
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Le Page
authors.forename: Mhairi J
authors.initials: MJ
authors.lastname: Maxwell
authors.forename: Jessica
authors.initials: J
authors.lastname: Stolp
authors.forename: Haoyao
authors.initials: H
authors.lastname: Guo
authors.forename: Abhirup
authors.initials: A
authors.lastname: Jayasimhan
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Hibbs
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
authors.forename: Jacques F
authors.initials: JF
authors.lastname: Miller
authors.forename: Magdalena
authors.initials: M
authors.lastname: Plebanski
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Silveira
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Slattery
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism*; D001323:Autoantibodies / Q000276:immunology; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D011236:Prediabetic State / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology
chemical_list: D018941:Antigens, CD19; D001323:Autoantibodies