A pivotal role for the natural interferon α–producing cells (plasmacytoid dendritic cells) in the pathogenesis of lupus

L Rönnblom, GV Alm - The Journal of experimental medicine, 2001 - rupress.org
L Rönnblom, GV Alm
The Journal of experimental medicine, 2001rupress.org
The human type I IFN gene family consists of 13 genes encoding IFN-α subtypes and one
gene each for IFN-ß and-ω. The type I IFN proteins show similarities with respect to both
structure and function; for instance, they are typically produced by cells exposed to virus and
interact with the same receptor, the IFNAR (1). The type I IFNs have well established direct
antiviral and antiproliferative effects, but also several prominent immunoregulatory actions
that have come into focus in recent years (1–3). The latter include the ability to promote …
The human type I IFN gene family consists of 13 genes encoding IFN-α subtypes and one gene each for IFN-ß and-ω. The type I IFN proteins show similarities with respect to both structure and function; for instance, they are typically produced by cells exposed to virus and interact with the same receptor, the IFNAR (1). The type I IFNs have well established direct antiviral and antiproliferative effects, but also several prominent immunoregulatory actions that have come into focus in recent years (1–3). The latter include the ability to promote survival and differentiation of antigen-activated Th1 cells. These effects of type I IFN may, in part, be due to their ability to activate signal transducer and activator of transcription (STAT) 4 and maintain expression of a functional IL-12R. Type I IFN can also cause maturation of efficiently antigen-presenting monocyte-derived dendritic cells (DCs) and stimulate B lymphocytes (4, 5).
The IFN-α–producing Cells. While many cell types produce type I IFN in vitro when exposed to double-stranded (ds) RNA and some RNA viruses, a specialized leukocyte is responsible for the IFN-α production induced by a wider spectrum of agents, including viruses, bacteria, protozoa, certain cell lines, and also unmethylated CpG-DNA (6–8). This major IFN-α–producing cell (IPC) was early on designated natural IPC (NIPC) and subsequent work (for a review see reference 6) revealed that NIPCs were infrequent (0.1% of PBMCs) but very productive on a per cell basis (10 pg IFN-α per cell). The expression of the IFN-α/ß genes induced in NIPCs was markedly dependent on costimulation (“priming”) of the cells by cytokines, in particular IL-3, GM-CSF, and type I IFNs. These cells lacked lineage specific surface antigens, but expressed MHC class II (for a review, see reference 6). The NIPCs were shown to express, eg, CD4, CD36, CD40, CD44, CD45RA, and CD83, but lacked CD80, CD86, and CD11c, suggesting they were immature DCs (9). Their phenotype was in fact similar to a subsequently identified DC precursor (10,
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