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A defect in central tolerance in NOD mice.

H Kishimoto¹, J Sprent

¹Department of Immunology, IMM4, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.

Nature Immunology

|October 23, 2001

Summary

Nonobese diabetic (NOD) mice exhibit impaired central tolerance, specifically in thymocyte negative selection. This defect in autoimmune-prone NOD mice affects both Fas-dependent and Fas-independent apoptosis pathways.

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Area of Science:

Immunology
Autoimmune Diseases
T cell Biology

Background:

Nonobese diabetic (NOD) mice are a key model for studying autoimmune diabetes.
Previous research attributed NOD mice's autoimmune predisposition to peripheral tolerance defects.
Central tolerance, occurring in the thymus, is crucial for eliminating self-reactive T cells.

Purpose of the Study:

To investigate potential defects in central tolerance mechanisms in NOD mice.
To characterize the nature and extent of impaired thymocyte negative selection in NOD mice.
To explore the molecular pathways involved in defective thymocyte apoptosis in NOD mice.

Main Methods:

In vivo and in vitro assays to assess thymocyte negative selection.
Analysis of thymocyte populations, particularly semi-mature thymocytes in the medulla.
Evaluation of both Fas-dependent and Fas-independent apoptosis pathways.
Measurement of caspase 8-homologous FLICE-inhibitory protein expression.

Main Results:

NOD mice demonstrate a significant defect in central tolerance (negative selection) of thymocytes.
This impairment is most pronounced in semi-mature medullary thymocytes.
The defect affects multiple apoptotic pathways and is independent of IAbetag7 expression.
Elevated FLICE-inhibitory protein levels correlate with defective Fas-dependent apoptosis.

Conclusions:

Central tolerance defects contribute to the autoimmune predisposition of NOD mice.
Impaired thymocyte negative selection is a critical factor in NOD mouse autoimmunity.
Disease onset in NOD mice likely results from combined central and peripheral tolerance failures.

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