Functionally impaired plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize human autoimmunity

Antonios Psarras, Adewonuola Alase, Agne Antanaviciute, Ian M. Carr, Md Yuzaiful Md Yusof, Miriam Wittmann, Paul Emery, George C. Tsokos and Edward M. Vital ()
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Antonios Psarras: University of Leeds
Adewonuola Alase: University of Leeds
Agne Antanaviciute: University of Leeds
Ian M. Carr: University of Leeds
Md Yuzaiful Md Yusof: University of Leeds
Miriam Wittmann: University of Leeds
Paul Emery: University of Leeds
George C. Tsokos: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School
Edward M. Vital: University of Leeds

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract Autoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons have a crucial role in the progression to established autoimmune diseases. The cellular source and regulation in disease initiation of these cytokines is not clear, but plasmacytoid dendritic cells have been thought to contribute to excessive type I interferon production. Here, we show that in preclinical autoimmunity and established systemic lupus erythematosus, plasmacytoid dendritic cells are not effector cells, have lost capacity for Toll-like-receptor-mediated cytokine production and do not induce T cell activation, independent of disease activity and the blood interferon signature. In addition, plasmacytoid dendritic cells have a transcriptional signature indicative of cellular stress and senescence accompanied by increased telomere erosion. In preclinical autoimmunity, we show a marked enrichment of an interferon signature in the skin without infiltrating immune cells, but with interferon-κ production by keratinocytes. In conclusion, non-hematopoietic cellular sources, rather than plasmacytoid dendritic cells, are responsible for interferon production prior to clinical autoimmunity.

Date: 2020
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DOI: 10.1038/s41467-020-19918-z

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