The pathogenesis of autoimmune diabetes mellitus.
There is increasing evidence that both DP and DR BB rats fail to clonally delete autoreactive T cells in the thymus that are important in the development of autoimmune IDDM. The DP BB rat also has a defect in its ability to generate a regulatory (RT6+) T-cell population that would prevent the onset of diabetes and, therefore, it becomes spontaneously diabetic. The DR rat develops autoreactive T cells, but does not express diabetes because of the concurrent development of a regulatory (RT6+) T-cell population. We suggest that in the BB rat, the initial immunological lesion is orchestrated by an APC in close proximity to pancreatic islet beta cells, and may be specifically directed to the beta cell itself. The release of cytokines in the vicinity of the beta cell destroys this highly susceptible target, causing the release of beta cell 'autoantigens'. These autoantigens, in turn, target autoreactive T cells to the beta cells, allowing a focal destructive process to spread throughout the pancreas. The ultimate destruction of the islets and the development of diabetes result from a cascading effect of this process, with the recruitment of other non-specific immune mediators. A similar process may also be initiated by APC within the thyroid of the rat, resulting in thyroiditis. The fact that the thyrocyte does not die is unexplained, but it could relate to the relative insensitivity of this cell type to various cytokines.
Rossini
A A
AA
Department of Medicine, University of Massachusetts Medical School, Worcester.
Mordes
J P
JP
Greiner
D L
DL
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D001685:Biological Factors / Q000502:physiology; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D016207:Cytokines; D003921:Diabetes Mellitus, Experimental / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007116:Immunization, Passive; D007153:Immunologic Deficiency Syndromes / Q000276:immunology / Q000473:pathology; D007515:Islets of Langerhans / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains / Q000276:immunology; D008954:Models, Biological; D051381:Rats; D011913:Rats, Inbred BB / Q000276:immunology; D013601:T-Lymphocytes / Q000473:pathology / Q000637:transplantation; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology
D001324:Autoantigens; D001685:Biological Factors; D016207:Cytokines