Autoimmune islet destruction in spontaneous type 1 diabetes is not beta-cell exclusive.
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.
Winer
Shawn
S
Hospital For Sick Children, Research Institute and Department of Pediatrics and Immunology, University of Toronto, Toronto, Ontario, Canada.
Tsui
Hubert
H
Lau
Ambrose
A
Song
Aihua
A
Li
Xiaomao
X
Cheung
Roy K
RK
Sampson
Anastazia
A
Afifiyan
Fatemeh
F
Elford
Alisha
A
Jackowski
George
G
Becker
Dorothy J
DJ
Santamaria
Pere
P
Ohashi
Pamela
P
Dosch
H-Michael
HM
D000818:Animals; D001323:Autoantibodies / Q000032:analysis / Q000276:immunology; D001483:Base Sequence; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D005455:Fluorescent Antibody Technique; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009414:Nerve Growth Factors / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D012583:Schwann Cells / Q000276:immunology / Q000378:metabolism; D013045:Species Specificity
D001323:Autoantibodies; D017931:DNA Primers; D005904:Glial Fibrillary Acidic Protein; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins