title: Priming and effector dependence on insulin B:9-23 peptide in NOD islet autoimmunity.
abstract: NOD mice with knockout of both native insulin genes and a mutated proinsulin transgene, alanine at position B16 in preproinsulin (B16:A-dKO mice), do not develop diabetes. Transplantation of NOD islets, but not bone marrow, expressing native insulin sequences (tyrosine at position B16) into B16:A-dKO mice rapidly restored development of insulin autoantibodies (IAAs) and insulitis, despite the recipients' pancreatic islets lacking native insulin sequences. Splenocytes from B16:A-dKO mice that received native insulin-positive islets induced diabetes when transferred into wild-type NOD/SCID or B16:A-dKO NOD/SCID mice. Splenocytes from mice immunized with native insulin B chain amino acids 9-23 (insulin B:9-23) peptide in CFA induced rapid diabetes upon transfer only in recipients expressing the native insulin B:9-23 sequence in their pancreata. Additionally, CD4(+) T cells from B16:A-dKO mice immunized with native insulin B:9-23 peptide promoted IAAs in NOD/SCID mice. These results indicate that the provision of native insulin B:9-23 sequences is sufficient to prime anti-insulin autoimmunity and that subsequent transfer of diabetes following peptide immunization requires native insulin B:9-23 expression in islets. Our findings demonstrate dependence on B16 alanine versus tyrosine of insulin B:9-23 for both the initial priming and the effector phase of NOD anti-islet autoimmunity.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center (UCHSC), Aurora, CO 80045-6511, USA.
authors.forename: Maki
authors.initials: M
authors.lastname: Nakayama
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Beilke
authors.forename: Jean M
authors.initials: JM
authors.lastname: Jasinski
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Dongmei
authors.initials: D
authors.lastname: Miao
authors.forename: Marcella
authors.initials: M
authors.lastname: Li
authors.forename: Marilyne G
authors.initials: MG
authors.lastname: Coulombe
authors.forename: Edwin
authors.initials: E
authors.lastname: Liu
authors.forename: John F
authors.initials: JF
authors.lastname: Elliott
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Gill
authors.forename: George S
authors.initials: GS
authors.lastname: Eisenbarth
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D017690:Cell Transplantation; D045142:Cross-Priming / Q000276:immunology; D003920:Diabetes Mellitus / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007114:Immunization; D007328:Insulin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D015996:Survival Rate
chemical_list: D001323:Autoantibodies; D007328:Insulin; D010446:Peptide Fragments; C097877:insulin B (9-23)