Diabetologia

, Volume 56, Issue 12, pp 2659–2668

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

  • Alexandra I. Ziegler
  • Melanie A. Le Page
  • Mhairi J. Maxwell
  • Jessica Stolp
  • Haoyao Guo
  • Abhirup Jayasimhan
  • Margaret L. Hibbs
  • Pere Santamaria
  • Jacques F. Miller
  • Magdalena Plebanski
  • Pablo A. Silveira
  • Robyn M. Slattery
Article

DOI: 10.1007/s00125-013-3038-2

Cite this article as:
Ziegler, A.I., Le Page, M.A., Maxwell, M.J. et al. Diabetologia (2013) 56: 2659. doi:10.1007/s00125-013-3038-2

Abstract

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.

Keywords

B cells CD19 signalling molecule Invasive insulitis Membrane-bound antigen NOD mice T cells Type 1 diabetes 

Abbreviations

APC

Antigen-presenting cell

B6

C57BL/6 mouse

BCR

B cell receptor

DC

Dendritic cell

FO

Follicular

HEL

Hen egg lysozyme

IGRP

Islet-specific glucose-6-phosphatase catalytic subunit-related protein

LN

Lymph node

MbAg

Membrane-bound antigen

MZ

Marginal zone

PI3K

Phosphoinositide 3-kinase

sAg

Soluble antigen

TCR

T cell receptor

Treg

Regulatory T cell

Supplementary material

125_2013_3038_MOESM1_ESM.pdf (208 kb)
ESM Fig. 1(PDF 208 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Alexandra I. Ziegler
    • 1
  • Melanie A. Le Page
    • 1
  • Mhairi J. Maxwell
    • 1
  • Jessica Stolp
    • 2
  • Haoyao Guo
    • 1
  • Abhirup Jayasimhan
    • 1
  • Margaret L. Hibbs
    • 1
  • Pere Santamaria
    • 3
    • 4
  • Jacques F. Miller
    • 5
  • Magdalena Plebanski
    • 1
  • Pablo A. Silveira
    • 2
  • Robyn M. Slattery
    • 1
  1. 1.Department of ImmunologyMonash UniversityMelbourneAustralia
  2. 2.Immunology ProgramGarvan Institute of Medical ResearchDarlinghurstAustralia
  3. 3.Julia McFarlane Diabetes Research Centre (JMDRC) and Dept of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Faculty of MedicineUniversity of CalgaryCalgaryCanada
  4. 4.Institut D’Investigacions Biomediques August Pi i SunyerBarcelonaSpain
  5. 5.Walter and Eliza Hall InstituteParkvilleAustralia

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