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Sensors of the innate immune system: their link to rheumatic diseases

Nature Reviews Rheumatology volume 6, pages 146–156 (2010)Cite this article

Subjects

Abstract

Evidence strongly suggests that excessive or protracted signaling, or both, by cell-surface or intracellular innate immune receptors is central to the pathogenesis of most autoimmune and autoinflammatory rheumatic diseases. The initiation of aberrant innate and adaptive immune responses in autoimmune diseases can be triggered by microbes and, at times, by endogenous molecules—particularly nucleic acids and related immune complexes—under sterile conditions. By contrast, most autoinflammatory syndromes are generally dependent on germline or de novo gene mutations that cause or facilitate inflammasome assembly. The consequent production of proinflammatory cytokines, principally interferon-α/β and tumor necrosis factor in autoimmune diseases, and interleukin-1β in autoinflammatory diseases, leads to the creation of autoamplification feedback loops and chronicity of these syndromes. These findings have resulted in a critical reappraisal of pathogenetic mechanisms, and provide a basis for the development of novel diagnostic and therapeutic modalities for these diseases.

Key Points

  • Toll-like receptors (TLRs), retinoid acid inducible gene-I-like receptors (RLRs) and nucleotide-binding and oligomerization domain-like receptors (NLRs) can detect the presence of pathogens and products of damaged tissues

  • Responses by these receptors usually benefit the host, but when inappropriately engaged by self molecules, or insufficiently inhibited, they can cause long-lasting immunopathology

  • In certain autoimmune rheumatic diseases, such as systemic lupus erythematosus, recognition of self nucleic acids by TLRs seems to be the major pathogenetic mechanism

  • In other diseases, such as rheumatoid arthritis and Sjögren's syndrome, recognition of products from microbes and damaged tissues by these or other innate sensors are likely to contribute

  • In autoinflammatory diseases, uncontrollable activation of the innate immune system is caused by mutations in components of the NLR system leading to inflammasome induction

  • These findings explain the efficacy of blocking proinflammatory cytokines in these diseases, and suggest that additional therapeutic targets will be identified within the signaling pathways of the innate immune sensors

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Figure 1: Innate immune sensors.
Figure 2: Breaching barriers for TLR recognition of self nucleic acids in systemic autoimmunity.
Figure 3: Trafficking of nucleic-acid-sensing TLRs.
Figure 4: Initiation and amplification stages in systemic autoimmunity.
Figure 5: Molecular basis of autoinflammatory diseases.

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Acknowledgements

The work of the authors is supported by National Institute of Health grants. Space limitations precluded citation of many original publications, and we apologize for these omissions.

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Authors and Affiliations

  1. Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, CA, USA

    Argyrios N. Theofilopoulos, Rosana Gonzalez-Quintial, Brian R. Lawson, Yi T. Koh, Dwight H. Kono & Roberto Baccala

  2. Department of Genetics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, CA, USA

    Bruce Beutler

  3. Allergan, 2525 Dupont Drive, Irvine, 92623, CA, USA

    Michael E. Stern

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Correspondence to Argyrios N. Theofilopoulos.

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Theofilopoulos, A., Gonzalez-Quintial, R., Lawson, B. et al. Sensors of the innate immune system: their link to rheumatic diseases. Nat Rev Rheumatol 6, 146–156 (2010). https://doi.org/10.1038/nrrheum.2009.278

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