Priming and effector dependence on insulin B:9-23 peptide in NOD islet autoimmunity.
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.
Nakayama
Maki
M
Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center (UCHSC), Aurora, CO 80045-6511, USA.
Beilke
Joshua N
JN
Jasinski
Jean M
JM
Kobayashi
Masakazu
M
Miao
Dongmei
D
Li
Marcella
M
Coulombe
Marilyne G
MG
Liu
Edwin
E
Elliott
John F
JF
Gill
Ronald G
RG
Eisenbarth
George S
GS
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
D001323:Autoantibodies; D007328:Insulin; D010446:Peptide Fragments; C097877:insulin B (9-23)