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


CONCLUSIONS
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.
Banwell
Brenda
B
Division of Neurology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
Bar-Or
Amit
A
Cheung
Roy
R
Kennedy
Julia
J
Krupp
Lauren B
LB
Becker
Dorothy J
DJ
Dosch
Hans-Michael
HM
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D002490:Central Nervous System / Q000276:immunology / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000503:physiopathology; D004044:Dietary Proteins / Q000276:immunology; D005260:Female; D015386:Hazardous Substances / Q000276:immunology; D006801:Humans; D007107:Immune System / Q000276:immunology / Q000503:physiopathology; D007154:Immune System Diseases / Q000276:immunology / Q000503:physiopathology; D007223:Infant; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D009103:Multiple Sclerosis / Q000276:immunology* / Q000503:physiopathology; D017634:Self Tolerance / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D001324:Autoantigens; D004044:Dietary Proteins; D015386:Hazardous Substances