Identification of mimicry peptides based on sequential motifs of epitopes derived from 65-kDa glutamic acid decarboxylase.
Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease with a predominantly non-hereditary etiology that results in a destruction of pancreatic beta cells by autoaggressive T lymphocytes. Neither the mechanism of initial stimulation of these T cells nor the nature of the environmental factors implicated in the disease have so far been identified. However, both issues are taken into account by the hypothesis of initial T cell activation by viral or bacterial mimicry peptides with sequence similarities to pancreatic self antigens. We determined sequential epitope motifs to search for mimicry peptides stimulating T cell lines specific for two epitopes derived from the IDDM autoantigen 65-kDa glutamic acid decarboxylase (GAD65). These were GAD65 (88-99), presented by HLA-DRB1*0101, and GAD65 (248-257), presented by HLA-DRB5*0101. T cell stimulation by peptides with substitutions in HLA anchor or T cell contact positions was analyzed to establish degenerate epitope motifs for database searching. Out of 28 tested candidate mimicry peptides derived from bacterial, viral and human proteins, 3 stimulated T cell lines and a T cell clone specific for epitope GAD65 (248-257). Our results demonstrate that mono- and polyclonal GAD65-specific T cells from IDDM patients can be stimulated by viral and bacterial peptides with little apparent sequence homology with autoantigenic epitopes. Moreover, in a synopsis with related published studies, our findings suggest that simple degenerate search motifs comprising principal T cell contacts plus HLA class II binding motifs may suffice to identify most mimicry peptides.
Bach
J M
JM
INSERM U25, Paris, France.
Otto
H
H
Jung
G
G
Cohen
H
H
Boitard
C
C
Bach
J F
JF
van Endert
P M
PM
D000328:Adult; D000906:Antibodies / Q000378:metabolism; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D008875:Middle Aged; D010455:Peptides / Q000737:chemistry / Q000276:immunology*
D000906:Antibodies; D018984:Epitopes, T-Lymphocyte; D010455:Peptides; D005968:Glutamate Decarboxylase