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Intraocular involvement of mycosis fungoides associated with immunophenotypic switch from CD4 to CD8.
Braue JA, Daniels AB, Zwerner JP, Kim SJ, Zic JA
(2018) Blood 131: 932-935
MeSH Terms: Aged, CD4 Antigens, CD8 Antigens, Eye Diseases, Female, Humans, Immunophenotyping, Middle Aged, Mycosis Fungoides, Prognosis, Skin Neoplasms
Added March 30, 2020
0 Communities
1 Members
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MeSH Terms
Mass Cytometry of Follicular Lymphoma Tumors Reveals Intrinsic Heterogeneity in Proteins Including HLA-DR and a Deficit in Nonmalignant Plasmablast and Germinal Center B-Cell Populations.
Wogsland CE, Greenplate AR, Kolstad A, Myklebust JH, Irish JM, Huse K
(2017) Cytometry B Clin Cytom 92: 79-87
MeSH Terms: B-Lymphocytes, Flow Cytometry, Germinal Center, HLA-DR Antigens, Humans, Immunophenotyping, Lymphoma, B-Cell, Lymphoma, Follicular, Plasma Cells, T-Lymphocyte Subsets
Show Abstract · Added December 10, 2016
BACKGROUND - Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma that has a risk of transformation to more aggressive lymphoma. Relatively little is known about the nonmalignant B-cell and T-cell subset composition within the tumor microenvironment and whether altered phenotypes are associated with patterns of lymphoma B-cell heterogeneity.
METHODS - Two mass cytometry (CyTOF) panels were designed to immunophenotype B and T cells in FL tumors. Populations of malignant B cells, nonmalignant B cells, and T cells from each FL tumor were identified and their phenotypes compared to B and T cells from healthy human tonsillar tissue.
RESULTS - Diversity in cellular phenotype between tumors was greater for the malignant B cells than for nonmalignant B or T cells. The malignant B-cell population bore little phenotypic similarity to any healthy B-cell subset, and unexpectedly clustered closer to naïve B-cell populations than GC B-cell populations. Among the nonmalignant B cells within FL tumors, a significant lack of GC and plasmablast B cells was observed relative to tonsil controls. In contrast, nonmalignant T cells in FL tumors were present at levels similar to their cognate tonsillar T-cell subsets.
CONCLUSION - Mass cytometry revealed that diverse HLA-DR expression on FL cells within individual tumors contributed greatly to tumor heterogeneity. Both malignant and nonmalignant B cells in the tumor bore little phenotypic resemblance to healthy GC B cells despite the presence of T follicular helper cells in the tumor. These findings suggest that ongoing signaling interactions between malignant B cells and intra-tumor T cells shape the tumor microenvironment. © 2016 International Clinical Cytometry Society.
© 2016 International Clinical Cytometry Society.
3 Communities
1 Members
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10 MeSH Terms
The L-Arginine Transporter Solute Carrier Family 7 Member 2 Mediates the Immunopathogenesis of Attaching and Effacing Bacteria.
Singh K, Al-Greene NT, Verriere TG, Coburn LA, Asim M, Barry DP, Allaman MM, Hardbower DM, Delgado AG, Piazuelo MB, Vallance BA, Gobert AP, Wilson KT
(2016) PLoS Pathog 12: e1005984
MeSH Terms: Animals, Blotting, Western, Cationic Amino Acid Transporter 2, Cell Line, Citrobacter rodentium, Disease Models, Animal, Enterobacteriaceae Infections, Host-Parasite Interactions, Humans, Immunophenotyping, Mice, Mice, Inbred C57BL, Mice, Knockout, Transfection
Show Abstract · Added October 27, 2016
Solute carrier family 7 member 2 (SLC7A2) is an inducible transporter of the semi-essential amino acid L-arginine (L-Arg), which has been implicated in immune responses to pathogens. We assessed the role of SLC7A2 in murine infection with Citrobacter rodentium, an attaching and effacing enteric pathogen that causes colitis. Induction of SLC7A2 was upregulated in colitis tissues, and localized predominantly to colonic epithelial cells. Compared to wild-type mice, Slc7a2-/-mice infected with C. rodentium had improved survival and decreased weight loss, colon weight, and histologic injury; this was associated with decreased colonic macrophages, dendritic cells, granulocytes, and Th1 and Th17 cells. In infected Slc7a2-/-mice, there were decreased levels of the proinflammatory cytokines G-CSF, TNF-α, IL-1α, IL-1β, and the chemokines CXCL1, CCL2, CCL3, CCL4, CXCL2, and CCL5. In bone marrow chimeras, the recipient genotype drove the colitis phenotype, indicative of the importance of epithelial, rather than myeloid SLC7A2. Mice lacking Slc7a2 exhibited reduced adherence of C. rodentium to the colonic epithelium and decreased expression of Talin-1, a focal adhesion protein involved in the attachment of the bacterium. The importance of SLC7A2 and Talin-1 in the intimate attachment of C. rodentium and induction of inflammatory response was confirmed in vitro, using conditionally-immortalized young adult mouse colon (YAMC) cells with shRNA knockdown of Slc7a2 or Tln1. Inhibition of L-Arg uptake with the competitive inhibitor, L-lysine (L-Lys), also prevented attachment of C. rodentium and chemokine expression. L-Lys and siRNA knockdown confirmed the role of L-Arg and SLC7A2 in human Caco-2 cells co-cultured with enteropathogenic Escherichia coli. Overexpression of SLC7A2 in human embryonic kidney cells increased bacterial adherence and chemokine expression. Taken together, our data indicate that C. rodentium enhances its own pathogenicity by inducing the expression of SLC7A2 to favor its attachment to the epithelium and thus create its ecological niche.
