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In type 1 diabetes a subset of anti-coxsackievirus B4 antibodies recognize autoantigens and induce apoptosis of pancreatic beta cells.

Bason C, Lorini R, Lunardi C, Dolcino M, Giannattasio A, d'Annunzio G, Rigo A, Pedemonte N, Corrocher R, Puccetti A - PLoS ONE (2013)

Bottom Line: Coxsackievirus B infection has been linked to the onset of type 1 diabetes; however its precise role has not been elucidated yet.We identified an immunodominant peptide recognized by the majority of individual patients'sera, that shares homology with Coxsackievirus B4 VP1 protein and with beta-cell specific autoantigens such as phogrin, phosphofructokinase and voltage-gated L-type calcium channels known to regulate beta cell apoptosis.Our results provide evidence that in autoimmune diabetes a subset of anti-Coxsackievirus antibodies are able to induce apoptosis of pancreatic beta cells which is considered the most critical and final step in the development of autoimmune diabetes without which clinical manifestations do not occur.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy.

ABSTRACT
Type 1 diabetes is characterized by autoimmune destruction of pancreatic beta cells. The role played by autoantibodies directed against beta cells antigens in the pathogenesis of the disease is still unclear. Coxsackievirus B infection has been linked to the onset of type 1 diabetes; however its precise role has not been elucidated yet. To clarify these issues, we screened a random peptide library with sera obtained from 58 patients with recent onset type 1 diabetes, before insulin therapy. We identified an immunodominant peptide recognized by the majority of individual patients'sera, that shares homology with Coxsackievirus B4 VP1 protein and with beta-cell specific autoantigens such as phogrin, phosphofructokinase and voltage-gated L-type calcium channels known to regulate beta cell apoptosis. Antibodies against the peptide affinity-purified from patients' sera, recognized the viral protein and autoantigens; moreover, such antibodies induced apoptosis of the beta cells upon binding the L-type calcium channels expressed on the beta cell surface, suggesting a calcium dependent mechanism. Our results provide evidence that in autoimmune diabetes a subset of anti-Coxsackievirus antibodies are able to induce apoptosis of pancreatic beta cells which is considered the most critical and final step in the development of autoimmune diabetes without which clinical manifestations do not occur.

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Related in: MedlinePlus

Antibodies against the T1DM and COXSA peptides bind autoantigens.A, B, C, T1DM peptide shares homology with IA-2β, 6-PFKP, CACNA1D autoantigens respectively; vertical line = identical amino acids; asterisk = conservative substitutions. D, Immunoblot analysis of beta cells lysates immunoprecipitated with affinity purified antibodies against T1DM peptide (Lane 1) or against COXSA peptide (Lane 2) or against the irrelevant peptide (Lane 3) revealed with specific anti-phogrin antibody, or E, with specific anti-PFKP antibody, or F, with specific anti-L-type calcium channel antibody: the two bands represent different isoforms of the CACNA1D molecule.
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pone-0057729-g002: Antibodies against the T1DM and COXSA peptides bind autoantigens.A, B, C, T1DM peptide shares homology with IA-2β, 6-PFKP, CACNA1D autoantigens respectively; vertical line = identical amino acids; asterisk = conservative substitutions. D, Immunoblot analysis of beta cells lysates immunoprecipitated with affinity purified antibodies against T1DM peptide (Lane 1) or against COXSA peptide (Lane 2) or against the irrelevant peptide (Lane 3) revealed with specific anti-phogrin antibody, or E, with specific anti-PFKP antibody, or F, with specific anti-L-type calcium channel antibody: the two bands represent different isoforms of the CACNA1D molecule.

Mentions: As type 1 diabetes is characterized by autoimmune injury of the pancreatic beta insulae, we next compared the T1DM peptide sequence with human proteins in a protein data bank and found that the peptide shares homology with 3 different beta-cell specific self-antigens: 1) IA-2β, also called phogrin (PTPRN2) (Fig. 2A), 2) the enzyme 6-phosphofructo-1-kinase (PFKP) (Fig. 2B), 3) voltage-dependent L-type calcium channel alpha-1D subunit (CACNA1D) (Fig. 2C).


