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New players driving inflammation in monogenic autoinflammatory diseases

Key Points

  • Over the past decade, major advances have been made in understanding the molecular link between disease-causing mutations and inflammation in patients with autoinflammatory diseases

  • A number of alterations in the pathways related to the maintenance of proteostasis have been implicated in monogenic autoinflammatory diseases

  • Next-generation sequencing technologies have been instrumental in the identification of new disease-causing genes

  • The identification of ADA2 mutations in patients with inflammation and vasculopathy and/or vasculitis provides evidence that autoinflammation is not limited to the malfunction of intracellular proteins

  • Newly discovered genes and pathways provide further evidence that autoinflammation and autoimmunity are not mutually exclusive processes

Abstract

Systemic autoinflammatory diseases are caused by abnormal activation of the cells that mediate innate immunity. In the past two decades, single-gene defects in different pathways, driving clinically distinct autoinflammatory syndromes, have been identified. Studies of these aberrant pathways have substantially advanced understanding of the cellular mechanisms that contribute to mounting effective and balanced innate immune responses. For example, mutations affecting the function of cytosolic immune sensors known as inflammasomes and the IL-1 signalling pathway can trigger excessive inflammation. A surge in discovery of new genes associated with autoinflammation has pointed to other mechanisms of disease linking innate immune responses to a number of basic cellular pathways, such as maintenance of protein homeostasis (proteostasis), protein misfolding and clearance, endoplasmic reticulum stress and mitochondrial stress, metabolic stress, autophagy and abnormalities in differentiation and development of myeloid cells. Although the spectrum of autoinflammatory diseases has been steadily expanding, a substantial number of patients remain undiagnosed. Next-generation sequencing technologies will be instrumental in finding disease-causing mutations in as yet uncharacterized diseases. As more patients are reported to have clinical features of autoinflammation and immunodeficiency or autoimmunity, the complex interactions between the innate and adaptive immune systems are unveiled.

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Figure 1: Proteostasis pathways.
Figure 2: Protein-misfolding-mediated inflammation.
Figure 3: Composition and function of the proteasome.
Figure 4: Intracellular and extracellular ADA2 function.

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Acknowledgements

F.M. is supported by a grant from the European Research Council (starting grant 281996), a Human Frontier Science Program career development award (CDA00059/2011) and a grant from the Swiss National Science Foundation (31003A-130476). The authors thank Y. Jamilloux and E. F. Remmers for critical reading of the manuscript, and Q. Zhou and J. Fekecs for help preparing a figure.

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Martinon, F., Aksentijevich, I. New players driving inflammation in monogenic autoinflammatory diseases. Nat Rev Rheumatol 11, 11–20 (2015). https://doi.org/10.1038/nrrheum.2014.158

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