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14 MeSH Terms
High-Dimensional Analysis of Acute Myeloid Leukemia Reveals Phenotypic Changes in Persistent Cells during Induction Therapy.
Ferrell PB, Diggins KE, Polikowsky HG, Mohan SR, Seegmiller AC, Irish JM
(2016) PLoS One 11: e0153207
MeSH Terms: Aged, Bone Marrow, Female, Flow Cytometry, Humans, Immunophenotyping, Induction Chemotherapy, Leukemia, Myeloid, Acute, Male, Middle Aged, Phenotype, Pilot Projects, Treatment Outcome, Young Adult
Show Abstract · Added April 14, 2016
The plasticity of AML drives poor clinical outcomes and confounds its longitudinal detection. However, the immediate impact of treatment on the leukemic and non-leukemic cells of the bone marrow and blood remains relatively understudied. Here, we conducted a pilot study of high dimensional longitudinal monitoring of immunophenotype in AML. To characterize changes in cell phenotype before, during, and immediately after induction treatment, we developed a 27-antibody panel for mass cytometry focused on surface diagnostic markers and applied it to 46 samples of blood or bone marrow tissue collected over time from 5 AML patients. Central goals were to determine whether changes in AML phenotype would be captured effectively by cytomic tools and to implement methods for describing the evolving phenotypes of AML cell subsets. Mass cytometry data were analyzed using established computational techniques. Within this pilot study, longitudinal immune monitoring with mass cytometry revealed fundamental changes in leukemia phenotypes that occurred over time during and after induction in the refractory disease setting. Persisting AML blasts became more phenotypically distinct from stem and progenitor cells due to expression of novel marker patterns that differed from pre-treatment AML cells and from all cell types observed in healthy bone marrow. This pilot study of single cell immune monitoring in AML represents a powerful tool for precision characterization and targeting of resistant disease.
4 Communities
2 Members
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14 MeSH Terms
Myelodysplastic Syndrome Revealed by Systems Immunology in a Melanoma Patient Undergoing Anti-PD-1 Therapy.
Greenplate AR, Johnson DB, Roussel M, Savona MR, Sosman JA, Puzanov I, Ferrell PB, Irish JM
(2016) Cancer Immunol Res 4: 474-480
MeSH Terms: Aged, Anemia, Refractory, with Excess of Blasts, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Disease Progression, Female, Flow Cytometry, Follow-Up Studies, Humans, Immunophenotyping, Melanoma, Myelodysplastic Syndromes, Programmed Cell Death 1 Receptor
Show Abstract · Added March 12, 2016
Antibodies aimed at blocking the interaction between programmed cell death-1 (PD-1) and its ligands have shown impressive efficacy in a variety of malignancies and are generally well tolerated. Research has focused intensely on T cells and their interaction with cells within melanoma tumors, while relatively little is understood about the systems immunology of the cells in the blood during checkpoint inhibitor therapy. Longitudinal cytomic analysis using mass cytometry can characterize all the cells in a small sample of blood and has the potential to reveal key shifts in the cellular milieu occurring during treatment. We report a case of advanced melanoma in which mass cytometry detected abnormal myeloid cells resulting from myelodysplastic syndrome (MDS) in the blood following treatment with an anti-PD-1 agent. Myeloid blasts comprised <1% of peripheral blood mononuclear cells (PBMC) 1 month after the start of treatment. Six months after starting therapy, myeloid blasts comprised 5% of PBMCs, and a bone marrow biopsy confirmed refractory anemia with excess blasts-2 (RAEB-2). Longitudinal mass cytometry immunophenotyping comprehensively characterized blast phenotype evolution and revealed elevated PD-1 expression on the surface of nonblast myeloid cells. These findings highlight the clinical significance of cytomic monitoring, indicate that the myeloid compartment should be monitored during checkpoint inhibitor therapy, and emphasize the value of systems immunology in medicine. Cancer Immunol Res; 4(6); 474-80. ©2016 AACR.
