Sir,
In recent years, infection by enteroviruses has been associated with seroconvertion of pancreatic islet specific autoantibodies, but the precise mechanism whereby an enterovirus can initiate an autoimmune response still remains elusive Citation1-3. Molecular mimicry is one of the hypotheses that have been elaborated to explain associations between enteroviruses and autoimmunity. This phenomenon describes a situation in which primary or tridimensional structural similarities between viral proteins and autoantigen determinants can lead to functional T and B cell cross-reactivity resulting in tissue damage and perpetuation of the autoimmune response [Citation4].
To assess molecular mimicry in terms of humoral immune responses induced by different enteroviruses and cross-reactivity with human β-cell autoantigens, we determined the presence of diabetes associated antibodies in sera from enterovirus-immunized rabbit. Enterovirus antisera were prepared by, immunizing New Zealand white rabbit with enteroviral antigens obtained from 16 strains of enterovirus serotypes most frequently isolated during last 30 years in Cuba (Echoviruses: E1, E2, E3, E4, E6, E9, E11, E30 and Coxsackieviruses: CVA7, CVA9, CVA16, CVA24, CVB1, CVB3, CVB5, CVB6). Antigens from non-inoculated Vero (monkey kidney), Hep-2 (laryngeal carcinoma) and PhuE-1 (fibroblastic diploid embrionary human) cells, obtained by the same method used to prepare the viral antigens [Citation5], were utilized as controls. Eight to 10 ml of antigen was injected intravenously on days 0, 7 and 21. Heart puncture bleeding was performed 7 days after the last injection. Rabbit sera were screened for three human islet autoantigens: glutamic acid decarboxylase antibodies (GADA), insulin autoantibodies (IAA) and tyrosine phosphatase antibodies (IA2A) using international workshop-validated assays [Citation2,Citation3,Citation6].
Our results revealed the presence of antibodies to β-cell autoantigen glutamic acid decarboxylase (GAD 65) in the hyperimmune rabbit sera immunized with E9, E11, E30, CVB1, CVB3 and CVB5. We did not detect IAA or IA2A in any of the sera studied. Sera from rabbits immunized with negative control antigen preparations were negative for the three islet-related autoantibodies ().
Table I. Glutamic acid decarboxylase (GADA), insulin (IAA) and tyrosine phosphatase autoantibodies (IA2A) in sera from enterovirus-immunized rabbits.
Note that we utilized rabbits to study molecular mimicry since, they are not susceptible to enteroviral infections [Citation7]. In this way, we minimize the possibility of viral replication in cells of the host animal that could generate humoral responses as consequence of β-cell damage and subsequent autoantigen release. Accordingly, the presence of GADA in sera from enterovirus-immunized rabbits suggests the existence of common determinants among enterovirus serotypes and the human β-cell autoantigen GAD 65 which are capable to activate the immune system upon immunization.
Interestingly, cross-reactivity was only detected in animals immunized with enteroviruses belonging to group B, in which a 6 amino acid homology between human GAD 65 and the non-structural enteroviral protein (P2C) has been reported [Citation4,Citation8,Citation9]. Accordingly, homology between these two proteins could explain the cross-reaction observed in our study.
It should be noted that, the enterovirus strains in which cross-reactivity was observed have a wide circulation in Cuba and elsewhere [Citation10]. We hypothesized that β-cell autoimmunity in humans could be triggered by repeated exposure to the mimicry motif as a result of the occurrence of different enterovirus infections throughout life. Although the evidence remains indirect, our findings support he hypothesis of molecular mimicry as a possible mechanism involved in the development of β-cell autoimmunity induced by enteroviruses.
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