Molecular mimicry in type 1 diabetes mellitus revisited: T-cell clones to GAD65 peptides with sequence homology to Coxsackie or proinsulin peptides do not crossreact with homologous counterpart.
Type 1 diabetes mellitus is a T-cell mediated autoimmune disease in which the insulin-producing pancreatic beta cells are selectively destroyed. Molecular mimicry and T-cell crossreactivity to beta-cell autoantigens and environmental agents with sequence similarities have been a proposed mechanism underlying the pathogenesis of type 1 diabetes, but actual crossreactivity has not yet been demonstrated. We isolated and investigated T cells reactive to GAD65 peptides and homologous peptides of the Coxsackie virus protein P2C and proinsulin from recent onset type 1 diabetes patients, and tested their fine specificity and cytokine production profile. Six T-cell lines specific for GAD65 peptides (amino acids 491-530) with homology to proinsulin (B20-C14) were isolated from six newly diagnosed patients with type 1 diabetes, but none of the stable T-cell lines crossreacted to the homologous proinsulin peptides. Similarly, none of four T-cell lines reactive to GAD65 peptides (amino acids 247-280) with sequence homology to Coxsackie P2C (amino acids 30-50) crossreacted to the homologous viral peptide. Two T-cell lines corecognized a GAD65 peptide and a Coxsackie P2C peptide. However, the antigen-specific T-cell clones from these T-cell lines were reacting either with the GAD65 peptide or the Coxsackie P2C peptide using different restriction elements without crossreacting to the homologous peptide. Our data demonstrate that homologous peptides previously proposed to serve as targets for crossreactivity indeed are immunogenic. Yet, T-cell clones did not crossreact with linear sequence homologies, despite strong T-cell responses to individual peptides.
Schloot
N C
NC
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Willemen
S J
SJ
Duinkerken
G
G
Drijfhout
J W
JW
de Vries
R R
RR
Roep
B O
BO
D000595:Amino Acid Sequence; D001324:Autoantigens / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology*; D002478:Cells, Cultured; D003429:Cross Reactions; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology*; D004770:Enterovirus / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006801:Humans; D007527:Isoenzymes / Q000276:immunology*; D018716:Molecular Mimicry / Q000276:immunology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology*; D011384:Proinsulin / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D017361:Viral Nonstructural Proteins / Q000276:immunology*
D001324:Autoantigens; D002352:Carrier Proteins; D007527:Isoenzymes; D010455:Peptides; D017361:Viral Nonstructural Proteins; D011384:Proinsulin; C076023:2C protein, viral; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2