Imaged parent items

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

Wadsworth Pediatric Multiple Sclerosis Study Group.
Annals of Neurology 2008;63:98-111

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

The cause of multiple sclerosis (MS) involves a complex interplay between environmental factors and genetic predisposition, associated with loss of self-tolerance and heightened reactivity to central nervous system (CNS) antigens. This process is thought to be mediated in part by some form of in vivo priming or abnormal sensitization of peripheral T cells reactive to CNS targets including myelin epitopes (reviewed in Hafler and colleagues1 and Bar-Or2).Whether these CNS autoreactive T cells are essential in mediating particular stages of disease (eg, initiation vs propagation), or whether they represent heightened immune reactivity generated in response to CNS tissue injury remains unknown. The specific epitopes and the environmental triggers that may lead to abnormal sensitization of myelin-reactive T cells, during either initiation or propagation of disease, have not been established. A variety of environmental triggers has been proposed, including common infections,3, 4 vitamin D deficiency,5 and dietary exposures.6 The possible contribution of dietary exposures to early events in MS, and in other autoimmune diseases such as type 1 (insulin-dependent) diabetes mellitus (T1D), has been debated over the years6–13 and continues to be of considerable interest14–19 because of the broad economic and health policy implications.

A major impediment to elucidating earliest events and putative environmental triggers in human autoimmune diseases, in general, relates to the considerable lag time between biological disease onset and clinical diagnosis. Childhood-onset clinically isolated syndromes (CIS) and MS provide a window into early disease mechanisms less susceptible to confounding by irrelevant exposures.

Here, we compare T-cell reactivities with target-organ and environmental dietary antigens in childhood-onset CIS/MS and in pediatric control cohorts, including children with T1D who represent an autoimmune disease that presents at a similar age and is thought to share a pathophysiology that involves a susceptible host, environmental triggers, and abnormal sensitization of T cells targeting self- (pancreatic) antigens. Our findings point to the presence of a relatively nonspecific abnormality of T-cell regulation in the early stages of both autoimmune diseases and challenge our view of the relation between CNS injury and CNS autoreactivity.

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