Person: Robson, Simon
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Robson
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Robson, Simon
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Publication CD39 Expression Identifies Terminally Exhausted CD8+ T Cells(Public Library of Science, 2015) Gupta, Prakash K.; Godec, Jernej; Wolski, David; Adland, Emily; Yates, Kathleen; Pauken, Kristen E.; Cosgrove, Cormac; Ledderose, Carola; Junger, Wolfgang; Robson, Simon; Wherry, E. John; Alter, Galit; Goulder, Philip J. R.; Klenerman, Paul; Sharpe, Arlene; Lauer, Georg; Haining, W. NicholasExhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion.Publication Autoimmune Hepatitis: Clinical Review with Insights into the Purinergic Mechanism of Disease(XIA & HE Publishing Ltd, 2013) Kapila, Nikhil; Higa, Jennifer T.; Longhi, Maria Serena; Robson, SimonAutoimmune hepatitis (AIH) is an important disorder that predominantly results in inflammatory liver disease in genetically predisposed women. The clinicopathological picture is characterized by symptoms associated with both systemic inflammation and hepatic dysfunction, and with increased serum aminotransferases, elevated IgG, autoantibodies, and interface hepatitis on liver biopsy. AIH usually results in liver injury as a consequence of chronic hepatitis and cirrhosis. However, rarely, patients may present with fulminant liver failure. Early diagnosis is important in all instances because the disease can be highly responsive to immunosuppressive therapeutic options. Left untreated, the disease is associated with high morbidity and mortality. Here we provide an overview of the current state of knowledge on AIH and summarize the treatment options for this serious condition in adults. We also discuss the pathogenesis of the disease as a possible consequence of autoimmunity and the breakdown of hepatic tolerance. We focus on regulatory T cell impairments as a consequence of changes in CD39 ectonucleotidase expression and altered purinergic signaling. Further understanding of hepatic tolerance may aid in the development of specific and well-tolerated therapies for AIH.Publication CD73 Is a Phenotypic Marker of Effector Memory Th17 Cells in Inflammatory Bowel Disease(Wiley, 2012-10-29) Doherty, Glen; Bai, Aiping; Hanidziar, Dusan; Longhi, Maria Serena; Lawlor, Garrett; Putheti, Prabhakar; Csizmadia, Eva; Nowak, Martina; Cheifetz, Adam; Moss, Alan; Robson, SimonPurinergic signaling and associated ectonucleotidases, such as CD39 and CD73, have been implicated in the pathogenesis of inflammatory bowel disease (IBD). CD39 is known to be a Treg memory cell marker, and here we determine the phenotype and function of CD73+CD4+ T lymphocytes in patients with IBD. We describe elevated levels of CD73+CD4+ T cells in the peripheral blood and intestinal lamina propria of patients with active IBD. The functional phenotype of these CD73+CD4+ T cells was further determined by gene expression, ecto-enzymatic activity, and suppressive assays. Increased numbers of CD73+CD4+ T cells in the periphery and lamina propria were noted during active inflammation, which returned to baseline levels following anti-TNF treatment. Peripheral CD73+CD4+ T cells predominantly expressed CD45RO, and were enriched with IL-17A+ cells. The CD73+CD4+ cell population expressed higher levels of RORC, IL-17A, and TNF, and lower levels of FOXP3 and/or CD25, than CD73−CD4+ T cells. Expression of CD73 by peripheral CD4+ T cells was increased by TNF, and decreased by an anti-TNF monoclonal antibody (infliximab). In vitro, these peripheral CD73+CD4+ T cells did not suppress proliferation of CD25− effector cells, and expressed higher levels of pro-inflammatory markers. We conclude that the CD73+CD4+ T-cell population in patients with active IBD are enriched with cells with a T-helper type 17 phenotype, and could be used to monitor disease activity during treatment.Publication Predictors of Endoscopic Inflammation in Patients with Ulcerative Colitis in Clinical Remission(Oxford University Press (OUP), 2013-04-01) Rosenberg, Laura; Lawlor, Garreth O.; Zenlea, Talia; Goldsmith, Jeffrey; Gifford, Anne; Falchuk, Kenneth; Wolf, Jacqueline; Cheifetz, Adam; Robson, Simon; Moss, Alan C.Objectives Patients with ulcerative colitis (UC) who are in clinical remission may still have underlying endoscopic inflammation, which is associated with inferior clinical outcomes. The goal of this study was to determine the prevalence of, and factors associated with, active endoscopic disease in patients with UC who are in clinical remission. Design Prospective observational study in a single center. Patients with UC in clinical remission (by SCCAI) were enrolled prospectively at time of surveillance colonoscopy. Disease phenotype, endoscopic activity (Mayo sub-score) and histological score (Geboes) were recorded, and blood was drawn for peripheral blood biomarkers. Results 149 patients in clinical remission were prospectively enrolled in this cohort; 81% had been in clinical remission for > 6 months, and 86% were currently prescribed maintenance medications. At endoscopy 45% of patients in clinical remission had any endoscopic inflammation (Mayo endoscopy sub-score >0) and 13% had scores >1. In a multivariate model, variables independently associated with a Mayo endoscopic score >1 were remission for < 6 months (p=.001), WBC (p=0.01) and CRP (p=0.009). A model combining these three variables had a sensitivity of 94% and a specificity of 73% for predicting moderate-severe endoscopic activity in patients in clinical remission (AUC 0.86). In an unselected sub-group of patients who had peripheral blood mononuclear cell mRNA profiling, GATA3 mRNA levels were significantly higher in patients with endoscopic activity. Conclusions Duration of clinical