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Abstract

Objective

To establish a new animal model in DRB1*0401 (DR4)–transgenic mice in which T cell tolerance to self type II collagen (CII) can be broken and allow for the development of autoimmune arthritis, to investigate the role of posttranslational modifications of the CII259–273 epitope in the induction and breaking of tolerance of DR4-restricted T cells, and to characterize DR4-restricted T cell recognition of the immunodominant CII259–273 epitope.

Methods

DR4-transgenic mice expressing either the entire human CII protein (HuCII) or only the immunodominant T cell epitope of heterologous CII (MMC) in joint cartilage were established on different genetic backgrounds, and susceptibility to collagen-induced arthritis (CIA) was tested.

Results

HuCII mice displayed stronger T cell tolerance to heterologous CII than did MMC mice. On the B10 background, arthritis developed only in MMC mice with a defective oxidative burst. However, MMC mice on the C3H background were susceptible to arthritis also with a functional oxidative burst. Significant recall responses in tolerized mice were detected only against the nonglycosylated CII259–273 epitope. Recognition of the CII259–273 epitope was heterogeneous, but the majority of T cells in DR4 mice specifically recognized the nonglycosylated side chain of lysine at position 264.

Conclusion

It is possible to break tolerance to self CII and induce arthritis in DR4 mice. However, arthritis susceptibility is tightly controlled by the genetic background and by the source of the transgenic element for expressing the heterologous CII peptide as a self CII protein in the joint. In contrast to CIA in Aq-expressing mice, the nonglycosylated CII259–273 epitope is clearly immunodominant in both tolerized and nontolerized DR4 mice.