Cytomegalovirus in autoimmunity: T cell crossreactivity to viral antigen and autoantigen glutamic acid decarboxylase.
Antigens of pathogenic microbes that mimic autoantigens are thought to be responsible for the activation of autoreactive T cells. Viral infections have been associated with the development of the neuroendocrine autoimmune diseases type 1 diabetes and stiff-man syndrome, but the mechanism is unknown. These diseases share glutamic acid decarboxylase (GAD65) as a major autoantigen. We screened synthetic peptide libraries dedicated to bind to HLA-DR3, which predisposes to both diseases, using clonal CD4(+) T cells reactive to GAD65 isolated from a prediabetic stiff-man syndrome patient. Here we show that these GAD65-specific T cells crossreact with a peptide of the human cytomegalovirus (hCMV) major DNA-binding protein. This peptide was identified after database searching with a recognition pattern that had been deduced from the library studies. Furthermore, we showed that hCMV-derived epitope can be naturally processed by dendritic cells and recognized by GAD65 reactive T cells. Thus, hCMV may be involved in the loss of T cell tolerance to autoantigen GAD65 by a mechanism of molecular mimicry leading to autoimmunity.
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, P. O. Box 9600, NL-2300 RC Leiden, The Netherlands.
H S
HS
Hiemstra
N C
NC
Schloot
P A
PA
van Veelen
S J
SJ
Willemen
K L
KL
Franken
J J
JJ
van Rood
R R
RR
de Vries
A
A
Chaudhuri
P O
PO
Behan
J W
JW
Drijfhout
B O
BO
Roep
D000956:Antigens, Viral / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D003429:Cross Reactions; D003587:Cytomegalovirus / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D013601:T-Lymphocytes / Q000276:immunology*
D000956:Antigens, Viral; D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D005968:Glutamate Decarboxylase