Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 183K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ridgway, W. M. Articles by Garrison Fathman, C. Search for Related Content PubMed PubMed Citation Articles by Ridgway, W. M. Articles by Garrison Fathman, C. Social Bookmarking                            What's this?

Articles

From the Stanford University School of Medicine, Department of Medicine, Division of Immunology and Rheumatology, Stanford, California 94305

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-A^g7 and I-A^k 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-A^g7 to I-A^k expression correlated with the peripheral T cell autoproliferative phenotype in the mice studied. T cells from the NOD, [NOD x NOD.I-A^null]F1, and NOD I-A^k transgenic mice demonstrated autoproliferative responses (after priming with self-peptides), whereas the NOD.H2^h4 (containing I-A^k) congenic and [NOD x NOD.H2^h4 congenic]F1 mice did not. Analysis of CD4⁺ NOD I-A^k transgenic primed lymph node cells showed that autoreactive CD4⁺ T cells in the NOD I-A^k transgenic mice were restricted exclusively by I-A^g7. Considered in the context of the avidity theory of T cell activation and selection, the reported poor peptide binding capacity of NOD I-A^g7 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.

Key Words: nonobese diabetic • insulin-dependent diabetes mellitus • thymic selection • T cell receptor repertoire • major histocompatibility complex and disease

Abbreviations used: HEL, hen egg lysozyme; Idd, insulin- dependent diabetes; MM, mouse myoglobin; NOD, nonobese diabetic; PI, propidium iodide; SWM, sperm whale myoglobin.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS