Abnormal T-cell reactivities in childhood inflammatory demyelinating disease and type 1 diabetes

Authors

  • Brenda Banwell MD,

    1. Division of Neurology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada
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  • Amit Bar-Or MD,

    Corresponding author
    1. Neuroimmunology Unit, Montreal Neurological Institute and McGill University, Montreal, Quebec, Canada
    • Departments of Neurology and Neurosurgery and Microbiology and Immunology, Experimental Therapeutics Program, Montreal Neurological Institute, McGill University, 3801 University Street, #111, Montreal, Quebec, H3A 2B4, Canada
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  • Roy Cheung MSc,

    1. Division of Immunology, Injury and Repair, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada
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  • Julia Kennedy MSc,

    1. Division of Neurology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada
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  • Lauren B. Krupp MD,

    1. Department of Neurology, Stony Brook University, Stony Brook, NY
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  • Dorothy J. Becker MD,

    1. Division of Endocrinology, Children's Hospital of Pittsburgh, Pittsburgh, PA
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  • Hans-Michael Dosch MD, PhD

    Corresponding author
    1. Division of Immunology, Injury and Repair, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada
    • Division of Immunology, Injury and Repair, Research Institute, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada
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  • Members of the Wadsworth Pediatric Multiple Sclerosis Study Group are listed in the Appendix on page xx.

Abstract

Objectives

Pediatric-onset multiple sclerosis offers a unique window into early targets and mechanisms of immune dysregulation. It is unknown whether heightened T-cell reactivities documented in adult patients, to both target-organ and environmental antigens, emerge in parallel or develop as early or late events. Our objectives were to determine the presence, pattern, and specificity of abnormal T-cell reactivities to such antigens in the earliest stages of the multiple sclerosis process.

Methods

Peripheral T-cell proliferative responses to self-, dietary, and control antigens were blindly evaluated in a large cohort of well-characterized children (n = 172) with central nervous system (CNS) inflammatory demyelination (n = 63), recent-onset type 1 (insulin-dependent) diabetes mellitus (T1D; n = 41), nonautoimmune neurological conditions (n = 39), and healthy children (n = 29).

Results

Children with inflammatory demyelination, CNS injury, and T1D exhibited heightened T-cell reactivities to self-antigens, and these responses were not strictly limited to the disease target organs. Children with autoimmune disease and CNS injury also exhibited abnormal T-cell responses against multiple cow-milk proteins. Responses to specific milk epitopes distinguished T1D from inflammatory demyelination and other neurological diseases.

Interpretation

Abnormal T-cell reactivities to self- and environmental antigens manifest in the earliest clinical stages of inflammatory demyelination and T1D. The pattern of heightened T-cell reactivities implicates both shared and distinct mechanisms of immune dysregulation in the different autoimmune diseases. Abnormal T-cell responses in children with tissue injury challenge the prevailing view that CNS autoreactive cells inherently mediate the disease in early multiple sclerosis. Ann Neurol 2007

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