The current paradigm of major histocompatibility complex (MHC) and disease association suggests that efficient binding of autoantigens by disease-associated MHC molecules leads to a T cell–mediated immune response and resultant autoimmune sequelae. The data presented below offer a different model for this association of MHC with autoimmune diabetes. We used several mouse lines expressing different levels of I-Ag7 and I-Ak on the nonobese diabetic (NOD) background to evaluate the role of MHC class II in the previously described NOD T cell autoproliferation. The ratio of I-Ag7 to I-Ak expression correlated with the peripheral T cell autoproliferative phenotype in the mice studied. T cells from the NOD, [NOD × NOD.I-Anull]F1, and NOD I-Ak transgenic mice demonstrated autoproliferative responses (after priming with self-peptides), whereas the NOD.H2h4 (containing I-Ak) congenic and [NOD × NOD.H2h4 congenic]F1 mice did not. Analysis of CD4+ NOD I-Ak transgenic primed lymph node cells showed that autoreactive CD4+ T cells in the NOD I-Ak transgenic mice were restricted exclusively by I-Ag7. Considered in the context of the avidity theory of T cell activation and selection, the reported poor peptide binding capacity of NOD I-Ag7 suggested a new hypothesis to explain the effects of MHC class II expression on the peripheral autoimmune repertoire in NOD mice. This new explanation suggests that the association of MHC with diabetes results from “altered” thymic selection in which high affinity self-reactive (potentially autoreactive) T cells escape negative selection. This model offers an explanation for the requirement of homozygous MHC class II expression in NOD mice (and in humans) in susceptibility to insulin-dependent diabetes mellitus.
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21 December 1998
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December 21 1998
Analysis of the Role of Variation of Major Histocompatibility Complex Class II Expression on Nonobese Diabetic (NOD) Peripheral T Cell Response
William M. Ridgway,
William M. Ridgway
From the Stanford University School of Medicine, Department of Medicine, Division of Immunology and Rheumatology, Stanford, California 94305
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Hiroaki Ito,
Hiroaki Ito
From the Stanford University School of Medicine, Department of Medicine, Division of Immunology and Rheumatology, Stanford, California 94305
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Marcella Fassò,
Marcella Fassò
From the Stanford University School of Medicine, Department of Medicine, Division of Immunology and Rheumatology, Stanford, California 94305
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Chen Yu,
Chen Yu
From the Stanford University School of Medicine, Department of Medicine, Division of Immunology and Rheumatology, Stanford, California 94305
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C. Garrison Fathman
C. Garrison Fathman
From the Stanford University School of Medicine, Department of Medicine, Division of Immunology and Rheumatology, Stanford, California 94305
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William M. Ridgway
From the Stanford University School of Medicine, Department of Medicine, Division of Immunology and Rheumatology, Stanford, California 94305
Hiroaki Ito
From the Stanford University School of Medicine, Department of Medicine, Division of Immunology and Rheumatology, Stanford, California 94305
Marcella Fassò
From the Stanford University School of Medicine, Department of Medicine, Division of Immunology and Rheumatology, Stanford, California 94305
Chen Yu
From the Stanford University School of Medicine, Department of Medicine, Division of Immunology and Rheumatology, Stanford, California 94305
C. Garrison Fathman
From the Stanford University School of Medicine, Department of Medicine, Division of Immunology and Rheumatology, Stanford, California 94305
Address correspondence to C. Garrison Fathman, Stanford University School of Medicine, Department of Medicine, Division of Immunology and Rheumatology, Rm. S021, Stanford, CA 94305-5111. Phone: 650-723-7887; Fax: 650-725-1958; E-mail: [email protected]
Received:
May 19 1998
Revision Received:
October 08 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 188 (12): 2267–2275.
Article history
Received:
May 19 1998
Revision Received:
October 08 1998
Citation
William M. Ridgway, Hiroaki Ito, Marcella Fassò, Chen Yu, C. Garrison Fathman; Analysis of the Role of Variation of Major Histocompatibility Complex Class II Expression on Nonobese Diabetic (NOD) Peripheral T Cell Response . J Exp Med 21 December 1998; 188 (12): 2267–2275. doi: https://doi.org/10.1084/jem.188.12.2267
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