NOD mouse diabetes: the ubiquitous mouse hsp60 is a beta-cell target antigen of autoimmune T cells.
In the NOD mouse, the onset of beta-cell destruction is associated with spontaneous development of T-lymphocytes reactive to members of the 60 kDa heat shock protein (hsp60) family, including the Mycobacterial (MT) and the human (H) hsp60 molecules. Diabetes in the NOD mouse is a spontaneous tissue-specific autoimmune disease occurring without prior immunization. Therefore, it has been suggested that the anti-hsp60 T cells involved in the autoimmune diabetes of NOD mice might reflect molecular mimicry between MT-hsp60 and a beta-cell tissue specific molecule sharing similar T cell epitopes, the p277 peptide of hsp60 in particular. We cloned and expressed the mouse hsp60 cDNA from a beta-cell tumour. This mouse beta-cell hsp60 cDNA was found to be identical in sequence to the hsp60 of mouse fibroblasts. We further report that NOD spleen cells and an NOD diabetogenic T cell clone C9 responded to the recombinant mouse hsp60 and to its peptide M-p277 to the same extent as to H-hsp60 and H-p277. Splenocytes of mice of other strains did not respond to p277. Moreover, treatment of 3 month old NOD mice with the non-modified self M-p277 peptide was as efficient as H-p277, from which it differs in one amino acid, in halting progression of the disease. Thus, anti-H-p277 T cells modulating diabetes in the NOD mouse are autoreactive, and are targeted at the mouse beta-cell hsp60, which is not tissue specific. These findings raise the question of how a non-tissue specific molecule may be a target of a tissue-specific autoimmune disease.
Birk
O S
OS
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Elias
D
D
Weiss
A S
AS
Rosen
A
A
van-der Zee
R
R
Walker
M D
MD
Cohen
I R
IR
D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D015153:Blotting, Western; D002455:Cell Division; D018834:Chaperonin 60 / Q000235:genetics / Q000276:immunology*; D003001:Cloning, Molecular; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D006360:Heat-Shock Proteins / Q000276:immunology / Q000627:therapeutic use; D007515:Islets of Langerhans / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology / Q000627:therapeutic use; D011817:Rabbits; D013601:T-Lymphocytes / Q000276:immunology*
D000941:Antigens; D018834:Chaperonin 60; D006360:Heat-Shock Proteins; D010446:Peptide Fragments; C095402:peptide 277, heat shock protein 60