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  • Review article
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Immune cell dysregulation as a mediator of fibrosis in systemic sclerosis

Nature Reviews Rheumatology volume 18, pages 683–693 (2022)Cite this article

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Abstract

Systemic sclerosis (SSc) is a destructive connective tissue disease characterized by dysregulation of the immune system and fibrosis in the skin and internal organs. The pathogenesis of SSc is complex and remains to be determined. So far, limited specific disease-modifying treatments are available for the effective control of fibrosis in patients with SSc. Studies from the past few years hint at the importance of immune dysfunctions, including the dysregulation of innate and adaptive immune cells, as well as the aberrant secretion of inflammatory and fibrotic cytokines, in the pathogenesis of SSc fibrosis. In this Review, we summarize the most pertinent findings concerning the involvement of dysregulated immune responses in fibrosis of the skin and lungs in SSc and highlight the current and potential immune-based targets for SSc therapeutics.

Key points

  • Immune abnormalities, including aberrantly activated immune cells and overproduction of pro-inflammatory and pro-fibrotic molecules, are the main hallmarks of systemic sclerosis (SSc) pathogenesis.

  • Advances in our knowledge of the immune cells and mediators in SSc fibrosis have revealed an increasing number of possible treatment targets.

  • Clinical trial data suggest that targeting immune cell types and cytokines involved in fibrosis has beneficial effects.

  • Tocilizumab, an antibody that targets the IL-6 receptor, is now approved for the treatment of SSc-associated interstitial lung disease owing to its effectiveness in preserving pulmonary function.

  • The high heterogeneity of the immune phenotypes that occur in SSc might contribute to the limited effect of some immune-targeted therapies, which might be overcome by combined or individualized therapy.

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Fig. 1: Roles of immune cells in the pathogenesis of SSc fibrosis.

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Acknowledgements

The authors thank Foo Yew Liew for giving advice on this manuscript. The work of the authors is supported by the National Natural Science Foundation of China (32288102 and 82271836).

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  1. These authors contributed equally: Dan Fang, Beidi Chen.

Authors and Affiliations

  1. Division of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China

    Dan Fang, Beidi Chen & Rong Mu

  2. Department of Internal Medicine and Clinical Immunology, Rennes University Hospital, Rennes, France

    Alain Lescoat

  3. Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Dinesh Khanna

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D.F. wrote the article. D.F., B.C., and R.M. provided substantial contributions to discussion of the content. All authors reviewed and/or edited the final manuscript before submission.

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Correspondence to Rong Mu.

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D.K. receives consulting fees from Acceleron, Actelion, Amgen, Boehringer Ingelheim, Chemomab, CSL Behring, Genentech/Roche, Horizon, Mitsubishi Tanabe Pharma, Paracrine Cell Therapy, Prometheus and Theraly. The other authors declare no competing interests.

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Fang, D., Chen, B., Lescoat, A. et al. Immune cell dysregulation as a mediator of fibrosis in systemic sclerosis. Nat Rev Rheumatol 18, 683–693 (2022). https://doi.org/10.1038/s41584-022-00864-7

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