scholarly journals miR-155 overexpressing monocytes resemble HLA highISG15 + synovial tissue macrophages from patients with rheumatoid arthritis and induce polyfunctional CD4+ T cell activation

2021 ◽  
Author(s):  
Anton M Olsson ◽  
Giovanni A M Povoleri ◽  
Domenico Somma ◽  
Michael L Ridley ◽  
Tatiana Rizou ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Tissue ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptive Immune Response ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Specific Gene ◽  
Monocytes And Macrophages ◽  
Inhibitory Molecules

Abstract MicroRNAs (miRs) are known to regulate pro-inflammatory effector functions of myeloid cells, and miR dysregulation is implicated in rheumatoid arthritis (RA), a condition characterised by inflammation and destruction of the joints. We showed previously that miR-155 is increased in myeloid cells in RA and induces pro-inflammatory activation of monocytes and macrophages, however its role at the interface between innate and adaptive immunity was not defined. Here, RNA-sequencing revealed that overexpression of miR-155 in healthy donor monocytes conferred a specific gene profile which bears similarities to that of RA synovial fluid-derived CD14+ cells and HLA highISG15 + synovial tissue macrophages, both of which are characterised by antigen presenting pathways. In line with this, monocytes in which miR-155 was overexpressed, displayed increased expression of HLA-DR and both co-stimulatory and co-inhibitory molecules, and induced activation of polyfunctional T cells. Together, these data underpin the notion that miR-155-driven myeloid cell activation in the synovium contributes not only to inflammation but may also influence the adaptive immune response.

scholarly journals IMMU-34. LANDSCAPE OF GLIOBLASTOMA-ASSOCIATED IMMUNITY BY INTEGRATION OF scRNA-SEQ AND SPATIAL TRANSCRIPTOMICS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii112-ii112
Author(s):  
Vidhya Ravi ◽  
Nicolas Neidert ◽  
Kevin Joseph ◽  
Juergen Beck ◽  
Oliver Schnell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Lymphoid Cells ◽  
T Cell Exhaustion ◽  
Cellular Interactions ◽  
Cell Exhaustion

Abstract The diversity of molecular states and cellular plasticity of immune cells within the glioblastoma (GBM) environment remain poorly investigated. Here, we conduct deep transcriptional profiling of lymphoid and myeloid cell populations by scRNA-sequencing, map potential cellular interactions and cytokine responses that lead to the dysfunctional and exhausted phenotype of T cells. We identified Interleukin 10 (IL-10) response during T cell activation, which lead to a dysfunctional state of T cells. By the use of a novel method: The nearest functionally connected neighbor (NFCN), an in-silico model to explore cell-cell interaction, the dysfunctional/exhausted phenotype was found to be driven by subset of myeloid cells defined by high expression of HMOX1. By using spatial transcriptomic RNA-sequencing, we identified a correlation between T cell exhaustion and colocalized mesenchymal gene expression. We found that HMOX1 expressing myeloid cells occupying regions marked by T cell exhaustion. Using a human neocortical slice model with myeloid cell depletion we confirmed the functional interaction of myeloid and lymphoid cell leading to the dysfunctional state of T cells. A comprehensive understanding of cellular states and plasticity of lymphoid cells in GBM aids in providing successful immunotherapeutic approaches.

scholarly journals VISTA Is a Novel Regulator of Macrophage Biology

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2320-2320
Author(s):  
Parth Shah ◽  
Mohamed Eltanbouly ◽  
Nicole Smits ◽  
Aurelien Sarde ◽  
Randolph Noelle ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Biology ◽  
Time Course ◽  
Cell Activation ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Mouse Bone Marrow ◽  
Rna Seq

Background:V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint receptor with an established role as an inhibitory receptor on T cells. However, its role in myeloid cell biology remains unclear. Owing to the much higher expression of VISTA on monocytes and macrophages, we investigated its role in regulating myeloid biology. Methods: Mouse bone marrow-derived macrophages (BMDMs) were differentiated and treated with agonistic anti-VISTA mAb under steady-state and conditions of M1 inflammatory polarization (LPS + IFN-𝛾). Human CD14+ monocytes were isolated from peripheral blood and treated with anti-VISTA in vitro. Phosphoarrays were used to assess signaling downstream of VISTA engagement and Luminex analysis was used to evaluate cytokine production. Time-course total RNA-seq was performed on BMDMs (at 1, 2, 4, 8 and 16 hours of anti-VISTA treatment). To evaluate the effect of anti-VISTA in vivo, single-cell RNA-seq (scRNA-seq) was performed on FACS sorted CD11b+ myeloid populations 12 hours after mice were treated with intravenous anti-VISTA. Results: Anti-VISTA treatment of BMDMs and human monocytes in vitro induced rapid phosphorylation events including robust phosphorylation of Raf-1 kinase at the suppressive serine residue 43.Next, we generated a comprehensive timestamp of VISTA activation in BMDMs in vitro by time-course deep RNA-seq analysis of agonistic anti-VISTA treated cells under rigorous M1 inflammatory polarization. This revealed a unique activation state marked by the upregulation of inhibitory cytokines IL-10 and IL1RA as well as ablation of IL-12 family cytokines, suggestive of an M2-like signature. The presence of an M2-like immunoregulatory signature defined by upregulation of the IL-10 was also seen in macrophages identified post clustering of in vivo scRNA-seq data on myeloid cells. Conclusion: Using novel agonistic anti-VISTA antibodies, we reveal that VISTA triggering on myeloid cells can induce an alternative anti-inflammatory cell-state, even under conditions of strong inflammatory polarization. This introduces VISTA as an intrinsic checkpoint of macrophage tolerance. Disclosures Noelle: Immunext: Employment, Equity Ownership, Patents & Royalties, Research Funding.

scholarly journals AB1164 A COST PER RESPONDER ANALYSIS OF ABATACEPT VERSUS ADALIMUMAB FOR THE TREATMENT OF RHEUMATOID ARTHRITIS AMONG PATIENTS WITH SHARED EPITOPE (SE) POSITIVITY FROM A UNITED STATES PAYER PERSPECTIVE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1872.1-1873
Author(s):  
S. H. Park ◽  
X. Han ◽  
F. Lobo ◽  
S. Nanji ◽  
D. Patel
Keyword(s):  
Rheumatoid Arthritis ◽  
United States ◽  
T Cell Activation ◽  
Real World ◽  
Cell Activation ◽  
Shared Epitope ◽  
Pharmacy Cost ◽  
Controlled Clinical Trial ◽  
Payer Perspective ◽  
Cost Per Responder

Background:The shared epitope (SE) is a significant genetic risk factor for rheumatoid arthritis (RA), and it has been proposed to be associated with T-cell activation and the production of anti-citrullinated protein antibody (ACPA).1-3The results from the Early AMPLE trial, a head-to-head trial comparing the efficacy of abatacept versus adalimumab among early moderate-to-severe RA patients with positive ACPA (ACPA+) and rheumatoid factor (RF), showed that at week 24, patients with SE positivity (SE+) responded better to abatacept compared to adalimumab across all efficacy measures evaluated (ACR20 [American College of Rheumatology], ACR50, ACR70, DAS[disease activity score]28-CRP[C-reactive protein]).4Objectives:To compare the cost per responder (CPR) between abatacept and adalimumab among RA patients with SE+ at week 24 using the Early AMPLE trial data from a United States (US) payer perspective.Methods:A CPR analysis was conducted for RA patients with SE+, ACPA+, and RF. Responders were defined as patients achieving ACR20, ACR50, ACR70, or DAS28-CRP ≤2.6 and efficacy data was sourced from the trial (Figure 1).4Approved product labels were referenced for treatment dosing regimen and wholesale acquisition cost was used to calculate pharmacy cost.5A real-world rebate scenario was considered for adalimumab (30%) to reflect the real-world pricing in the US market. The CPR was calculated as the total pharmacy cost divided by the proportion of responders.Results:The total pharmacy cost at week 24 was $26,273 per patient for abatacept and $21,731 per patient for adalimumab. With achieving ACR70 as the definition of responder, the CPR at 24-week was $46,337 for abatacept and $74,935 for adalimumab, a difference of $28,598 (Table 1). The CPR was consistently lower for abatacept compared to adalimumab across all clinical measures, with difference ranging from $7,099 to $43,609.Table 1.Overall cost per responder resultsAbataceptAdalimumabDifferenceACR20$30,303.74$37,403.06-$7,099.32ACR50$34,254.68$48,077.83-$13,823.15ACR70$46,337.46$74,935.10-$28,597.64DAS28-CRP ≤2.6$52,546.68$96,155.65-$43,608.97Conclusion:While the pharmacy cost was higher for abatacept compared to adalimumab driven by the rebate, due to its higher clinical efficacy, the CPR was consistently lower for SE+ RA patients treated with abatacept. The results may be useful for US healthcare decision makers in understanding how to optimize treatment for SE+ RA patient while minimizing costs in today’s budget constrained environment.References:[1]Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis.Arthritis and rheumatism. 1987;30(11):1205-13.[2]Holoshitz J. The rheumatoid arthritis HLA-DRB1 shared epitope.Curr Opin Rheumatol. 2010;22(3):293-8.[3]Sakkas LI, Bogdanos DP, Katsiari C, et al. Anti-citrullinated peptides as autoantigens in rheumatoid arthritis-relevance to treatment.Autoimmun Rev. 2014;13(11):1114-20.[4]Fleischmann R, Weinblatt M, Ahmad H, et al. Efficacy of abatacept and adalimumab in patientsn with early rheumatoid arthritis with multiple poor prognostic factors: post hoc analysis of a randomized controlled clinical trial (AMPLE).Rheumatol Ther. 2019;6(4): 559-571.[5]Truven Health Analytics. Redbook online. Accessed October 11, 2019.Disclosure of Interests:Sang Hee Park Consultant of: Pharmerit International, which received consultancy fees from Bristol-Myers Squibb (US), Inc. for this study, Xue Han Employee of: BMS, Francis Lobo Shareholder of: Bristol-Myers Squibb (US), Employee of: Bristol-Myers Squibb (US), Sakina Nanji Consultant of: Pharmerit International, which received consultancy fees from Bristol-Myers Squibb (US), Inc. for this study, Dipen Patel Consultant of: Pharmerit International, which received consultancy fees from Bristol-Myers Squibb (US), Inc. for this study

Abstract 442: Endoplasmic Reticulum (ER) Stress in the Subfornical Organ (SFO) Induces Peripheral Inflammation in Angiotensin II (Ang-II)-dependent Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Heinrich E Lob ◽  
Jiunn Song ◽  
Scott D Butler ◽  
Allyn L Mark ◽  
Robin L Davisson
Keyword(s):  
T Cell ◽  
Er Stress ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptive Immune Response ◽  
Fold Increase ◽  
Peripheral Inflammation ◽  
Ang Ii ◽  
Peripheral Vascular ◽  
Control Virus

The SFO is implicated in peripheral T cell activation and the genesis of Ang-II-dependent hypertension. Our recent studies show that ER stress in the SFO is also a key mechanism underlying the development of Ang-II hypertension. Because the ER is closely integrated with initiation of the adaptive immune response, we hypothesized that ER stress in the SFO contributes to peripheral inflammation in Ang-II hypertension. First, 5 days of intracerebroventricular (ICV) infusion of thapsigargin (Tg, 1 ug/day), a chemical ER stress inducer, caused a significant increase in CD3 + T cells in aortas (Tg: 11.9 ± 3.5 x 10 3 cells/aorta vs. Vehicle: 2.2 ± 0.7 x 10 3 cells/aorta , n = 6, p<0.05) and blood (Tg: 9.9 ± 1.8 x 10 4 cells/ mL vs. Vehicle: 2.9 ± 0.6 x 10 4 cells/ mL, n = 6, p<0.05). Furthermore, quantitative real-time PCR of SFO micropunches showed a 15-fold increase of TNF-α, a pro-inflammatory cytokine, a 3-fold increase of CCL5, a T cell attracting chemokine and a 3-fold increase in CD3, a T cell marker, (n = 4, p<0.05). To test the functional role of ER stress in the SFO in peripheral T cell activation, we targeted an adenovirus encoding GRP78 (AdGRP78), a molecular ER stress inhibitor, to this brain region during chronic systemic Ang-II infusion (600 ng/kg/min, 14 days). Our results demonstrate a significant reduction in T cell accumulation in aortas compared to control virus (AdLacZ) treatment (AdGRP78: 0.5 ± 0.07 x 10 4 cells/aorta vs. AdLacZ: 8.7 ± 2.1 x 10 4 cells/aorta, n = 6, p<0.05). These data show that 1) brain ER stress induces inflammation in the SFO and peripheral vascular T cell activation, and 2) ER stress in the SFO is linked to peripheral vascular T cell activation in Ang-II-dependent hypertension. These results suggest that ER stress and inflammation in the SFO induce peripheral vascular T cell activation and inflammation in Ang-II hypertension.

