Explore the vast range of titles available.

We previously reported that CCL17 gene-deficient mice are protected from developing pain-like behaviour and exhibit less disease in destabilization of medial meniscus (DMM)-induced OA, as well as in high-fat diet (HFD)-exacerbated DMM-induced OA. Here, we explored if therapeutic neutralization of CCL17, using increasing doses of a neutralizing monoclonal antibody (mAb), would lead to a dose-dependent benefit in these two models. DMM-induced OA was initiated in male mice either fed with a control diet (7% fat) or 8 weeks of a 60% HFD, followed by therapeutic intraperitoneal administration (i.e. when pain is evident) of an anti-CCL17 mAb (B293, 25mg/kg, 5mg/kg or 1mg/kg) or isotype control (BM4; 25mg/kg). Pain-like behaviour and arthritis were assessed by relative static weight distribution and histology, respectively. The effects of B293 (25mg/kg) on HFD-induced metabolic changes, namely oral glucose tolerance test, insulin tolerance test and liver triglyceride levels, were examined. Therapeutic administration of B293 results in a dramatic amelioration of DMM-induced OA pain-like behaviour and the inhibition of disease progression, compared to BM4 (isotype control) treatment. A similar therapeutic effect was observed in HFD-exacerbated OA pain-like behaviour and disease. B293 treatment did not alter the measured HFD-induced metabolic changes. Based on the data presented, CCL17 could be a therapeutic target in OA patients with joint injury alone or with obesity.

Mouse spleens contain three populations of conventional ($CD11c^{high}$) dendritic cells (DCs) that play distinct functions. The CD8⁺ DC are unique in that they can present exogenous antigens on their MHC class I molecules, a process known as cross-presentation. It is unclear whether this special ability is because only the CD8⁺ DC can capture the antigens used in cross-presentation assays, or because this is the only DC population that possesses specialized machinery for cross-presentation. To solve this important question we examined the splenic DC subsets for their ability to both present via MHC class II molecules and cross-present via MHC class I using four different forms of the model antigen ovalbumin (OVA). These forms include a cell-associated form, a soluble form, OVA expressed in bacteria, or OVA bound to latex beads. With the exception of bacterial antigen, which was poorly cross-presented by all DC, all antigenic forms were cross-presented much more efficiently by the CD8⁺ DC. This pattern could not be attributed simply to a difference in antigen capture because all DC subsets presented the antigen via MHC class II. Indeed, direct assessments of endocytosis showed that CD8⁺ and CD8⁻ DC captured comparable amounts of soluble and bead-associated antigen, yet only the CD8⁺ DC cross-presented these antigenic forms. Our results indicate that cross-presentation requires specialized machinery that is expressed by CD8⁺ DC but largely absent from CD8⁻ DC. This conclusion has important implications for the design of vaccination strategies based on antigen targeting to DC.

Objectives Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that is difficult to treat. There is currently no optimal stratification of patients with SLE, and thus, responses to available treatments are unpredictable. Here, we developed a new stratification scheme for patients with SLE, based on the computational analysis of patients’ whole‐blood transcriptomes. Methods We applied machine learning approaches to RNA‐sequencing (RNA‐seq) data sets to stratify patients with SLE into four distinct clusters based on their gene expression profiles. A meta‐analysis on three recently published whole‐blood RNA‐seq data sets was carried out, and an additional similar data set of 30 patients with SLE and 29 healthy donors was incorporated in this study; a total of 161 patients with SLE and 57 healthy donors were analysed. Results Examination of SLE clusters, as opposed to unstratified SLE patients, revealed underappreciated differences in the pattern of expression of disease‐related genes relative to clinical presentation. Moreover, gene signatures correlated with flare activity were successfully identified. Conclusion Given that SLE disease heterogeneity is a key challenge hindering the design of optimal clinical trials and the adequate management of patients, our approach opens a new possible avenue addressing this limitation via a greater understanding of SLE heterogeneity in humans. Stratification of patients based on gene expression signatures may be a valuable strategy allowing the identification of separate molecular mechanisms underpinning disease in SLE. Further, this approach may have a use in understanding the variability in responsiveness to therapeutics, thereby improving the design of clinical trials and advancing personalised therapy. We examined whole‐blood RNA‐seq data from a total of 161 patients with systemic lupus erythematosus and 57 healthy donors, uncovering four distinct subtypes of patients with distinct gene expression patterns. Our study provides an innovative patient stratification framework, which is likely to be useful in future studies looking at different responses to treatments, potentially enabling improved therapeutic decisions and more reliable prediction of response to therapy.

Cytotoxic T lymphocytes and natural killer cells are essential effectors of anti-tumor immune responses in vivo . Dendritic cells (DC) 'prime' tumor antigen-specific cytotoxic T lymphocytes; thus, we investigated whether DC might also trigger the innate, NK cell-mediated anti-tumor immunity. In mice with MHC class I-negative tumors, adoptively transferred- or Flt3 ligand-expanded DC promoted NK cell-dependent anti-tumor effects. In vitro studies demonstrated a cell-to-cell contact between DC and resting NK cells that resulted in a substantial increase in both NK cell cytolytic activity and IFN-γ production. Thus, DC are involved in the interaction between innate and adaptive immune responses.

Dendritic cell activation of CD4 T cells in the lymph node draining a site of infection or vaccination is widely considered the central event in initiating adaptive immunity. The accepted dogma is that this occurs by stimulating local activation and antigen acquisition by dendritic cells, with subsequent lymph node migration, however the generalizability of this mechanism is unclear. Here we show that in some circumstances antigen can bypass the injection site inflammatory response, draining freely and rapidly to the lymph nodes where it interacts with subcapsular sinus (SCS) macrophages resulting in their death. Debris from these dying SCS macrophages is internalized by monocytes recruited from the circulation. This coordinated response leads to antigen presentation by monocytes and interactions with naïve CD4 T cells that can drive the initiation of T cell and B cell responses. These studies demonstrate an entirely novel pathway leading to initiation of adaptive immune responses .

Objectives Plasmacytoid dendritic cells (pDCs), through the production of type 1 interferons (IFNs) and other cytokines, are major contributors to systemic lupus erythematosus (SLE) pathogenesis. IL‐3 promotes pDC survival, but its role in SLE is not well characterised. This study investigated serum IL‐3 and IFN levels, and a whole blood ‘IL‐3 gene signature’, in human SLE. Methods Serum cytokine levels were measured by ELISA in n = 42 SLE patients, and n = 44 healthy donors. IL‐3‐regulated genes were determined by RNASeq of healthy donor whole blood cells (WBCs) stimulated in vitro with IL‐3 for 6 or 24 h. Whole blood cell RNASeq analysis was undertaken in a separate cohort of n = 31 SLE patients, and n = 28 healthy donors. Results Serum IL‐3 levels correlated with IFNα (r = 0.612, 95% CI 0.455–0.733, P < 0.001) and type III IFN (r = 0.585, 95% CI 0.406–0.720, P < 0.0001). IL‐3 stimulation of WBC in vitro altered 794 genes (−1 ≥ logFC ≥ 1, FDR < 0.05), of which 35 overlapped with genes differentially expressed between SLE and healthy donors. These 35 genes were expressed in 27/31 SLE donors, revealing the presence of an ‘IL‐3 gene signature’. There was strong correlation between the IL‐3 signature and an IFN signature, as determined by hierarchical clustering of the 500 most variable genes in SLE donors (r = 0.939, 95% CI 0.898–0.964, P < 0.0001). Conclusion A dual IL‐3/IFN gene signature is a feature of SLE. An association between IL‐3 and IFN raises the possibility that dual blockade of IL‐3 and IFN may be especially useful for SLE patients with this dual cytokine gene signature. Through analysis of serum cytokine levels, and whole blood transcriptional profiling, a correlation between IL‐3 and interferon (IFN) (type I and type III) has been identified in systemic lupus erythematosus (SLE) patients. A correlation between both IFN‐α and type III IFN and IL‐3 in serum was seen, as was the presence of an ‘IL‐3 gene signature’ in a majority of SLE patients, which correlated strongly with an IFN gene signature.

