Plasmacytoid Dendritic Cells and Type I Interferon Signature in Lichen Striatus

Abstract

Background and aims Vd2 T cells have predominantly been investigated in tumour immuno-surveillance and the host defense against viral invasion. The precise role of Vd2 T cells in the pathogenesis of SLE remains elusive. Methods We measured the proportion of peripheral Vd2 T cells as well as the status and chemokine receptor expression profiles in SLE patients and healthy control (HC). In addition, Vd2 T cell infiltration in the kidneys of patients with lupus nephritis was examined. Results The percentage of peripheral Vd2 T cells in new-onset SLE was decreased, and negatively correlated with the SLE Disease Activity Index score and the severity of proteinuria. These cells had a decreased apoptosis but an increased proliferation , and they showed increased accumulation in SLE kidneys. Moreover, IL-21 production and CD40L, CCR4, CCR7, CCR8, CXCR1 and CX3CR1 expression in Vd2 T cells from SLE patients was significantly higher than from HC (p<0.05), and these factors were down-regulated in association with the repopulation of peripheral Vd2 T cells in patients who were in remission (p<0. Background and aims Systemic Lupus Erythematosus (SLE) is associated with an increased IFN gene signature detectable in the peripheral blood. Plasmacytoid dendritic cells (pDC) are potent producers of IFNa in response to TLR9 and TLR7-agonists. pDCs which express high levels of CD123 (IL-3Ra) can be depleted by JNJ-56022473 (JNJ-473), a novel Fc-engineered neutralising and depleting therapeutic antibody targeting CD123. Methods We investigated the effects of pDC depletion with JNJ-473 on IFNa production and gene expression within SLE patient PBMC (n=8) stimulated with TLR-agonists, SLE-immune complexes (IC, SLE IgG with necrotic cell lysates (NCL)) and sera from SLE patients with NCL. Results Stimulation with CpGc, SLE-IC or SLE sera was able to induce high levels of IFNa, which was greatly decreased by pDC depletion with JNJ-473. SLE-IC and SLE sera stimulation also induced the differential expression of hundreds of genes and could induce similar genes to TLR9-agonism. pDC depletion with JNJ-473 prevented the upregulation of TLR9-induced genes. JNJ-473 conferred minimal effects on the induction of genes in response to the TLR4-agonist LPS. Furthermore , a distinct 11-gene IFN signature was induced by CpGc and SLE-IC that was significantly reduced by treatment with JNJ-473, suggesting that the depletion of pDCs with JNJ-473 could have distinct and specific effects on the detectable IFN signature in many SLE patients. Conclusions Depletion of pDCs with JNJ-473 is able to dramatically decrease IFNa production and IFN gene signature induced by TLR9-agonists and SLE-IC. Background and aims Glucocorticoid-induced Leucine Zipper (GILZ) is a GC-inducible gene with multiple immune-regulatory functions, and GILZ deficiency in mice results in the development of a lupus-like phenotype. In Systemic Lupus Erythematosus (SLE), plasmacytoid dendritic cells (pDCs) are major producers of Type 1 interferons (IFN) in response to nucleic acid-containin...

Possible role of plasmacytoid dendritic cells in pityriasis lichenoides

“…Fifth, tumour necrosis factor (TNF)‐α inhibitors, known to be secondary inducers of IFN‐α, have also been reported to induce PL . Finally, PL has been reported in association with several cutaneous inflammatory disorders, including psoriasis, alopecia areata, and lichen striatus, for which evidence suggests that pDCs play a significant role in their underlying pathogenesis …”

“…Recently, much evidence has accumulated on the central role played by the pDCs and their product, type I IFNs, in several skin diseases characterized by the ID pattern. 6,[8][9][10][11] Initially, Fah et al reported high MxA expression not only in acute viral skin lesions, but also in autoimmune conditions with an ID pattern, such as LE and LP. 12 This indicated an activation of the type I IFN system in these autoimmune skin disorders.…”

“…6,14 The predominant source of type-I IFNs in these disorders are the pDCs, which have been shown to play a major role in LE, LP, DM and lichen striatus. 6,8,10,11 In the current study, our hypothesis concerning the role of pDCs in the pathogenesis of PL was based on several observations. First, PL is characterized histopathologically by an ID pattern, which suggests that pDCs and type I IFNs probably play an important role in its pathogenesis, similar to the role they play in other dermatoses with ID such as LE and LP.…”

“…In addition to several infectious (especially viral) and neoplastic cutaneous conditions, pDCs and their main product, type I IFNs, have been shown to be involved in the pathogenesis of multiple cutaneous inflammatory/autoimmune entities, including some that are characterized histopathologically by an ID pattern, such as lupus erythrematosus (LE), lichen planus (LP), dermatomyositis (DM), lichen sclerosus (LS) and lichen striatus. [6][7][8][9][10][11] Given this, we aimed to investigate pDCs and type I IFNs in PL in order to uncover part of the underlying pathogenesis of PL.…”

Association between bilateral segmental vitiligo and lichen striatus: an expression of mosaicism?

“…Both lesions may appear over Blaschko and Sherrington lines, which brings out the question of a somatic mosaic origin . The lesions also may be induced by interferon therapy, and both present CD8 + T‐lymphocytes infiltrate . Cutaneous mosaicisms are clinical expressions of disorders that affect a mosaic area on the skin; this concept is a principle for understanding somatic mosaicism, which refers to the occurrence of two genetically distinct populations of cells within an individual derived from a postzygotic mutation.…”