Enterovirus infection can induce immune responses that cross-react with beta-cell autoantigen tyrosine phosphatase IA-2/IAR.
Insulin-dependent (type 1) diabetes is characterized by progressive destruction of insulin-producing beta cells probably by autoreactive T lymphocytes. Viral infections, especially those caused by coxsackieviruses, are postulated to play a role in the pathogenesis of the disease in humans. One mechanism by which viral infections could initiate or accelerate diabetogenic processes is "molecular mimicry," induction of antiviral immune responses cross-reacting with epitopes in the beta-cell autoantigens. Tyrosine phosphatases (IA-2, IAR) represent a major target autoantigen in type 1 diabetes. Both humoral and cellular immune responses are directed to the carboxy-terminal (C-terminal) part of the protein. This region has a 5-amino acid sequence identity, followed by five amino acid similarity with the conservative motif in the VP1-protein of enteroviruses (PALTAVETGA/HT), which is a highly immunogenic B- and T-cell epitope in enterovirus infection-induced immune responses. This observation prompted us to investigate potential humoral cross-reactions between immune responses induced by tyrosine phosphatases and enteroviruses. The reactivities of various peptide- and virus-induced rabbit antisera clearly demonstrated that cross-reactions do exist, and in both directions. Using epitope mapping, we were able to show that several diabetes-linked epitopes in IA-2 were also recognized by CBV-4-induced antisera. Immunization of female NOD-mice with formalin-inactivated purified strain of coxsackievirus B4 (CBV-4-E2) induced an immune response that recognized the IA-2/IAR diabetogenic peptide. The results obtained with human paired sera, collected during enterovirus infection, indicated that enterovirus infection in humans may also occasionally induce a humoral response that cross-reacts with IA-2/IAR.
Härkönen
T
T
Enterovirus Laboratory, National Public Health Institute, Helsinki, Finland. taina.Härkönen@ktl.fi
Lankinen
H
H
Davydova
B
B
Hovi
T
T
Roivainen
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D002213:Capsid / Q000276:immunology; D036022:Capsid Proteins; D003429:Cross Reactions; D029821:Enterovirus A, Human / Q000276:immunology; D029822:Enterovirus B, Human / Q000276:immunology; D004769:Enterovirus Infections / Q000097:blood / Q000276:immunology*; D018604:Epitope Mapping; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D005260:Female; D007114:Immunization; D007515:Islets of Langerhans / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D017955:Poliovirus / Q000276:immunology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000276:immunology*; D011817:Rabbits; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8
D001324:Autoantigens; D036022:Capsid Proteins; D018985:Epitopes, B-Lymphocyte; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C442539:VP0 protein, Poliovirus; C442540:VP1 protein, Poliovirus; C516862:PTPRN protein, human; C102889:PTPRN2 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516863:Ptprn protein, mouse; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8