Abstract
Viral infections are associated with autoimmunity in type 1 diabetes. Here, we asked whether this association could be explained by variations in host immune response to a putative type 1 etiological factor, namely coxsackie B viruses (CVB). Heterogeneous antibody responses were observed against CVB capsid proteins. Heterogeneity was largely defined by different binding to VP1 or VP2. Antibody responses that were anti-VP2 competent but anti-VP1 deficient were unable to neutralize CVB, and were characteristic of children who developed early insulin-targeting autoimmunity, suggesting an impaired ability to clear CVB in early childhood. In contrast, children who developed a GAD-targeting autoimmunity had robust VP1 and VP2 antibody responses to CVB. We further found that 20% of memory CD4+ T cells responding to the GAD65247-266 peptide share identical T cell receptors to T cells responding to the CVB4 p2C30-51 peptide, thereby providing direct evidence for the potential of molecular mimicry as a mechanism for GAD autoimmunity. Here, we highlight functional immune response differences between children who develop insulin-targeting and GAD-targeting autoimmunity, and suggest that children who lose B cell tolerance to insulin within the first years of life have a paradoxical impaired ability to mount humoral immune responses to coxsackie viruses.
Highlights
We show a functionally relevant heterogeneity in the antibody response to CVB, putative etiological agents in type 1 diabetes, and demonstrate that children who developed early insulin-targeting autoimmunity had CVB response profiles associated with weak protection, whereas competent responses to CVB were observed in children who developed glutamic acid decarboxylase (GAD)-targeting autoimmunity
We further showed the potential for cross-reactivity between CVB and GAD at the level of the T-cell receptor (TCR)
The findings are consistent with heterogeneity in beta cell autoimmunity and the mechanisms that promote autoimmunity to different beta cell autoantigens
Summary
In an initial analysis of sera from patients with type 1 diabetes and controls, anti-VP3 antibodies for all six CVB serotypes were rare and were, not measured in the remainder of the samples (Supplementary Fig. 1). All children who developed early insulin autoimmunity had no or weak anti-VP1 antibody responses (Fig. 3a). Anti-VP1 antibodies were negative at the development of autoimmunity in the early insulin autoimmunity children (Supplementary Fig. 4).
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