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

Pancreatic islets of Langerhans are enveloped by peri-islet Schwann cells (pSC), which express glial fibrillary acidic protein (GFAP) and S100beta. SC-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 lymphocytic choriomeningitis virus (rip-LCMV) glycoprotein/CD8(+) T-cell receptor(9p) double-transgenic mice with virus-induced diabetes, suggesting that pSC death is not an obligate consequence of local inflammation and 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.