Molecular mimicry in type 1 diabetes: immune cross-reactivity between islet autoantigen and human cytomegalovirus but not Coxsackie virus.
Type 1 diabetes is caused by a T cell-mediated autoimmune destruction of the pancreatic beta cells. Molecular mimicry between viral pathogens and beta cell protein has been a popular theory to explain loss of tolerance in type 1 diabetes. However, functional data in support of this hypothesis have been lacking, presumably because the homologies were defined on the basis of linear similarities in peptide sequences, which ignores the criteria of HLA versus T cell receptor contact residues in peptide epitopes required for T cell recognition. We applied a HLA-binding dedicated peptide microarray analysis using autoreactive T cell clones specific for the autoantigen GAD65 to determine the algorithm of T cell recognition by this given T cell clone. The subsequent database search identified a 100% fit with cytomegalovirus peptide, which was subsequently shown to be recognized by these clonal T cells. However, T cell clones reactive with linear homologies previously described as putative candidates for T cell cross-reactivity between GAD65 and Coxsackie virus peptide were unable to recognize the homologous counterparts.
Roep
B O
BO
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands. boroep@lumc.nl
Hiemstra
H S
HS
Schloot
N C
NC
De Vries
R R P
RR
Chaudhuri
A
A
Behan
P O
PO
Drijfhout
J W
JW
D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D000956:Antigens, Viral / Q000737:chemistry / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D002478:Cells, Cultured; D003429:Cross Reactions / Q000276:immunology*; D003587:Cytomegalovirus / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000276:immunology*; D004770:Enterovirus / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005968:Glutamate Decarboxylase / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology*; D007527:Isoenzymes / Q000737:chemistry / Q000276:immunology*; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology
D000956:Antigens, Viral; D001324:Autoantigens; D000939:Epitopes; D007527:Isoenzymes; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2