Determinant capture as a possible mechanism of protection afforded by major histocompatibility complex class II molecules in autoimmune disease.

Author:

Deng H1,Apple R1,Clare-Salzler M1,Trembleau S1,Mathis D1,Adorini L1,Sercarz E1

Affiliation:

1. Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90024-1489.

Abstract

How peptide-major histocompatibility complex (MHC) class II complexes are naturally generated is still unknown, but accumulating evidence suggests that unfolding proteins or long peptides can become bound to class II molecules at the dominant determinant before proteolytic cleavage. We have compared the immunogenicity of hen egg-white lysozyme (HEL) in nonobese diabetic (NOD), (NOD x BALB/c)F1, and E(d) alpha transgenic NOD mice. We find that a response to the subdominant ANOD-restricted determinant disappears upon introduction of an E(d) molecule, and is restored when scission of HEL separates this determinant from its adjoining, competitively dominant, E(d)-restricted determinant. This suggests that the E(d) molecule binds and protects its dominant determinant on a long peptide while captured neighboring determinants are lost during proteolysis. These results provide clear evidence for "determinant capture" as a mechanism of determinant selection during antigen processing and a possible explanation for MHC-protective effects in insulin-dependent diabetes mellitus.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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