Research article

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

Philip L Carl¹ , Brenda RS Temple² and Philip L Cohen³

¹  Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA

²  R. L. Juliano Structural Bioinformatics Core Facility, University of North Carolina, Chapel Hill, NC 27599, USA

³  Division of Rheumatology, University of Pennsylvania School of Medicine and Philadelphia VA Medical Center, Philadelphia, PA 19104, USA

author email corresponding author email

Arthritis Research & Therapy 2005, 7:R1360-R1374doi:10.1186/ar1832

Published:	6 October 2005

Abstract

Patients with systemic autoimmune diseases usually produce high levels of antibodies to self-antigens (autoantigens). The repertoire of common autoantigens is remarkably limited, yet no readily understandable shared thread links these apparently diverse proteins. Using computer prediction algorithms, we have found that most nuclear systemic autoantigens are predicted to contain long regions of extreme structural disorder. Such disordered regions would generally make poor B cell epitopes and are predicted to be under-represented as potential T cell epitopes. Consideration of the potential role of protein disorder may give novel insights into the possible role of molecular mimicry in the pathogenesis of autoimmunity. The recognition of extreme autoantigen protein disorder has led us to an explicit model of epitope spreading that explains many of the paradoxical aspects of autoimmunity – in particular, the difficulty in identifying autoantigen-specific helper T cells that might collaborate with the B cells activated in systemic autoimmunity. The model also explains the experimentally observed breakdown of major histocompatibility complex (MHC) class specificity in peptides associated with the MHC II proteins of activated autoimmune B cells, and sheds light on the selection of particular T cell epitopes in autoimmunity. Finally, the model helps to rationalize the relative rarity of clinically significant autoimmunity despite the prevalence of low specificity/low avidity autoantibodies in normal individuals.