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Harnessing programmed cell death as a therapeutic strategy in rheumatic diseases

Nature Reviews Rheumatology volume 7, pages 152–160 (2011)Cite this article

Subjects

Abstract

Programmed cell death (PCD) is a key process in the regulation of immune cell development and peripheral immune homeostasis. Caspase-dependent apoptosis, as well as a number of alternative cell death mechanisms, account for immune cell PCD induced by cell-intrinsic and extrinsic pathways. In animal models, compelling evidence has emerged that genetic defects in PCD can result in autoimmune disease. Autoimmune disease can arise from single-gene mutations that affect PCD, and defective PCD has been observed in some tissues and cells from patients with rheumatic disease. Selectively inducing PCD in autoreactive B and T cells is very attractive as a therapeutic strategy because it offers the possibility of permanent elimination of these pathogenic cell subsets. In addition, the anti-inflammatory effects of apoptotic cells may add to the therapeutic benefit of induced PCD. Immune cell subsets vary widely in their sensitivity to specific inducers of cell death, and understanding these differences is key to predicting the outcome of inducing apoptosis for therapeutic means. Here, we review approaches that have been used to induce PCD in the treatment of autoimmune disease, and describe the prospects of bringing these experimental strategies into clinical practice.

Key Points

  • Apoptosis, or programmed cell death, is mediated by extrinsic death receptors or intrinsic signals triggered in response to cellular stress, and is essential in maintaining immune cell populations

  • The caspase family of intracellular proteases are the main effectors of apoptosis, but caspase-independent necrotic or autophagic cell death also occur

  • Uptake of apoptotic cells by antigen-presenting cells promotes immunological tolerance by suppressing the ability of these cells to activate the immune system; conversely, phagocytosis of necrotic or infected cells activates immune responses

  • Genetic mutations or variants in regulators of cell death or dead cell clearance can predispose to autoimmunity

  • A number of current therapies for autoimmune disease lead to immune cell depletion via the induction of apoptosis

  • Improved understanding of the mechanisms that regulate the sensitivity of immune cells to apoptosis has revealed new targets for therapies designed to specifically deplete autoreactive lymphocytes

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Figure 1: Extrinsic and intrinsic apoptosis pathways.

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Acknowledgements

This work was supported by funds from the NIAMS intramural research program. We would like to thank Eric Hanson and Michael Ombrello for critical reading of this manuscript. Min Deng is a student in the Clinical Research Training program, a joint program of the NIH and Pfizer.

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  1. Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, 10 Center Drive, Building 10, Room 13C103, Bethesda, 20892-1930, MD, USA

    Madhu Ramaswamy, Min Deng & Richard M. Siegel

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All authors contributed equally to researching data for the article, discussing the content, and writing the article. M. Ramaswamy and R. M. Siegel performed review/editing of the manuscript before submission.

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Correspondence to Richard M. Siegel.

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Ramaswamy, M., Deng, M. & Siegel, R. Harnessing programmed cell death as a therapeutic strategy in rheumatic diseases. Nat Rev Rheumatol 7, 152–160 (2011). https://doi.org/10.1038/nrrheum.2010.225

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