Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope

• Published in: Nature (London) Vol. 435; no. 7039; pp. 224 - 228
• Main Authors: Kent, Sally C., Chen, Yahua, Bregoli, Lisa, Clemmings, Sue M., Kenyon, Norma Sue, Ricordi, Camillo, Hering, Bernhard J., Hafler, David A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.05.2005; Nature Publishing; Nature Publishing Group
• Subjects: Alleles; Amino Acid Sequence; Autoimmune diseases; Biological and medical sciences; Case-Control Studies; Clone Cells - cytology; Clone Cells - immunology; Diabetes; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - pathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Epitopes, T-Lymphocyte - immunology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; HLA-DR Antigens - immunology; HLA-DRB1 Chains; Humanities and Social Sciences; Humans; Insulin; Insulin - immunology; letter; Lymph nodes; Lymph Nodes - cytology; Lymph Nodes - immunology; Lymphocytes; Medical sciences; Molecular Sequence Data; multidisciplinary; Pancreas; Pancreas - immunology; Properties; Receptors, Antigen, T-Cell - chemistry; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Science; Science (multidisciplinary); Substrate Specificity; T cells; T-Lymphocytes - cytology; T-Lymphocytes - immunology; United States; Endocrinopathy; Autoimmunity; Human; Immunopathology; Pancreatic hormone; Antigenic determinant; Lymph node; Type 1 diabetes; Pathogenesis; T-Lymphocyte; Autoimmune disease; Insulin
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature03625

Insulin sparks autoimmunity Autoimmune reactions, in which the body's white blood cells harm its own tissues, cause many diseases including diabetes, multiple sclerosis and arthritis. It is not known why immune cells target certain organs, and in particular for childhood diabetes, why only insulin-producing cells are killed. Nakayama et al . now report that this may be because insulin itself is a primary autoantigen for autoimmune diabetes. In NOD mice, the standard animal model for diabetes, when the part of the insulin molecule that gives rise to autoantibodies is altered, autoimmune diabetes disappears. This also suggests that deletional immune therapy could be a practical proposition. The possible clinical relevance of this work is confirmed by a separate study by Kent et al . of human patients with type 1 diabetes. T lymphocytes found in the draining lymph nodes around the pancreas specifically recognize part of the insulin protein. This has implications for antigen specific therapies and islet-cell transplantation in diabetes. In autoimmune type 1 diabetes, pathogenic T lymphocytes are associated with the specific destruction of insulin-producing β-islet cells 1 , 2 . Identification of the autoantigens involved in triggering this process is a central question. Here we examined T cells from pancreatic draining lymph nodes, the site of islet-cell-specific self-antigen presentation 3 . We cloned single T cells in a non-biased manner from pancreatic draining lymph nodes of subjects with type 1 diabetes and from non-diabetic controls. A high degree of T-cell clonal expansion was observed in pancreatic lymph nodes from long-term diabetic patients but not from control subjects. The oligoclonally expanded T cells from diabetic subjects with DR4, a susceptibility allele for type 1 diabetes 4 , recognized the insulin A 1–15 epitope restricted by DR4. These results identify insulin-reactive, clonally expanded T cells from the site of autoinflammatory drainage in long-term type 1 diabetics, indicating that insulin may indeed be the target antigen causing autoimmune diabetes.