Autoimmune islet destruction in spontaneous type 1 diabetes is not β-cell exclusive

• Published in: Nature medicine Vol. 9; no. 2; pp. 198 - 205
• Main Authors: Dosch, H -Michael, Winer, Shawn, Tsui, Hubert, Lau, Ambrose, Song, Aihua, Li, Xiaomao, Cheung, Roy K, Sampson, Anastazia, Afifiyan, Fatemeh, Elford, Alisha, Jackowski, George, Becker, Dorothy J, Santamaria, Pere, Ohashi, Pamela
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.02.2003
• Subjects: Animals; Autoantibodies - analysis; Autoantibodies - immunology; Base Sequence; Diabetes Mellitus, Type 1 - immunology; DNA Primers; Female; Fluorescent Antibody Technique; Glial Fibrillary Acidic Protein - metabolism; Islets of Langerhans - immunology; Islets of Langerhans - pathology; Male; Mice; Mice, Inbred Strains; Nerve Growth Factors - metabolism; S100 Calcium Binding Protein beta Subunit; S100 Proteins - metabolism; Schwann Cells - immunology; Schwann Cells - metabolism; Species Specificity
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm818

Pancreatic islets of Langerhans are enveloped by peri-islet Schwann cells (pSC), which express glial fibrillary acidic protein (GFAP) and S100beta. pSC-autoreactive T- and B-cell responses arise in 3- to 4-week-old diabetes-prone non-obese diabetic (NOD) mice, followed by progressive pSC destruction before detectable beta-cell death. Humans with probable prediabetes generate similar autoreactivities, and autoantibodies in islet-cell autoantibody (lCA) -positive sera co-localize to pSC. Moreover, GFAP-specific NOD T-cell lines transferred pathogenic peri-insulitis to NOD/severe combined immunodeficient (NOD/SCID) mice, and immunotherapy with GFAP or S100beta prevented diabetes. pSC survived in rat insulin promoter Iymphocytic choriomeningitis virus (rip-LCMV) glycoprotein/CD8+ T-cell receptor(gp) double-transgenic mice with virus-induced diabetes, suggesting that pSC death is not an obligate consequence of local inflammation and beta-cell destruction. However, pSC were deleted in spontaneously diabetic NOD mice carrying the CD8+/8.3 T-cell receptor transgene, a T cell receptor commonly expressed in earliest islet infiltrates. Autoimmune targeting of pancreatic nervous system tissue elements seems to be an integral, early part of natural type 1 diabetes.