Most nuclear systemic autoantigens are extremely disordered proteins: implications for the etiology of systemic autoimmunity

Why some proteins become autoantigens is one of the mysteries of immunology. Indeed, as Paul Plotz put it in a recent review, "The repertoire of target autoantigens is a Wunderkammer – a collection of curiosities – of molecules with no obvious linking principle" [1]. Most immunologists believe, probably with good reason, that making real progress in understanding and treating autoimmune diseases depends on solving this mystery.While a single property might explain why these few proteins become autoantigens, it seems more likely that a combination of factors unites these proteins. Plotz divides such factors into four groups: structural properties, catabolism and fate after cell death, concentration and the microenvironment, and immunological and inflammatory properties. This paper will primarily deal with the first of Plotz's factors, the structural properties of autoantigens. Among the structural properties he lists are, citing the work of Dohlman and colleagues [2,3]: a highly charged surface, repetitive surface elements, bound nucleic acid, and the presence of a coiled coil. In this paper, we provide computational evidence that the first three of these properties can be understood as arising from the fact that most nuclear systemic autoantigens are extremely disordered proteins, and suggest that the fourth property, the presence of a coiled coil, occurs far less frequently than does disorder. We also show that several of the other factors mentioned by Plotz that may influence the selection of autoantigens also fit nicely into the picture of nuclear systemic autoantigens as extremely disordered proteins. We will argue that disordered proteins are apt to be poor activators of B cells for multiple reasons, and hence that B cells targeted to extremely disordered proteins are apt to escape immune deletion. Furthermore, because extremely disordered proteins tend to be highly sensitive to proteolysis and are predicted to have poor affinity for major histocompatibility co