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Lighting the fires within: the cell biology of autoinflammatory diseases

Key Points

  • Autoinflammatory diseases are marked by uncontrolled inflammation in the absence of autoantibodies or autoreactive T cell responses.

  • The genetic basis of familial autoinflammatory diseases involves mutations in the genes encoding regulatory proteins with key roles in innate immune responses.

  • Autoinflammatory diseases involving increased production of interleukin-1β (IL-1β) result from enhanced activation of the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome, owing to activating NLRP3 mutations, or from loss-of-function mutations in interleukin-1 receptor antagonist.

  • Spondyloarthropathies and related conditions can arise from abnormal innate immune responses that are caused by misfolding and accumulation of the HLA-B27 protein.

  • The discovery of the genetic basis of autoinflammatory diseases has led to a new era of targeted therapies for these conditions.

Abstract

Autoinflammatory diseases are characterized by seemingly unprovoked pathological activation of the innate immune system in the absence of autoantibodies or autoreactive T cells. Discovery of the causative mutations underlying several monogenic autoinflammatory diseases has identified key regulators of innate immune responses. Recent studies have highlighted the role of misfolding, oligomerization and abnormal trafficking of pathogenic mutant proteins in triggering autoinflammation, and suggest that more common rheumatic diseases may have an autoinflammatory component. This coincides with recent discoveries of new links between endoplasmic reticulum stress and inflammatory signalling pathways, which support the emerging view that autoinflammatory diseases may be due to pathological dysregulation of stress-sensing pathways that normally function in host defence.

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Figure 1: The spectrum of autoimmune and autoinflammatory diseases.
Figure 2: Consequences of protein misfolding and intracellular signalling complexes that activate autoinflammatory disease.
Figure 3: The NLRP1, NLRP3, NLRC4 and AIM2 inflammasomes.

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Acknowledgements

We would like to thank M. Pelletier, I. Aksentijevich and R. Goldbach-Mansky for critical reading and helpful comments on the manuscript. This work was supported by the Intramural Research Program of the US National Institutes of Health.

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Infevers: the registry of hereditary auto-inflammatory disorders mutations

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Glossary

Gout

An autoinflammatory disease triggered by crystalline uric acid and characterized by episodic flares of arthritis that can progress to destructive joint damage.

Spondyloarthropathies

A group of immune-mediated inflammatory disorders that affect the vertebral column. Spondyloarthropathies also frequently affect the entheses (the areas of tendon and ligament insertion into bone).

ER stress

Stress caused by the perturbation of endoplasmic reticulum (ER) functions that are necessary for cellular homeostasis. The unfolded protein response is the collective outcome of ER stress and must be tightly regulated, as otherwise it is directly linked to the pathogenesis of several diseases.

Inflammasome

A large multiprotein complex usually comprising a NOD-like receptor (NLR), the adaptor protein ASC and pro-caspase 1. The assembly of the inflammasome leads to the activation of caspase 1, which cleaves pro-interleukin-1β (pro-IL-1β) and pro-IL-18 to generate the active pro-inflammatory cytokines.

Immunoproteasome

The standard proteasome is composed of 14 α- and β-subunits, of which three (β1, β2 and β5) are involved in peptide-bond cleavage. Interferon-γ induces the expression of the immunosubunits β1i, β2i and β5i, which can replace the catalytic subunits of the standard proteasome to generate the immunoproteasome, which has distinct cleavage-site preferences.

NADPH oxidases

Plasma membrane- and phagosomal membrane-bound enzyme complexes that transfer electrons from NADPH to molecular oxygen, promoting the generation of the reactive oxygen species superoxide.

Mitophagy

Selective removal of mitochondria under conditions of nutrient starvation or mitochondrial stress.

Autophagy

An evolutionarily conserved process in which acidic double-membrane vacuoles sequester intracellular contents (such as damaged organelles and macromolecules) and target them for degradation through fusion to secondary lysosomes.

Colchicine

An inhibitor of microtubule polymerization that has anti-inflammatory properties, possibly through blockade of neutrophil chemotaxis. Colchicine is effective in treating acute attacks of gout and protecting against recurrent flares. It is also an effective treatment for familial Mediterranean fever, but not for other genetic autoinflammatory syndromes.

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Park, H., Bourla, A., Kastner, D. et al. Lighting the fires within: the cell biology of autoinflammatory diseases. Nat Rev Immunol 12, 570–580 (2012). https://doi.org/10.1038/nri3261

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