Background: An important issue in autoimmune diseases mediated by T cells, such as experimental allergic encephalomyelitis (EAE), is the affinity of the disease-inducing determinants for MHC class II proteins. Tolerance, either due to clonal deletion or anergy induction, is thought to require high-affinity interactions between peptides and MHC molecules. Low-affinity binding is compatible with the hypothesis that breaking tolerance to self proteins does not have to occur for onset of disease. In contrast, a high- affinity interaction implies thai an event leading to a breakdown of tolerance is central to the autoimmune process. Materials and Methods: Detergent-solubilized and affinity-purified I-A(u) was incubated with varying concentrations of a set of peptides from myelin basic protein and a biotinylated peptide agonist. The specific complexes were separated from excess peptide by capture on antibody-coated plates, and the affinity of the peptides was measured by adding europium-labeled streptavidin and measuring the resultant fluorescence. Results: The immunodominant and encephalitogenic determinant, Ac 1-11, was shown to bind to I-A(u) relatively poorly (IC50 = 100 μM), demonstrating that in this protein, immunodominance did not correlate with high-affinity binding. In contrast with the natural sequence, the ability of shorter analogs to induce EAE did correlate with their apparent affinity. Conclusions: The dominance of the natural determinant does not arise from a high-affinity interaction with the MHC class II molecule. This suggests that other mechanisms are operative and that the specific T cell for this peptide/MHC ligand is of high affinity.
CITATION STYLE
Fugger, L., Liang, J., Gautam, A., Rothbard, J. B., & McDevitt, H. O. (1996). Quantitative analysis of peptides from myelin basic protein binding to the MHC class II protein, I-A(u), which confers susceptibility to experimental allergic encephalomyelitis. Molecular Medicine, 2(2), 181–188. https://doi.org/10.1007/bf03401615
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