Incomplete immune response to coxsackie B viruses associates with early autoimmunity against insulin.
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.
DFG-Center for Regenerative Therapies Dresden, Dresden, Germany.
Michelle P
MP
Ashton
DFG-Center for Regenerative Therapies Dresden, Dresden, Germany.
Anne
A
Eugster
DFG-Center for Regenerative Therapies Dresden, Dresden, Germany.
Denise
D
Walther
DFG-Center for Regenerative Therapies Dresden, Dresden, Germany.
Natalie
N
Daehling
Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany.
Stephanie
S
Riethausen
DFG-Center for Regenerative Therapies Dresden, Dresden, Germany.
Denise
D
Kuehn
Department of Molecular Pathology, University Hospital Tübingen, Tübingen, Germany.
Karin
K
Klingel
Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany.
Andreas
A
Beyerlein
Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany.
Stephanie
S
Zillmer
Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany.|Forschergruppe Diabetes e.V., Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Anette-Gabriele
AG
Ziegler
DFG-Center for Regenerative Therapies Dresden, Dresden, Germany.|Forschergruppe Diabetes e.V., Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Ezio
E
Bonifacio
D000293:Adolescent; D000906:Antibodies / Q000276:immunology; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D036022:Capsid Proteins / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003384:Coxsackievirus Infections / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000821:virology*; D029822:Enterovirus B, Human / Q000276:immunology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000276:immunology*; D008297:Male
D000906:Antibodies; D036022:Capsid Proteins; D007328:Insulin; D005968:Glutamate Decarboxylase