New Latent Epitope Activation Mechanism

What is it about?

The central and conceptually new finding of this work is that mutations to one site of an antigen can increase the structural mobility or flexibility of a topographically remote, latent epitope of the antigen, which can in turn facilitate the conformational adaptation required for antibody binding (activation of the latent epitope). This exquisite, previously unrecognized latent epitope activation—achieved either in vitro by remote mutations as we demonstrated or in vivo conceivably by remote protein•protein interactions or remote polymorphisms—may be a fundamental feature of antibody-mediated autoimmune diseases. This feature has implications for development of novel treatments that aim to disrupt the pathogenic autoantibody•autoantigen interactions in antibody-mediated autoimmune diseases by reducing the main-chain flexibility of a target B-cell epitope using chemical or biological therapeutics. Such treatments have advantages over targeting pathogenic autoantibodies using molecular decoys. The latter requires large numbers of decoys to block a stock of distinct, pathogenic autoantibodies and the DNA recombination and affinity maturation mechanisms can lead to resistance against the decoys, whereas the former requires only one chemical or biological binder to rigidify the B-cell epitope and make it inaccessible to a repertoire of distinct, pathogenic autoantibodies thus obviating potential resistance against the binder.

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