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Incomplete immune response to coxsackie B viruses associates with early autoimmunity against insulin

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

Early insulin autoimmunity is associated with a reduced anti-VP1 CVB antibody response.Anti-CVB antibodies in sera from 89 children genetically at risk for type 1 diabetes and followed for beta cell autoantibody development in the BABYDIET study. Anti-VP1 (a), anti-VP2 (b) and anti-VP4 (c) antibodies at 3 years of age (y axis) are shown in children stratified as beta cell autoantibody negative throughout follow-up (no autoimmunity), beta cell autoantibody seroconversion before age 3 years with IAA as the first detected autoantibodies (early insulin), and beta cell autoantibody seroconversion with GAD as the first detected autoantibody target (GAD). Each point is an individual and the horizontal bar indicates the median. For the early insulin autoimmunity children, the unique symbols correspond to data points of an individual child. *p-value < 0.05 or **p-value < 0.01 based on comparison with early insulin autoimmunity group for the corresponding CVB serotype using the Mann Whitney U test.
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f3: Early insulin autoimmunity is associated with a reduced anti-VP1 CVB antibody response.Anti-CVB antibodies in sera from 89 children genetically at risk for type 1 diabetes and followed for beta cell autoantibody development in the BABYDIET study. Anti-VP1 (a), anti-VP2 (b) and anti-VP4 (c) antibodies at 3 years of age (y axis) are shown in children stratified as beta cell autoantibody negative throughout follow-up (no autoimmunity), beta cell autoantibody seroconversion before age 3 years with IAA as the first detected autoantibodies (early insulin), and beta cell autoantibody seroconversion with GAD as the first detected autoantibody target (GAD). Each point is an individual and the horizontal bar indicates the median. For the early insulin autoimmunity children, the unique symbols correspond to data points of an individual child. *p-value < 0.05 or **p-value < 0.01 based on comparison with early insulin autoimmunity group for the corresponding CVB serotype using the Mann Whitney U test.

Mentions: All children who developed early insulin autoimmunity had no or weak anti-VP1 antibody responses (Fig. 3a). Anti-VP1 antibody responses in these children were lower than the responses in children who did not develop beta cell autoimmunity (p < 0.05 for CVB 1, 2, 3, 4, 5) and children who developed GAD autoimmunity (p < 0.05 CVB1, 2, 5 and p < 0.001 CVB3, 4, 6). Anti-VP1 antibodies were also negative at the development of autoimmunity in the early insulin autoimmunity children (Supplementary Fig. 4). No differences between the autoantibody negative children and early insulin autoimmunity children or children who developed GAD autoimmunity were observed for anti-VP2 and anti-VP4 antibodies (Fig. 3b,c). Importantly, the majority of early insulin autoimmunity children had anti-VP2 or anti-VP4 antibodies at age 3 years, suggesting that they had been previously exposed to CVB (Fig. 3b,c).


Incomplete immune response to coxsackie B viruses associates with early autoimmunity against insulin
Early insulin autoimmunity is associated with a reduced anti-VP1 CVB antibody response.Anti-CVB antibodies in sera from 89 children genetically at risk for type 1 diabetes and followed for beta cell autoantibody development in the BABYDIET study. Anti-VP1 (a), anti-VP2 (b) and anti-VP4 (c) antibodies at 3 years of age (y axis) are shown in children stratified as beta cell autoantibody negative throughout follow-up (no autoimmunity), beta cell autoantibody seroconversion before age 3 years with IAA as the first detected autoantibodies (early insulin), and beta cell autoantibody seroconversion with GAD as the first detected autoantibody target (GAD). Each point is an individual and the horizontal bar indicates the median. For the early insulin autoimmunity children, the unique symbols correspond to data points of an individual child. *p-value < 0.05 or **p-value < 0.01 based on comparison with early insulin autoimmunity group for the corresponding CVB serotype using the Mann Whitney U test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5015062&req=5

f3: Early insulin autoimmunity is associated with a reduced anti-VP1 CVB antibody response.Anti-CVB antibodies in sera from 89 children genetically at risk for type 1 diabetes and followed for beta cell autoantibody development in the BABYDIET study. Anti-VP1 (a), anti-VP2 (b) and anti-VP4 (c) antibodies at 3 years of age (y axis) are shown in children stratified as beta cell autoantibody negative throughout follow-up (no autoimmunity), beta cell autoantibody seroconversion before age 3 years with IAA as the first detected autoantibodies (early insulin), and beta cell autoantibody seroconversion with GAD as the first detected autoantibody target (GAD). Each point is an individual and the horizontal bar indicates the median. For the early insulin autoimmunity children, the unique symbols correspond to data points of an individual child. *p-value < 0.05 or **p-value < 0.01 based on comparison with early insulin autoimmunity group for the corresponding CVB serotype using the Mann Whitney U test.
Mentions: All children who developed early insulin autoimmunity had no or weak anti-VP1 antibody responses (Fig. 3a). Anti-VP1 antibody responses in these children were lower than the responses in children who did not develop beta cell autoimmunity (p < 0.05 for CVB 1, 2, 3, 4, 5) and children who developed GAD autoimmunity (p < 0.05 CVB1, 2, 5 and p < 0.001 CVB3, 4, 6). Anti-VP1 antibodies were also negative at the development of autoimmunity in the early insulin autoimmunity children (Supplementary Fig. 4). No differences between the autoantibody negative children and early insulin autoimmunity children or children who developed GAD autoimmunity were observed for anti-VP2 and anti-VP4 antibodies (Fig. 3b,c). Importantly, the majority of early insulin autoimmunity children had anti-VP2 or anti-VP4 antibodies at age 3 years, suggesting that they had been previously exposed to CVB (Fig. 3b,c).

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus