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

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.

TNF-α Regulates Human Plasmacytoid Dendritic Cells by Suppressing IFN-α Production and Enhancing T Cell Activation

“…As the main drivers of type I IFN responses, pDCs have been implicated in many diseases, especially chronic viral infections, cancer, and autoimmunity (23)(24)(25)(26). Multiple regulatory surface receptors (e.g., BDCA-2, ILT7, BST2, and NKp44) control the aberrant production of type I IFNs by TLR-activated pDCs (12,27,28).…”

Type I Interferons in Systemic Autoimmune Diseases: Distinguishing Between Afferent and Efferent Functions for Precision Medicine and Individualized Treatment

“…α (Psarras et al, 2020). Consistently with these findings, when explored at single cell level by RNAsec, peripheral blood pDCs in SLE were found unable to produce IFN-α (Nehar-Belaid et al, 2020).…”

Measuring IFN activity in suspected SLE: a valuable step?

“…In line with previous studies, serum autoantibody levels against DNA or RNA binding proteins were significantly higher in this subset of patients with overexpressed interferon activity. Interestingly, recent data in preclinical autoimmunity revealed that one potential source for the high expression of type I interferon in the skin is the keratinocytes and not the pDCs as previously thought [23].…”