Association of autoantibodies with the IFN signature and NETosis in patients with systemic lupus erythematosus.

Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a variety of disease symptoms and an unpredictable clinical course. To improve treatment outcome, stratification based on immunological manifestations commonly seen in patients with SLE such as autoantibodies, type I interferon (IFN) signature and neutrophil extracellular trap (NET) release may help. It is assumed that there is an association between these immunological phenomena, since NET release induces IFN production and IFN induces autoantibody formation via B-cell activation.

In vitro T cell responses to PD-1 blockade are reduced by IFN-α but do not predict therapy response in melanoma patients.

PD-1 blockade therapy has revolutionized melanoma treatment, but still not all patients benefit and pre-treatment identification of those patients is difficult. Increased expression of inflammatory markers such as interleukin (IL)-6 in blood of patients correlates with poor treatment response. We set out to study the effect of inflammatory cytokines on PD-1 blockade in vitro.

mA Reader YTHDC1 Impairs Respiratory Syncytial Virus Infection by Downregulating Membrane CX3CR1 Expression.

Respiratory syncytial virus (RSV) is the most prevalent cause of acute lower respiratory infection in young children. Currently, the first RSV vaccines are approved by the FDA. Recently, N6-methyladenosine (mA) RNA methylation has been implicated in the regulation of the viral life cycle and replication of many viruses, including RSV.

Airway and Blood Monocyte Transcriptomic Profiling Reveals an Antiviral Phenotype in Infants With Severe Respiratory Syncytial Virus Infection.

Background: Respiratory syncytial virus (RSV) infection is the primary cause of lower respiratory tract infections in children <5 years of age. Monocytes, especially in the respiratory tract, are suggested to contribute to RSV pathology, but their role is incompletely understood. With transcriptomic profiling of blood and airway monocytes, we describe the role of monocytes in severe RSV infection.

Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain.

The current paradigm is that inflammatory pain passively resolves following the cessation of inflammation. Yet, in a substantial proportion of patients with inflammatory diseases, resolution of inflammation is not sufficient to resolve pain, resulting in chronic pain. Mechanistic insight into how inflammatory pain is resolved is lacking.

Signaling by the inhibitory receptor CD200R is rewired by type I interferon.

CD200 receptor 1 (CD200R) is an inhibitory immunoreceptor that suppresses Toll-like receptor (TLR)–induced cytokine production through the adaptor protein Dok2 and the GTPase activating protein (GAP) p120-RasGAP, which can be cleaved during mild cellular stress. We found that in the presence of cleaved p120-RasGAP, CD200R lost its capacity to inhibit phosphorylation of ribosomal S6 protein (rpS6), suggesting the reduced activity of mammalian target of rapamycin complex 1 (mTORC1). Furthermore, treatment of human peripheral blood mononuclear cells (PBMC) with interferon-α (IFN-α) resulted in increased amounts of cleaved p120-RasGAP.

CD200R1L is a functional evolutionary conserved activating receptor in human neutrophils.

Inhibitory and activating immune receptors play a key role in modulating the amplitude and duration of immune responses during infection and in maintaining immune balance in homeostatic conditions. The CD200 Receptor (CD200R) gene family in humans encodes one inhibitory receptor, CD200R1, and one putative activating member, CD200R1 Like (CD200R1L). It is demonstrated that CD200R1L is endogenously expressed by human neutrophils and activates cellular functions such as reactive oxygen species (ROS) production via Syk, PI3Kβ, PI3Kδ, and Rac GTPase signaling.

Identification of a novel conserved signaling motif in CD200 receptor required for its inhibitory function.

The inhibitory signaling of CD200 receptor 1 (CD200R) has been attributed to its NPxY signaling motif. However, NPxY-motifs are present in multiple protein families and are mostly known to mediate protein trafficking between subcellular locations rather than signaling. Therefore, we investigated whether additional motifs specify the inhibitory function of CD200R.

The prevalence of frailty and post-treatment outcomes in elderly women with pelvic floor disorders.

Introduction And Hypothesis: Women seeking treatment for pelvic floor disorders (PFD) may have a high prevalence of frailty, which could potentially impact the risks of treatment. The present study was aimed to assess the prevalence of frailty in patients with PFD and additionally to compare post-treatment complications between frail and non-frail patients.

Methods: This is a prospective observational study conducted in a single secondary referral centre for PFD.

Signal Inhibitory Receptor on Leukocytes-1 is highly expressed on lung monocytes, but absent on mononuclear phagocytes in skin and colon.

Signal Inhibitory Receptor on Leukocytes-1 (SIRL-1) is expressed on human blood monocytes and granulocytes and inhibits myeloid effector functions. On monocytes, but not granulocytes, SIRL-1 expression is low or absent in individuals with the single nucleotide polymorphism (SNP) rs612529C. The expression of SIRL-1 in tissue and the influence of rs612529 hereon is currently unknown.

Parturition mode recommendation and symptoms of pelvic floor disorders after obstetric anal sphincter injuries.

Introduction And Hypothesis: Our primary objective was to evaluate parturition mode (PM) recommendations following obstetric anal sphincter injuries (OASIs) and adherence to these recommendations and to evaluate recurrence of OASIs in women who had a subsequent vaginal delivery (VD). The hypothesis was that adherence to the PM recommendations leads to a reasonable OASI recurrence rate.

Methods: This was a retrospective observational cohort study of patients with previous OASIs between 2010 and 2016.

Differential Signalling and Kinetics of Neutrophil Extracellular Trap Release Revealed by Quantitative Live Imaging.

