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

AbstractAutoimmune 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.

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Plasmacytoid dendritic cells are functionally exhausted while non-haematopoietic sources of type I interferon dominate human autoimmunity

10.1101/502047 ◽

2018 ◽

Cited By ~ 2

Author(s):

Antonios Psarras ◽

Adewonuola Alase ◽

Agne Antanaviciute ◽

Ian M. Carr ◽

Md Yuzaiful Md Yusof ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell Activation ◽

Lupus Erythematosus ◽

Cell Activation ◽

Connective Tissue Diseases ◽

Plasmacytoid Dendritic Cells ◽

Type I Interferons ◽

Type I ◽

Effector Cells ◽

Transcriptional Signature

ABSTRACTAutoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons (IFNs) have a crucial role in the progression to established autoimmune diseases such as systemic lupus erythematosus (SLE). However, their cellular source and regulation in disease initiation are unclear. The current paradigm suggests that plasmacytoid dendritic cells (pDCs) are activated in SLE contributing to excessive IFN production. Here, we show that in preclinical autoimmunity, established SLE, and primary Sjögren’s Syndrome, pDCs are not effector cells, but rather have lost their capacity for TLR-mediated IFN-α and TNF production and fail to induce T cell activation, independently of disease activity and blood IFN signature. In addition, pDCs present a transcriptional signature of cellular stress and senescence accompanied by increased telomere erosion. Instead, we demonstrate a marked enrichment of IFN signature in non-lesional skin in preclinical autoimmunity. In these individuals and SLE patients, type I IFNs were abundantly produced by keratinocytes in the absence of infiltrating leucocytes. These findings revise our understanding of the role of IFN in the initiation of human autoimmunity, with non-haematopoietic tissues perpetuating IFN responses, which in turn predict clinical disease. These data indicate potential therapeutic targets outside the conventional immune system for treatment and prevention.

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OP0306 Downregulation of micrornas in plasmacytoid dendritic cells is associated with a type i interferon signature in systemic lupus erythematosus and antiphospholipid syndrome

10.1136/annrheumdis-2017-eular.2372 ◽

2017 ◽

Author(s):

LL Van Den Hoogen ◽

JA van Roon ◽

RD Fritsch-Stork ◽

CP Bekker ◽

A Pandit ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Dendritic Cells ◽

Antiphospholipid Syndrome ◽

Lupus Erythematosus ◽

Type I Interferon ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Systemic Lupus ◽

Interferon Signature

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Smoking enhances Toll-like receptor-9 responsiveness and type I interferon production in plasmacytoid dendritic cells in patients with cutaneous lupus erythematosus

Journal of the American Academy of Dermatology ◽

10.1016/j.jaad.2015.05.023 ◽

2015 ◽

Vol 73 (2) ◽

pp. e81 ◽

Cited By ~ 3

Author(s):

François Chasset ◽

Camille Francès ◽

Laurent Arnaud

Keyword(s):

Dendritic Cells ◽

Lupus Erythematosus ◽

Type I Interferon ◽

Cutaneous Lupus Erythematosus ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Interferon Production ◽

Toll Like Receptor ◽

Cutaneous Lupus

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Type I Interferon Inhibition and Dendritic Cell Activation during Gammaherpesvirus Respiratory Infection

Journal of Virology ◽

10.1128/jvi.00360-07 ◽

2007 ◽

Vol 81 (18) ◽

pp. 9778-9789 ◽

Cited By ~ 24

Author(s):

Janet L. Weslow-Schmidt ◽

Nancy A. Jewell ◽

Sara E. Mertz ◽

J. Pedro Simas ◽

Joan E. Durbin ◽

...

Keyword(s):

Dendritic Cells ◽

Dendritic Cell ◽

Cell Activation ◽

Type I Interferon ◽

Plasmacytoid Dendritic Cells ◽

The Body ◽

Type I ◽

Type I Ifn ◽

Dendritic Cell Activation ◽

Murine Gammaherpesvirus

ABSTRACT The respiratory tract is a major mucosal site for microorganism entry into the body, and type I interferon (IFN) and dendritic cells constitute a first line of defense against viral infections. We have analyzed the interaction between a model DNA virus, plasmacytoid dendritic cells, and type I IFN during lung infection of mice. Our data show that murine gammaherpesvirus 68 (γHV68) inhibits type I IFN secretion by dendritic cells and that plasmacytoid dendritic cells are necessary for conventional dendritic cell maturation in response to γHV68. Following γHV68 intranasal inoculation, the local and systemic IFN-α/β response is below detectable levels, and plasmacytoid dendritic cells are activated and recruited into the lung with a tissue distribution that differs from that of conventional dendritic cells. Our results suggest that plasmacytoid dendritic cells and type I IFN have important but independent roles during the early response to a respiratory γHV68 infection. γHV68 infection inhibits type I IFN production by dendritic cells and is a poor inducer of IFN-α/β in vivo, which may serve as an immune evasion strategy.

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