©2016 American Association for Cancer Research.
4 Communities
2 Members
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13 MeSH Terms
Multiparameter analysis of stimulated human peripheral blood mononuclear cells: A comparison of mass and fluorescence cytometry.
Nicholas KJ, Greenplate AR, Flaherty DK, Matlock BK, Juan JS, Smith RM, Irish JM, Kalams SA
(2016) Cytometry A 89: 271-80
MeSH Terms: Antigens, CD, Flow Cytometry, Gene Expression, Humans, Immunophenotyping, Lanthanoid Series Elements, Leukocytes, Mononuclear, Lymphocyte Activation, Mass Spectrometry, Multivariate Analysis
Show Abstract · Added November 25, 2015
Mass and fluorescence cytometry are quantitative single cell flow cytometry approaches that are powerful tools for characterizing diverse tissues and cellular systems. Here mass cytometry was directly compared with fluorescence cytometry by studying phenotypes of healthy human peripheral blood mononuclear cells (PBMC) in the context of superantigen stimulation. One mass cytometry panel and five fluorescence cytometry panels were used to measure 20 well-established lymphocyte markers of memory and activation. Comparable frequencies of both common and rare cell subpopulations were observed with fluorescence and mass cytometry using biaxial gating. The unsupervised high-dimensional analysis tool viSNE was then used to analyze data sets generated from both mass and fluorescence cytometry. viSNE analysis effectively characterized PBMC using eight features per cell and identified similar frequencies of activated CD4+ T cells with both technologies. These results suggest combinations of unsupervised analysis programs and extended multiparameter cytometry will be indispensable tools for detecting perturbations in protein expression in both health and disease.
© 2015 International Society for Advancement of Cytometry.
4 Communities
2 Members
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10 MeSH Terms
Characterizing Phenotypes and Signaling Networks of Single Human Cells by Mass Cytometry.
Leelatian N, Diggins KE, Irish JM
(2015) Methods Mol Biol 1346: 99-113
MeSH Terms: Cell Line, Flow Cytometry, Humans, Immunophenotyping, Leukocytes, Mononuclear, Phenotype, Phosphorylation, Signal Transduction, Single-Cell Analysis
Show Abstract · Added November 9, 2015
Single cell mass cytometry is revolutionizing our ability to quantitatively characterize cellular biomarkers and signaling networks. Mass cytometry experiments routinely measure 25-35 features of each cell in primary human tissue samples. The relative ease with which a novice user can generate a large amount of high quality data and the novelty of the approach have created a need for example protocols, analysis strategies, and datasets. In this chapter, we present detailed protocols for two mass cytometry experiments designed as training tools. The first protocol describes detection of 26 features on the surface of human peripheral blood mononuclear cells. In the second protocol, a mass cytometry signaling network profile measures 25 node states comprised of five key signaling effectors (AKT, ERK1/2, STAT1, STAT5, and p38) quantified under five conditions (Basal, FLT3L, SCF, IL-3, and IFNγ). This chapter compares manual and unsupervised data analysis approaches, including bivariate plots, heatmaps, histogram overlays, SPADE, and viSNE. Data files in this chapter have been shared online using Cytobank ( http://www.cytobank.org/irishlab/ ).
3 Communities
2 Members
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9 MeSH Terms
RAS/MAPK Activation Is Associated with Reduced Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Therapeutic Cooperation Between MEK and PD-1/PD-L1 Immune Checkpoint Inhibitors.
