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  • Review Article
  • Published:

Perception of self: distinguishing autoimmunity from autoinflammation

Nature Reviews Rheumatology volume 11, pages 483–492 (2015)Cite this article

Subjects

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

Abstract

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.

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Figure 1: Stratification of autoimmune and autoinflammatory diseases based on cytokine signature.
Figure 2: NLRP3 inflammasome activation and the reciprocal interference of type I IFN on acute inflammasome-dependent IL-1β production (signal 1 and 2).
Figure 3: MAVS in the NLRP3 inflammasome and the RIG-I signalling cascade.
Figure 4: NLRP3 inflammasome activation and the reciprocal interference of type I IFN on chronic inflammasome-dependent IL-1β production (signal 3).

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  1. Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, University Medical Centre Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, Netherlands

    Tessa S. van Kempen, Mark H. Wenink, Emmerik F. A. Leijten & Timothy R. D. J. Radstake

  2. Department of Paediatric Immunology, University Medical Centre Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, Netherlands

    Marianne Boes

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T.S.v.K researched data for the article. T.S.v.K., T.R.D.J.R and M.B. wrote the manuscript. All authors made a substantial contribution to the discussion of the review and reviewed and edited the manuscript before submission.

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van Kempen, T., Wenink, M., Leijten, E. et al. Perception of self: distinguishing autoimmunity from autoinflammation. Nat Rev Rheumatol 11, 483–492 (2015). https://doi.org/10.1038/nrrheum.2015.60

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