title: Marginal-zone B-cells of nonobese diabetic mice expand with diabetes onset, invade the pancreatic lymph nodes, and present autoantigen to diabetogenic T-cells.
abstract: OBJECTIVE
  B-cells are important for disease pathogenesis in the nonobese diabetic (NOD) mouse model of type 1 diabetes. Recent studies demonstrate that marginal-zone B-cells (MZBs), which connect innate with adaptive immune responses, are increased in NOD mice. However, beyond this, the contribution of different B-cell subsets to diabetes pathogenesis is poorly understood.
  
  
  METHODS
  To better understand the role of different B-cell subsets in the etiology of type 1 diabetes, we have examined the MZB compartment in NOD mice, with respect to their number, distribution, and function.
  
  
  RESULTS
  We demonstrate that splenic MZB numbers in female NOD mice undergo a marked, approximately threefold expansion between approximately 12 and 16 weeks of age, coincident with the onset of frank diabetes. Functionally, NOD MZBs are hyperresponsive to toll-like receptor 9 ligation and CD40 ligation, as well as sphingosine-1-phosphate-dependent chemotactic cues, suggesting an increased sensitivity to selective innate- and activation-induced stimuli. Intriguingly, at 16 weeks of age, approximately 80% of female NOD mice present with MZB-like cells in the pancreatic lymph node (PLN). These MZB-like cells express major histocompatibility complex class II and high levels of CD80 and CD86, and their presence in the PLN is associated with an increased frequency of activated Vbeta4(+) CD4(+) T-cells. Significantly, we demonstrate that purified MZBs are able to present the autoantigen insulin to diabetogenic T-cells.
  
  
  CONCLUSIONS
  These data are consistent with MZBs contributing to the pathogenesis of type 1 diabetes as antigen-presenting cells. By integrating innate-derived inflammatory signals with the activation of autoreactive T-cells, MZBs may help to direct T-cell responses against beta-cell self-constituents.
authors.affiliation: Senior Research Fellow, Gene Therapy and Autoimmunity Group, Arthritis and Inflammation Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, N5W 2010, Australia.
authors.forename: Eliana
authors.initials: E
authors.lastname: Mariño
authors.forename: Marcel
authors.initials: M
authors.lastname: Batten
authors.forename: Joanna
authors.initials: J
authors.lastname: Groom
authors.forename: Stacey
authors.initials: S
authors.lastname: Walters
authors.forename: David
authors.initials: D
authors.lastname: Liuwantara
authors.forename: Fabienne
authors.initials: F
authors.lastname: Mackay
authors.forename: Shane T
authors.initials: ST
authors.lastname: Grey
mesh_terms: D000818:Animals; D001324:Autoantigens; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D050417:Insulin-Secreting Cells / Q000473:pathology*; D008198:Lymph Nodes / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016688:Mice, Inbred NOD; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D001324:Autoantigens