Since the early 1990s, numerous cancer Ag have been defined and for a handful of these there is now some clinical experience, which has made it possible to assess their value as targets for cancer immunotherapy. The cancer‐testis Ag have been particularly attractive because their expression is limited to cancer and virtually no non‐malignant cells apart from germ cells and trophoblast. Among these, NY‐ESO‐1 has been the focus of our attention. The exceptional immunogenicity of this Ag coupled with its widespread distribution among many cancer types make it a very good vaccine candidate, with the potential to be used in vaccines against many types of malignancies. This article reviews emerging knowledge about the biology of NY‐ESO‐1 and experience with the early clinical development of vaccines directed against NY‐ESO‐1. These early studies have yielded a wealth of information about the immunology of NY‐ESO‐1 and set the scene for future clinical strategies for immune targeting of cancer.

[...]only one FS which was temporally associated with a TIV was reported in Western Australia between 2008 and 2009 during the WAIVE studies, where cumulatively 37,946 children (26,037 in 2008 and 11,909 in 2009) were vaccinated [7]. [...]based on all the available post-marketing surveillance and clinical study data prior to the 2010 SH season, one could not have predicted the increase in reports of FS in children less than 5 years which were associated with the bioCSL 2010 SH TIV.

Dendritic cells (DCs) play major roles in immunosurveillance. In peripheral tissues, ‘immature’ DCs are dedicated to capturing antigens. Detection of pathogens through Toll‐like receptors (TLRs) triggers DC migration to the lymph nodes (LNs), where they acquire a ‘mature’ phenotype specialized at presenting antigens. However, DCs migrate from tissues and mature even in the absence of overt infections. This has been attributed to detection of commensal flora in the skin, the gut or other peripheral tissues in the steady state. To test this assumption, we have analyzed the DCs contained in the lymphoid organs of germ‐free mice and of mice lacking the TLR adapter molecules, MyD88 and TRIF. We show that the proportion and expression of maturation markers in DC immigrants in the LNs of these mice are similar to those in normal mice. These results suggest that DC migration from tissues, followed by their phenotypic maturation, is regulated in the steady state by an inherent program of DC differentiation or by the release of low levels of inflammatory signals from normal tissues.

In contrast to the well-studied αβ T cells, which recognize peptide antigens presented by major histocompatibility complex (MHC) and MHC-like molecules, how γδ T cells recognize antigens remains largely a mystery. One major class of γδ T cells, designated Vγ9Vδ2 + , is activated by small, phosphorylated nonpeptide antigens, or phosphoantigens, produced by microbes and cancer cells. Rigau et al. found that these cells needed the combination of two immunoglobulin superfamily members, butyrophilin 2A1 (BTN2A1) and BTN3A1, on their cell surface to recognize these phosphoantigens. BTN2A1 directly binds the Vγ9 + domain of the T cell receptor (TCR), whereas a second ligand, potentially BTN3A1, binds the Vδ2 and γ-chain regions on the opposite side of the TCR. A better understanding of this unexpected form of T cell antigen recognition should inform and enhance future γδ T cell–mediated immunotherapies. Science , this issue p. eaay5516 A key ligand is involved in the recognition of pathogen- or cancer-associated phosphoantigens by γδ immunological T cells. Gamma delta (γδ) T cells are essential to protective immunity. In humans, most γδ T cells express Vγ9Vδ2 + T cell receptors (TCRs) that respond to phosphoantigens (pAgs) produced by cellular pathogens and overexpressed by cancers. However, the molecular targets recognized by these γδTCRs are unknown. Here, we identify butyrophilin 2A1 (BTN2A1) as a key ligand that binds to the Vγ9 + TCR γ chain. BTN2A1 associates with another butyrophilin, BTN3A1, and these act together to initiate responses to pAg. Furthermore, binding of a second ligand, possibly BTN3A1, to a separate TCR domain incorporating Vδ2 is also required. This distinctive mode of Ag-dependent T cell activation advances our understanding of diseases involving pAg recognition and creates opportunities for the development of γδ T cell–based immunotherapies.