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

Nature Medicine volume 9, pages 198–205 (2003)Cite this article

Abstract

Pancreatic islets of Langerhans are enveloped by peri-islet Schwann cells (pSC), which express glial fibrillary acidic protein (GFAP) and S100β. 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 β-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 S100β prevented diabetes. pSC survived in rat insulin promoter Iymphocytic choriomeningitis virus (rip–LCMV) glycoprotein/CD8+ T-cell receptorgp double-transgenic mice with virus-induced diabetes, suggesting that pSC death is not an obligate consequence of local inflammation and β-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.

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Figure 1: GFAP+ pSC are the first target tissue in NOD prediabetes.
Figure 2: B- and T-cell autoimmunity to pSC constituents in NOD females.
Figure 3: pSC autoimmunity in human T1D.
Figure 4: Autoimmunity to pSC antigens induces insulitis and modifies adoptively transferred diabetes development.
Figure 5: Differential effects of two transgenic TCR diabetes models.

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Acknowledgements

We thank M. Trucco and R. Boti for provision of purified human islets from the Pittsburgh JDRF Diabetes Center; D. Homeard for transmission electron microscopy; D. Midha, C. McKerlie and D. Winer for helpful discussions; and A. Darnley and K. Reilly for collection of human blood samples and ICA assays. This work was supported by grants from the Canadian Institutes of Health Research, the Juvenile Diabetes Research Foundation, the National Institutes of Health and the Renziehausen Fund.

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Author notes

  1. Shawn Winer and Hubert Tsui: S.W. and H.T. contributed equally to this study.

Authors and Affiliations

  1. Research Institute and Departments of Pediatrics and Immunology, Hospital For Sick Children, University of Toronto, Toronto, Ontario, Canada

    Shawn Winer, Hubert Tsui, Ambrose Lau, Aihua Song, Roy K. Cheung, Anastazia Sampson, Fatemeh Afifiyan & H -Michael Dosch

  2. Syn*X Pharma Inc., Toronto, Ontario, Canada

    Xiaomao Li & George Jackowski

  3. Departments of Medical Biophysics and Immunology, UHN, Ontario Cancer Institute, Toronto, Ontario, Canada

    Alisha Elford & Pamela Ohashi

  4. Department of Pediatrics, Children's Hospital and University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Dorothy J. Becker

  5. Department of Microbiology and Infectious Diseases and Julia MacFarlane Diabetes Research Centre, Faculty of Medicine, Health Sciences Centre, University of Calgary, Calgary, Canada

    Pere Santamaria

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Correspondence to H -Michael Dosch.

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Competing interests

G.J. and X.L., of SynX Pharma Inc., Toronto, Ontario, employed proteomics technology to make the original observation of GFAP autoantibodies in sera from humans and NOD mice with probable prediabetes. The company filed for patent protection and provided some of the funding from the present study in the form of a peer-reviewed, joint University-Industry grant from the Canadian Institutes of Health Research (CHIR). X.L. has since moved to become a Professor of Biochemistry and principal of the Biotech Center for Applied Research and Training at Seneca College, Toronto.

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Winer, S., Tsui, H., Lau, A. et al. Autoimmune islet destruction in spontaneous type 1 diabetes is not β-cell exclusive. Nat Med 9, 198–205 (2003). https://doi.org/10.1038/nm818

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