In type 1 diabetes a subset of anti-coxsackievirus B4 antibodies recognize autoantigens and induce apoptosis of pancreatic beta cells.

Bason C, Lorini R, Lunardi C, Dolcino M, Giannattasio A, d'Annunzio G, Rigo A, Pedemonte N, Corrocher R, Puccetti A - PLoS ONE (2013)

Antibodies against the T1DM and COXSA peptides bind autoantigens.A, B, C, T1DM peptide shares homology with IA-2β, 6-PFKP, CACNA1D autoantigens respectively; vertical line = identical amino acids; asterisk = conservative substitutions. D, Immunoblot analysis of beta cells lysates immunoprecipitated with affinity purified antibodies against T1DM peptide (Lane 1) or against COXSA peptide (Lane 2) or against the irrelevant peptide (Lane 3) revealed with specific anti-phogrin antibody, or E, with specific anti-PFKP antibody, or F, with specific anti-L-type calcium channel antibody: the two bands represent different isoforms of the CACNA1D molecule.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585221&req=5

pone-0057729-g002: Antibodies against the T1DM and COXSA peptides bind autoantigens.A, B, C, T1DM peptide shares homology with IA-2β, 6-PFKP, CACNA1D autoantigens respectively; vertical line = identical amino acids; asterisk = conservative substitutions. D, Immunoblot analysis of beta cells lysates immunoprecipitated with affinity purified antibodies against T1DM peptide (Lane 1) or against COXSA peptide (Lane 2) or against the irrelevant peptide (Lane 3) revealed with specific anti-phogrin antibody, or E, with specific anti-PFKP antibody, or F, with specific anti-L-type calcium channel antibody: the two bands represent different isoforms of the CACNA1D molecule.
Mentions: As type 1 diabetes is characterized by autoimmune injury of the pancreatic beta insulae, we next compared the T1DM peptide sequence with human proteins in a protein data bank and found that the peptide shares homology with 3 different beta-cell specific self-antigens: 1) IA-2β, also called phogrin (PTPRN2) (Fig. 2A), 2) the enzyme 6-phosphofructo-1-kinase (PFKP) (Fig. 2B), 3) voltage-dependent L-type calcium channel alpha-1D subunit (CACNA1D) (Fig. 2C).

Bottom Line: Coxsackievirus B infection has been linked to the onset of type 1 diabetes; however its precise role has not been elucidated yet.We identified an immunodominant peptide recognized by the majority of individual patients'sera, that shares homology with Coxsackievirus B4 VP1 protein and with beta-cell specific autoantigens such as phogrin, phosphofructokinase and voltage-gated L-type calcium channels known to regulate beta cell apoptosis.Our results provide evidence that in autoimmune diabetes a subset of anti-Coxsackievirus antibodies are able to induce apoptosis of pancreatic beta cells which is considered the most critical and final step in the development of autoimmune diabetes without which clinical manifestations do not occur.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy.

ABSTRACT
Type 1 diabetes is characterized by autoimmune destruction of pancreatic beta cells. The role played by autoantibodies directed against beta cells antigens in the pathogenesis of the disease is still unclear. Coxsackievirus B infection has been linked to the onset of type 1 diabetes; however its precise role has not been elucidated yet. To clarify these issues, we screened a random peptide library with sera obtained from 58 patients with recent onset type 1 diabetes, before insulin therapy. We identified an immunodominant peptide recognized by the majority of individual patients'sera, that shares homology with Coxsackievirus B4 VP1 protein and with beta-cell specific autoantigens such as phogrin, phosphofructokinase and voltage-gated L-type calcium channels known to regulate beta cell apoptosis. Antibodies against the peptide affinity-purified from patients' sera, recognized the viral protein and autoantigens; moreover, such antibodies induced apoptosis of the beta cells upon binding the L-type calcium channels expressed on the beta cell surface, suggesting a calcium dependent mechanism. Our results provide evidence that in autoimmune diabetes a subset of anti-Coxsackievirus antibodies are able to induce apoptosis of pancreatic beta cells which is considered the most critical and final step in the development of autoimmune diabetes without which clinical manifestations do not occur.

Show MeSH
Related in: MedlinePlus