title: Characterization of antibody responses to endogenous and exogenous antigen in the nonobese diabetic mouse.
abstract: It is suggested that a T-helper cell 2 (Th2) shift and Th2 spreading of autoimmunity following immunization with beta-cell antigen causes diabetes protection. To address this, antibody titer and subclass to insulin, glutamic acid decarboxylase (GAD)65, IA-2, and IA-2beta proteins were measured by radiobinding assays in untreated or immunized female nonobese diabetic mice. Untreated nonobese diabetic mice developed autoantibodies to insulin (IAA), but not GAD or IA-2/IA-2beta, and IAA-positive mice had increased diabetes risk (P < 0.001). IAA were IgG1 and IgG2b. In immunized mice, IgG1 and lesser IgG2b insulin antibodies were promoted by subcutaneous injection of insulin plus incomplete Freund's adjuvant, insulin plus Montanide ISA 720, and glucagon plus incomplete Freund's adjuvant, but not by incomplete Freund's adjuvant plus GAD65, IA-2beta, or phenylethanolamine N-methyltransferase, or adjuvant alone. Diabetes incidence was significantly reduced in immunized groups with elevated insulin antibody (IA) responses. Spreading of antibody responses to GAD or IA-2/IA-2beta following immunization was rare, and antibody epitope spreading was only detected in IA-2beta immunized mice. Humoral autoimmunity in nonobese diabetic mice is, therefore, limited to IAA with Th2 subclass phenotype and is associated with increased diabetes risk. This contrasts the diabetes protection provided by immunization protocols that promote this response and suggests that Th2 immunity may not be the principal regulator of beta-cell destruction in autoimmune diabetes.
authors.affiliation: Diabetes Research Institute and 3rd Medical Department, Krankenhaus München-Schwabing, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Koczwara
authors.forename: Mike
authors.initials: M
authors.lastname: Schenker
authors.forename: Sandra
authors.initials: S
authors.lastname: Schmid
authors.forename: Katharina
authors.initials: K
authors.lastname: Kredel
authors.forename: Anette-Gabriele
authors.initials: AG
authors.lastname: Ziegler
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
mesh_terms: D000276:Adjuvants, Immunologic; D000536:Aluminum Hydroxide; D000818:Animals; D000918:Antibody Specificity; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology*; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D002417:Cattle; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D015721:Diphtheria-Tetanus-Pertussis Vaccine; D005260:Female; D005934:Glucagon / Q000276:immunology* / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007328:Insulin / Q000276:immunology*; D007527:Isoenzymes / Q000276:immunology*; D008353:Mannitol / Q000031:analogs & derivatives*; D008565:Membrane Proteins / Q000008:administration & dosage / Q000276:immunology*; D008780:Methyltransferases / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D009829:Oleic Acids; D050918:Phosphatidylethanolamine N-Methyltransferase; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000008:administration & dosage / Q000276:immunology*; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology; D012306:Risk; D013045:Species Specificity; D013552:Swine; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D001323:Autoantibodies; D001324:Autoantigens; D015721:Diphtheria-Tetanus-Pertussis Vaccine; C096322:ICA512 autoantibody; D007074:Immunoglobulin G; D007328:Insulin; D007527:Isoenzymes; D008565:Membrane Proteins; D009829:Oleic Acids; D011993:Recombinant Fusion Proteins; C001681:mannide monooleate; D008353:Mannitol; D000536:Aluminum Hydroxide; D005934:Glucagon; D008780:Methyltransferases; D050918:Phosphatidylethanolamine N-Methyltransferase; C516862:PTPRN protein, human; C102889:PTPRN2 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516863:Ptprn protein, mouse; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2