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Moving towards a systems-based classification of innate immune-mediated diseases

Nature Reviews Rheumatology volume 16, pages 222–237 (2020)Cite this article

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Abstract

Autoinflammation as a distinct disease category was first reported in 1999 as a group of monogenic disorders characterized by recurrent episodes of systemic and organ-specific inflammation, known as periodic fever syndromes. Since this original description, the focus has shifted considerably to the inclusion of complex multifactorial conditions with an autoinflammatory basis. Furthermore, the boundaries of what are considered to be autoinflammatory disorders are constantly evolving and currently encompass elements of immunodeficiency and autoimmunity. Notable developments in the intervening 20 years include substantial progress in understanding how the different inflammasomes are activated, how infection is sensed by the innate immune system and how intracellular signalling systems are consequently activated and integrated with many different cellular functions in the autoinflammatory process. With these developments, the field of autoinflammation is moving from a gene-centric view of innate immune-mediated disease towards a systems-based concept, which describes how various convergent pathways, including pyrin and the actin cytoskeleton, protein misfolding and cellular stress, NF-κB dysregulation and interferon activation, contribute to the autoinflammatory process. The development and adoption of a systems-based concept of systemic autoinflammatory diseases is anticipated to have implications for the development of treatments that target specific components of the innate immune system.

Key points

  • The definition of autoinflammatory disease has evolved since its original description, with increasing awareness of the influence of various processes in the pathogenesis, including metabolism, cytoskeletal perturbation and infection.

  • The scope of what is considered autoinflammation is widening and now includes not only monogenic periodic fever syndromes but also polygenic conditions and disorders with autoimmune and immunodeficiency components.

  • Gene-centric classifications of disease have often been quite restrictive, and a move towards systems-based classifications would be beneficial in the investigation and management of these disorders.

  • Many autoinflammatory disorders arise, either partly or fully, because of ‘collateral damage’ caused by the innate immune system striving to maintain cellular homeostasis, such as in pyrin-linked cytoskeletal imbalance.

  • Appreciation of the complex overlap between the manifold systems related to autoinflammation, autoimmunity and immunodeficiency can enable the exploration of therapeutic interventions that were not previously considered.

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Fig. 1: Pyrin and the cytoskeleton in systemic autoinflammatory diseases.
Fig. 2: The unfolded protein response.
Fig. 3: Defects in NF-κB pathway-related genes.
Fig. 4: The interferon pathway.
Fig. 5: The autoinflammatory disease landscape.
Fig. 6: The overlapping therapeutic options in autoinflammatory disease.

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Acknowledgements

The authors are supported by the EU Horizon 2020 research and innovation programme (ImmunAID; grant agreement number 779295). The authors thank T. Scambler, F. Berenbaum and S. Lara-Reyna for critical reading of the manuscript.

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Authors and Affiliations

  1. Leeds Institute of Rheumatic and Musculoskeletal Medicine, St James’s University Hospital, Leeds, UK

    Sinisa Savic, Emily A. Caseley & Michael F. McDermott

  2. National Institute for Health Research–Leeds Biomedical Research Centre, Chapel Allerton Hospital, Leeds, UK

    Sinisa Savic

  3. Department of Clinical Immunology and Allergy, St James’s University Hospital, Leeds, UK

    Sinisa Savic

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  1. Sinisa Savic
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  2. Emily A. Caseley
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  3. Michael F. McDermott
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The authors contributed equally to all aspects of the article.

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Correspondence to Sinisa Savic or Michael F. McDermott.

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S.S. declares that he has received a travel grant and honoraria from SOBI and Novartis. The other authors declare no competing interests.

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Nature Reviews Rheumatology thanks I. Touitou, M. Gattorno, T. Vogel and S. Masters for their contribution to the peer review of this work.

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Glossary

Pattern recognition receptor

A protein that recognizes conserved molecular structures either found in pathogens, such as bacteria and viruses (pathogen-associated molecular patterns), or released by damaged cells (damage-associated molecular patterns).

Filamentous actin

(F-actin). Actin is the most abundant protein in eukaryotic cells and can be present in either a linear polymeric form or as filamentous actin.

Autophagy

A highly regulated process of ‘self-eating’ whereby cell organelles and their contents can be repurposed for other uses.

Hypomorphic mutations

Types of mutation that cause a partial loss of gene function or in which the wild-type gene product is expressed at a reduced level.

Anhidrotic ectodermal dysplasia

A form of ectodermal dysplasia characterized by abnormal development of ectodermal tissues including the skin, hair, teeth and sweat glands, resulting in an inability to sweat (anhidrosis).

Stop-gain variant

A mutation resulting in a premature termination codon (that is, a stop was gained), which signals the end of translation and results in a shortened protein product.

Itaconate

A derivate of the tricarboxylic acid cycle, which has a key role in the regulation of macrophage function; it has been shown to decrease production of pro-inflammatory mediators in lipopolysaccharide-treated macrophages and to ameliorate sepsis and psoriasis in animal models, revealing a novel biological action beyond its regular roles in antimicrobial defences.

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Savic, S., Caseley, E.A. & McDermott, M.F. Moving towards a systems-based classification of innate immune-mediated diseases. Nat Rev Rheumatol 16, 222–237 (2020). https://doi.org/10.1038/s41584-020-0377-5

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