title: Class-switched anti-insulin antibodies originate from unconventional antigen presentation in multiple lymphoid sites.
abstract: Autoantibodies to insulin are a harbinger of autoimmunity in type 1 diabetes in humans and in non-obese diabetic mice. To understand the genesis of these autoantibodies, we investigated the interactions of insulin-specific T and B lymphocytes using T cell and B cell receptor transgenic mice. We found spontaneous anti-insulin germinal center (GC) formation throughout lymphoid tissues with GC B cells binding insulin. Moreover, because of the nature of the insulin epitope recognized by the T cells, it was evident that GC B cells presented a broader repertoire of insulin epitopes. Such broader recognition was reproduced by activating naive B cells ex vivo with a combination of CD40 ligand and interleukin 4. Thus, insulin immunoreactivity extends beyond the pancreatic lymph node-islets of Langerhans axis and indicates that circulating insulin, despite its very low levels, can have an influence on diabetogenesis.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Wan
authors.affiliation: Department of Medicine, Vanderbilt University Medical School, Nashville, TN 37232.
authors.forename: James W
authors.initials: JW
authors.lastname: Thomas
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 unanue@wustl.edu.
authors.forename: Emil R
authors.initials: ER
authors.lastname: Unanue
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018858:Germinal Center / Q000276:immunology* / Q000473:pathology; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology*; D007328:Insulin / Q000235:genetics / Q000276:immunology*; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: D019013:CD40 Antigens; D007328:Insulin; D015847:Interleukin-4