Loi S, Dushyanthen S, Beavis PA, Salgado R, Denkert C, Savas P, Combs S, Rimm DL, Giltnane JM, Estrada MV, Sánchez V, Sanders ME, Cook RS, Pilkinton MA, Mallal SA, Wang K, Miller VA, Stephens PJ, Yelensky R, Doimi FD, Gómez H, Ryzhov SV, Darcy PK, Arteaga CL, Balko JM
(2016) Clin Cancer Res 22: 1499-509
MeSH Terms: Animals, B7-H1 Antigen, Biomarkers, Cell Line, Tumor, Disease Models, Animal, Disease Progression, Female, Gene Expression Profiling, Humans, Immunomodulation, Immunophenotyping, Lymphocytes, Tumor-Infiltrating, Mice, Mitogen-Activated Protein Kinases, Mortality, Phenotype, Programmed Cell Death 1 Receptor, Protein Kinase Inhibitors, Signal Transduction, Transcriptome, Triple Negative Breast Neoplasms, ras Proteins
Show Abstract · Added April 6, 2017
PURPOSE - Tumor-infiltrating lymphocytes (TIL) in the residual disease (RD) of triple-negative breast cancers (TNBC) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking.
EXPERIMENTAL DESIGN - We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1-targeted immunotherapy in mouse models of breast cancer.
RESULTS - Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras-MAPK signaling were significantly correlated with lower TILs. MEK inhibition upregulated cell surface MHC expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PD-L1/PD-1 inhibition enhanced antitumor immune responses in mouse models of breast cancer.
CONCLUSIONS - These data suggest the possibility that Ras-MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PD-L1-targeted therapies. Furthermore, Ras/MAPK activation and MHC expression may be predictive biomarkers of response to immune checkpoint inhibitors.
©2015 American Association for Cancer Research.
1 Communities
2 Members
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22 MeSH Terms
Cutting Edge: Redox Signaling Hypersensitivity Distinguishes Human Germinal Center B Cells.
Polikowsky HG, Wogsland CE, Diggins KE, Huse K, Irish JM
(2015) J Immunol 195: 1364-1367
MeSH Terms: B-Lymphocyte Subsets, B-Lymphocytes, Cell Differentiation, Gene Expression, Germinal Center, Humans, Hydrogen Peroxide, Immunophenotyping, Oxidation-Reduction, Palatine Tonsil, Phenotype, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Receptors, Antigen, B-Cell, Signal Transduction
Show Abstract · Added July 13, 2015
Differences in the quality of BCR signaling control key steps of B cell maturation and differentiation. Endogenously produced H2O2 is thought to fine tune the level of BCR signaling by reversibly inhibiting phosphatases. However, relatively little is known about how B cells at different stages sense and respond to such redox cues. In this study, we used phospho-specific flow cytometry and high-dimensional mass cytometry (CyTOF) to compare BCR signaling responses in mature human tonsillar B cells undergoing germinal center (GC) reactions. GC B cells, in contrast to mature naive B cells, memory B cells, and plasmablasts, were hypersensitive to a range of H2O2 concentrations and responded by phosphorylating SYK and other membrane-proximal BCR effectors in the absence of BCR engagement. These findings reveal that stage-specific redox responses distinguish human GC B cells.
Copyright © 2015 by The American Association of Immunologists, Inc.
3 Communities
3 Members
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14 MeSH Terms
Abacavir-reactive memory T cells are present in drug naïve individuals.
Lucas A, Lucas M, Strhyn A, Keane NM, McKinnon E, Pavlos R, Moran EM, Meyer-Pannwitt V, Gaudieri S, D'Orsogna L, Kalams S, Ostrov DA, Buus S, Peters B, Mallal S, Phillips E
(2015) PLoS One 10: e0117160
MeSH Terms: Anti-HIV Agents, Cross Reactions, Dideoxynucleosides, Drug Hypersensitivity, Epitopes, T-Lymphocyte, HIV Infections, HLA-B Antigens, Humans, Immunologic Memory, Immunophenotyping, Leukocytes, Mononuclear, Lymphocyte Count, Phenotype, T-Lymphocyte Subsets, Time Factors, Vaccination, Yellow Fever Vaccine
Show Abstract · Added March 30, 2020
BACKGROUND - Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population.
METHODS - To determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling.
RESULTS - Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.
CONCLUSIONS - We propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection.
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