Molecular signatures and new candidates to target the pathogenesis of rheumatoid arthritis

2010 ◽  
Vol 42A (4) ◽  
pp. 267-282 ◽  
Author(s):  
U. Ungethuem ◽  
T. Haeupl ◽  
H. Witt ◽  
D. Koczan ◽  
V. Krenn ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell Activation ◽  
Gene Networks ◽  
Cell Activation ◽  
Joint Disease ◽  
Disease Stage ◽  
Unknown Etiology ◽  
Coxa Vara ◽  
Molecular Signatures ◽  
Loss Of Function

Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease of unknown etiology and pronounced interpatient heterogeneity. To characterize RA at the molecular level and to uncover pathomechanisms, we performed genome-wide gene expression analysis. We identified a set of 1,054 genes significantly deregulated in pair-wise comparisons between RA and osteoarthritis (OA) patients, RA and normal donors (ND), or OA and ND. Correlation analysis revealed gene sets regulated identically in all three groups. As a prominent example secreted phosphoprotein 1 (SPP1) was identified to be significantly upregulated in RA compared with both OA and ND. SPP1 expression was found to correlate with genes expressed during an inflammatory response, T-cell activation and apoptosis, suggesting common underlying regulatory networks. A subclassification of RA patients was achieved on the basis of proteoglycan 4 (PRG4) expression, distinguishing PRG4 high and low expressors and reflecting the heterogeneity of the disease. In addition, we found that low PRG4 expression was associated with a more aggressive disease stage, which is in accordance with PRG4 loss-of-function mutations causing camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Altogether we provide evidence for molecular signatures of RA and RA subclasses, sets of new candidate genes as well as for candidate gene networks, which extend our understanding of disease mechanisms and may lead to an improved diagnosis.

scholarly journals Triggering receptor expressed on myeloid cells-2 expression in the brain is required for maximal phagocytic activity and improved neurological outcomes following experimental stroke

2018 ◽  
Vol 39 (10) ◽  
pp. 1906-1918 ◽  
Author(s):  
Kota Kurisu ◽  
Zhen Zheng ◽  
Jong Youl Kim ◽  
Jian Shi ◽  
Atsushi Kanoke ◽  
...  
Keyword(s):  
Cell Activation ◽  
Infarct Volume ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Cerebrovascular Diseases ◽  
Stroke Recovery ◽  
Experimental Stroke ◽  
Neurological Outcomes ◽  
Intact Brain ◽  
The Brain

Triggering receptor expressed on myeloid cells-2 (TREM2) is an innate immune receptor that promotes phagocytosis by myeloid cells such as microglia and macrophages. We previously showed that TREM2 deficiency worsened outcomes from experimental stroke and impeded phagocytosis. However, myeloid cells participating in stroke pathology include both brain resident microglia and circulating macrophages. We now clarify whether TREM2 on brain microglia or circulating macrophages contribute to its beneficial role in ischemic stroke by generating bone marrow (BM) chimeric mice. BM chimera mice from TREM2 knockout (KO) or wild type (Wt) mice were used as donor and recipient mice. Mice were subjected to experimental stroke, and neurological function and infarct volume were assessed. Mice with intact TREM2 in brain microglia showed better neurological recovery and reduced infarct volumes, compared with mice lacking microglial TREM2. Myeloid cell activation and numbers of phagocytes were decreased in mice lacking brain TREM2, compared with mice with intact brain TREM2. These results suggest that TREM2 expression is important for post-stroke recovery, and that TREM2 expression on brain resident microglia is more essential to this recovery, than that of circulating macrophages. These findings might suggest a new therapeutic target for cerebrovascular diseases.