A wide variety of microbial and inflammatory factors induce DNA release from neutrophils as neutrophil extracellular traps (NETs). Consensus on the kinetics and mechanism of NET release has been hindered by the lack of distinctive methods to specifically quantify NET release in time. Here, we validate and refine a semi-automatic live imaging approach for quantification of NET release.

Immune checkpoints and rheumatic diseases: what can cancer immunotherapy teach us?

The recent success of immune checkpoint blockade in cancer therapy illustrates the importance of the inhibitory receptors cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in the regulation of antitumour immune responses. However, blocking signalling by these inhibitory immune checkpoint receptors is also associated with substantial inflammatory effects that can resemble autoimmune responses, which is consistent with the role of these receptors in protecting the host from excessive inflammation. The human genome encodes over 300 inhibitory receptors, which represent as many opportunities to modulate inflammation in a disease-specific and tissue-specific manner.

Fucose-based PAMPs prime dendritic cells for follicular T helper cell polarization via DC-SIGN-dependent IL-27 production.

Dendritic cells (DCs) orchestrate antibody-mediated responses to combat extracellular pathogens including parasites by initiating T helper cell differentiation. Here we demonstrate that carbohydrate-specific signalling by DC-SIGN drives follicular T helper cell (TFH) differentiation via IL-27 expression. Fucose, but not mannose, engagement of DC-SIGN results in activation of IKKε, which collaborates with type I IFNR signalling to induce formation and activation of transcription factor ISGF3.

Human immature Langerhans cells restrict CXCR4-using HIV-1 transmission.

Background: Sexual transmission is the main route of HIV-1 infection and the CCR5-using (R5) HIV-1 is predominantly transmitted, even though CXCR4-using (X4) HIV-1 is often abundant in chronic HIV-1 patients. The mechanisms underlying this tropism selection are unclear. Mucosal Langerhans cells (LCs) are the first immune cells to encounter HIV-1 and here we investigated the role of LCs in selection of R5 HIV-1 using an ex vivo epidermal and vaginal transmission models.

Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome.

Production of the proinflammatory cytokine interleukin 1β (IL-1β) by dendritic cells is crucial in host defense. Here we identify a previously unknown role for dectin-1 in the activation of a noncanonical caspase-8 inflammasome in response to fungi and mycobacteria. Dectin-1 induced both the production and maturation of IL-1β through signaling routes mediated by the kinase Syk.

Innate signaling in HIV-1 infection of dendritic cells.

Purpose Of Review: This review summarizes the current knowledge of innate signaling events that are involved in HIV-1 infection. We here focus on dendritic cells, which are among the first cells that encounter HIV-1 after exposure.

Recent Findings: HIV-1 triggers multiple pattern recognition receptors on dendritic cells that facilitate infection and transmission to T cells.

Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4⁺ T cells but are incapable of cross-presentation.

Langerhans cells (LCs) are a subset of DCs that reside in the upper respiratory tract and are ideally suited to sense respiratory virus infections. Measles virus (MV) is a highly infectious lymphotropic and myelotropic virus that enters the host via the respiratory tract. Here, we show that human primary LCs are capable of capturing MV through the C-type lectin Langerin.

HIV-1 exploits innate signaling by TLR8 and DC-SIGN for productive infection of dendritic cells.

Pattern-recognition receptors (PRRs) elicit antiviral immune responses to human immunodeficiency virus type 1 (HIV-1). Here we show that HIV-1 required signaling by the PRRs Toll-like receptor 8 (TLR8) and DC-SIGN for replication in dendritic cells (DCs). HIV-1 activated the transcription factor NF-kappaB through TLR8 to initiate the transcription of integrated provirus by RNA polymerase II (RNAPII).

Langerin functions as an antiviral receptor on Langerhans cells.

Langerhans cells (LC) are the first dendritic cells (DC) to encounter pathogens entering the body via mucosa or skin. Equipped with pattern recognition receptors (PRR), LC are able to detect and respond to these pathogens. An important PRR, in human exclusively expressed by LC, is the C-type lectin Langerin.

Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori.

Cooperation between different innate signaling pathways induced by pattern-recognition receptors (PRRs) on dendritic cells (DCs) is crucial for tailoring adaptive immunity to pathogens. Here we show that carbohydrate-specific signaling through the C-type lectin DC-SIGN tailored cytokine production in response to distinct pathogens. DC-SIGN was constitutively associated with a signalosome complex consisting of the scaffold proteins LSP1, KSR1 and CNK and the kinase Raf-1.

Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-kappaB activation through Raf-1 and Syk.

The C-type lectin dectin-1 activates the transcription factor NF-kappaB through a Syk kinase-dependent signaling pathway to induce antifungal immunity. Here we show that dectin-1 expressed on human dendritic cells activates not only the Syk-dependent canonical NF-kappaB subunits p65 and c-Rel, but also the noncanonical NF-kappaB subunit RelB. Dectin-1, when stimulated by the beta-glucan curdlan or by Candida albicans, induced a second signaling pathway mediated by the serine-threonine kinase Raf-1, which integrated with the Syk pathway at the point of NF-kappaB activation.

DC-SIGN and CD150 have distinct roles in transmission of measles virus from dendritic cells to T-lymphocytes.

Measles virus (MV) is among the most infectious viruses that affect humans and is transmitted via the respiratory route. In macaques, MV primarily infects lymphocytes and dendritic cells (DCs). Little is known about the initial target cell for MV infection.