Authors: Meager, A.¹; Peterson, P.²; Willcox, N.

Source: Clinical & Experimental Immunology, Volume 154, Number 1, October 2008 , pp. 141-151(11)

Publisher: Wiley-Blackwell

Abstract:

Summary

In sporadic autoimmune disorders, dendritic cells are increasingly being incriminated as agents provocateurs. However, the mechanisms and any `danger signals' that induce them to autoimmunize remain enigmatic. Here, we focus on unexpected clues from two prototypic/ highly informative autoimmune syndromes, acquired thymoma-associated myasthenia gravis and the monogenic autoimmune polyendocrine syndrome type-1 (APS1), caused by mutations in the AutoImmune Regulator (AIRE). Both involve the thymus, and in both we find early, persistent, highly prevalent and high-titre neutralizing autoantibodies against type-I interferons, regardless of the exact AIRE genotype or the characteristically variable clinical phenotype in APS1. Thus these key innate↔adaptive immune intermediaries are now implicated in APS1 and paraneoplastic myasthenia as well as in systemic lupus erythematosus and other sporadic autoimmune disorders. The currently accepted notion that autoimmunization proceeds automatically (by `default') does not explain how, when or where autoimmune responses are initiated against which targets in APS1, or whether exogenous or internal danger signals are involved, or predict whether the primary auto-immunogenic targets are AIRE-dependent. As the parallels between these syndromes must hold novel clues to these puzzles, they demand explanations. To unify these and other findings, we propose that autoimmunization occurs centrally in aberrant thymic environments rendered `dangerous' by AIRE-deficiency (possibly by excess undegraded nucleic acids/dead cell debris). The ensuing autoreactivity focuses early on the locally abundant type I interferons and then on other peripheral tissue autoantigens that are still expressed despite the absence of AIRE. These ideas raise numerous questions that others may already have the materials to address.

Keywords: AIRE; APECED; autoimmunity; autoimmunization; autoantibody; myasthenia gravis; self-tolerance; thymic epithelial cells; thymoma; thymus; type I interferon

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1365-2249.2008.03739.x

Affiliations: 1: Biotherapeutics, National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potter's Bar, Herts, UK, 2: Molecular Pathology, Institute of General and Molecular Pathology, Biomedicum, Ravila 19, University of Tartu, Tartu, Estonia, and

Publication date: 2008-10-01

Related content

• In this: publication
• By this: publisher
• In this Subject: Microbiology ,  Allergy & Immunology
• By this author: Meager, A. ;  Peterson, P. ;  Willcox, N.

Website © Publishing Technology. Article copyright remains with the publisher, society or author(s) as specified within the article.

• Terms and conditions
• Privacy policy
• Information for advertisers