IMMU-04. UNVEILING THE TUMOR-METABOLOME-IMMUNITY AXIS OF GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi92-vi92
Author(s):  
Mirco Friedrich ◽  
Lukas Bunse ◽  
Roman Sankowski ◽  
Wolfgang Wick ◽  
Marco Prinz ◽  
...  
Keyword(s):  
T Cell ◽  
Single Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Myeloid Cell ◽  
Tumor Evolution ◽  
Large Neutral Amino Acid ◽  
Immune Microenvironment ◽  
Idh Mutations

Abstract The glioma microenvironment orchestrates tumor evolution, progression, and resistance to therapy. In high-grade gliomas, microglia and monocyte-derived macrophages constitute up to 70% of the tumor mass. However, the dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype. We report the unexpected and clinically highly relevant finding that human as well as murine gliomas with Isocitrate Dehydrogenase (IDH)1-R132H, a key oncogenic driver mutation of glioma, subdue their innate immune microenvironment by prompting a multifaceted reprogramming of myeloid and T cell metabolism. We employed integrated single-cell transcriptomic, time-of-flight mass cytometry and proteomic analyses of human healthy cortex control and glioma samples to identify myeloid cell subsets with distinct fates in IDH-mutated glioma that diverge from canonical trajectories of antigen-presenting cells as a result of a monocyte-to-macrophage differentiation block. Moving beyond single time point assessments, we now longitudinally describe differential immune cell infiltration and phenotype dynamics during glioma progression that are orchestrated by a fluctuating network of resident microglial cells and educated recruited immune cells. IDH mutations in glioma induce a tolerogenic alignment of their immune microenvironment through increased tryptophan uptake via large neutral amino acid transporter (LAT1)-CD98 and subsequent activation of the aryl hydrocarbon receptor (AHR) in educated blood-borne macrophages. In experimental tumor models, this immunosuppressive phenotype was reverted by LAT1-CD98 and AHR inhibitors. Taken together with direct effects on T cell activation, our findings not only link this oncogenic metabolic pathway to distinct immunosuppressive pathways but also provide the rationale and novel molecular targets for the development of immunotherapeutic concepts addressing the disease-defining microenvironmental effects of IDH mutations.

scholarly journals Passively transferred IgG enhances humoral immunity to a red blood cell alloantigen in mice

2020 ◽  
Vol 4 (7) ◽  
pp. 1526-1537
Author(s):  
David R. Gruber ◽  
Amanda L. Richards ◽  
Heather L. Howie ◽  
Ariel M. Hay ◽  
Jenna N. Lebedev ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
T Cell Activation ◽  
Humoral Immunity ◽  
Cell Activation ◽  
Adaptive Immune Response ◽  
Immunoglobulin M ◽  
Third Party ◽  
Cd4 T Cell ◽  
Specific Subset

Abstract Antibodies are typically thought of as the endpoint of humoral immunity that occur as the result of an adaptive immune response. However, affinity-matured antibodies can be present at the initiation of a new immune response, most commonly because of passive administration as a medical therapy. The current paradigm is that immunoglobulin M (IgM), IgA, and IgE enhance subsequent humoral immunity. In contrast, IgG has a “dual effect” in which it enhances responses to soluble antigens but suppresses responses to antigens on red blood cells (RBCs) (eg, immunoprophylaxis with anti-RhD). Here, we report a system in which passive antibody to an RBC antigen promotes a robust cellular immune response leading to endogenous CD4+ T-cell activation, germinal center formation, antibody secretion, and immunological memory. The mechanism requires ligation of Fcγ receptors on a specific subset of dendritic cells that results in CD4+ T-cell activation and expansion. Moreover, antibodies cross-enhance responses to a third-party antigen, but only if it is expressed on the same RBC as the antigen recognized by the antibody. Importantly, these observations were IgG subtype specific. Thus, these findings demonstrate that antibodies to RBC alloantigens can enhance humoral immunity in an IgG subtype-specific fashion and provide mechanistic elucidation of the enhancing effects.

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