Perception of self: distinguishing autoimmunity from autoinflammation

• Published in: Nature reviews. Rheumatology Vol. 11; no. 8; pp. 483 - 492
• Main Authors: van Kempen, Tessa S., Wenink, Mark H., Leijten, Emmerik F. A., Radstake, Timothy R. D. J., Boes, Marianne
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2015; Nature Publishing Group
• Subjects: 692/420/256/2177; 692/420/2780; 692/698/1543/1565; 692/699/1670; Antibiotics; Arthritis; Autoantigens - immunology; Autoimmune diseases; Autoimmunity; Care and treatment; Cytokines; Genes; Genetic aspects; Health aspects; Humans; Immunology; Inflammation; Inflammation - immunology; Interferon Type I - immunology; Interleukin-1beta - immunology; Interleukins; Medicine & Public Health; Metabolites; Mitochondria; Peptides - immunology; review-article; Rheumatic diseases; Rheumatic Diseases - immunology; Rheumatology; Self image
• ISSN: 1759-4790; 1759-4804; 1759-4804
• DOI: 10.1038/nrrheum.2015.60

Key Points Autoimmunity and autoinflammatory disorders are distinct in terms of the predominance of underlying innate or adaptive immune mechanisms, therapeutic responses to biologic agents and cytokine gene expression patterns (signatures) in blood When not leading to autoimmunity, autoinflammatory diseases have an IL-1β/IL-18-dominated signature, whereas autoimmune diseases are driven by type I interferon (IFN) IL-1β and type I IFN counter-regulate each other by activating selective metabolic signalling pathways that interfere with adaptive immune responses Hypotheses that have been proposed to explain autoimmunity initiation include molecular mimicry, for which data are limited, and conformational changes in native proteins, which can drive immunogenic self-peptide presentation The current 'immunoediting' hypothesis suggests that cancer cells harbouring somatic mutations trigger adaptive immunity, including cross-reactive antibody responses In addition to somatic mutations, conformational changes in proteins can result from alternative reading frames and post-translational modifications, thereby adjusting the immunogenicity of T-cell responses The distinction between autoimmunity and autoinflammation has become an important issue in rheumatic diseases. The mechanisms by which the immune system is tolerant to self-antigens—and how this tolerance can be lost in some situations—is a central point in this distinction. In this Review, van Kempen et al . explores the different pathways at work in autoimmune and autoinflammatory diseases, and how this knowledge might help improve treatment strategies. Rheumatic diseases can be divided in two groups, autoinflammatory and autoimmune disorders. The clinical presentation of both types of diseases overlap, but the pathological pathways underlying rheumatic autoinflammation and autoimmunity are distinct and are the subject of ongoing research. There are a number of ways in which these groups of diseases differ in terms of disease mechanisms and therapeutic responses. First, autoinflammatory diseases are driven by endogenous danger signals, metabolic mediators and cytokines, whereas autoimmunity involves the activation of T and B cells, the latter requiring V-(D)-J recombination of receptor-chain gene segments for maturation. Second, the efficacy of biologic agents directed against proinflammatory cytokines (for example IL-1β and TNF) also highlights differences between autoinflammatory and autoimmune processes. Finally, whereas autoinflammatory diseases are mostly driven by inflammasome-induced IL-1β and IL-18 production, autoimmune diseases are associated with type I interferon (IFN) signatures in blood. In this Review, we provide an overview of the monocyte intracellular pathways that drive autoinflammation and autoimmunity. We convey recent findings on how the type I IFN pathway can modulate IL-1β signalling (and vice versa), and discuss why IL-1β-mediated autoinflammatory diseases do not perpetuate into autoimmunity. The origins of intracellular autoantigens in autoimmune disorders are also discussed. Finally, we suggest how new mechanistic knowledge of autoinflammatory and autoimmune diseases might help improve treatment strategies to benefit patient care.