remission, WCC and CRP can predict the probability of on-going endoscopic activity despite clinical remission in patients with UC. These parameters could be used to identify patients who require intensification of treatment to achieve mucosal healing.Publication Lectin-Reactive Anti-α-Gal in Patients with Crohnʼs Disease: Correlation with Clinical Phenotypes(Oxford University Press (OUP), 2013-12-01) Safaie, Parham; Ham, Maggie; Kuang, Peter; Mehta, Anand S.; Wang, Mengjun; Cheifetz, Adam; Robson, Simon; Lau, Daryl; Block, Timothy M.; Moss, Alan C.Background Patients with inflammatory bowel disease have higher proportions of immunoglobulin G (IgG) antibodies lacking N-galactose, also called agalactosyl IgG, in their serum. Such agalactosyl IgGs have been associated with disease activity and the immunogenicity of biologics. The aim was to describe the relationship between circulating levels of a subset of agalactosyl IgGs (anti-α-Gal) and Crohn’s disease (CD) phenotypes. Methods Prospectively collected serum samples of a well-characterized cohort of patients with inflammatory bowel disease and controls were used. Serum anti-α-Gal levels were measured by a high-affinity enzyme-linked immunosorbent assay and referenced to a standard control. Results Serum samples from 167 subjects were tested; 62 with CD, 76 with ulcerative colitis, and 29 controls. Agalactosyl anti-α-Gal levels were significantly higher in active CD than in active ulcerative colitis (P = 0.0043) or healthy controls (P < 0.0001). Among patients with CD, agalactosyl anti-α-Gal levels were significantly higher in those with a history of arthritis, than those without (P = 0.0002), but lower in those taking immunomodulators (P = 0.03). There was no correlation between agalactosyl anti-α-Gal levels and indices of Crohn’s severity, including C-reactive protein levels or Harvey– Bradshaw index. Patients who were primary or secondary nonresponders to infliximab had similar agalactosyl anti-α-Gal levels to clinical responders. Conclusions Patients with CD have greater amounts of agalactosylated anti-α-Gal antibodies in their serum, particularly in those with associated joint disease. This increase seems to be independent of indices of disease activity, but is influenced by immunomodulator use.Publication Vitamin D Levels in Adults with Crohnʼs Disease Are Responsive to Disease Activity and Treatment(Oxford University Press (OUP), 2014-05) Brigham, Maggie; Longhi, Maria Serena; Lahiff, Conor; Cheifetz, Adam; Robson, Simon; Moss, Alan C.Background: Vitamin D deficiency is common in patients with Crohn’s disease (CD), although whether this impairs immune responsiveness, and is related to disease activity per se, remains unclear. We sought to investigate vitamin D pathways in patients with CD according to measures of inflammation and immune response. Methods: Prospectively collected samples of a well-characterized cohort of patients with CD were used to measure serum 25(OH)-vitamin D levels by enzyme-linked immunoassay. Related gene expression was determined by polymerase chain reaction in T cells. The effect of vitamin D on the proliferation of isolated CD4+ cells was determined. Results: Patients with active CD had lower serum vitamin D levels than those in clinical remission; this measurement was independent of season or reported use of vitamin D supplements. Harvey–Bradshaw Index scores, but not C-reactive protein, correlated with serum vitamin D levels. Gene expression of the vitamin D receptor was higher in peripheral blood T cells from patients with active disease than in those in remission. The proportion of CD25hi CD4+ cells from patients with CD increased in the presence of vitamin D. After treatment with infliximab, significant increases in serum vitamin D levels were noted in patients. Conclusions: Low vitamin D levels are associated with disease activity in CD and increase after infliximab treatment.Publication CD39 and CD161 Modulate Th17 Responses in Crohn's Disease(The American Association of Immunologists, 2014-08-29) Bai, Aiping; Moss, Alan; Kokkotou, Efi; Usheva, Anny; Sun, Xiaofeng; Cheifetz, Adam; Zheng, Yi; Longhi, Maria Serena; Gao, Wenda; Wu, Yan; Robson, SimonCD39 (ENTPD1) is expressed by subsets of pathogenic human CD4+ T cells, such as T helper type 17 (Th17) cells. These Th17 cells are considered important in intestinal inflammation, such as seen in Crohn’s disease. Recently, CD161 (NKR-P1A) has been shown to be a phenotypic marker of human Th17 cells. In this study, we report that co-expression of CD161 and CD39 not only identifies these cells but also promotes Th17 generation. We note that human CD4+CD39+CD161+ T cells can be induced under stimulatory conditions that promote Th17 in vitro. Furthermore, CD4+CD39+CD161+ cells purified from blood and intestinal tissues, from both healthy controls and patients with Crohn’s disease, are of the Th17 phenotype and exhibit pro-inflammatory functions. CD39 is co-expressed with CD161, and this association augments acid sphingomyelinase (ASM) activity upon stimulation of CD4+ T cells. These pathways regulate mTOR and STAT3 signaling to drive the Th17 phenotype. Inhibition of ASM activity by pharmacological blockers or knockdown of ASM abrogates STAT3 signaling, thereby limiting IL-17 production in CD4+ T cells obtained from both controls and patients with active Crohn’s disease. Increased levels of CD39+CD161+ CD4+ T cells in blood or lamina propria are noted in patients with Crohn’s disease; and levels directly correlate with clinical disease activity. Hence, co-expression of CD39 and CD161 by CD4+ T cells might serve as a biomarker to monitor Th17 responsiveness. Collectively, CD39 and CD161 modulate human Th17 responses in Crohn's disease through alterations in purinergic nucleotide-mediated responses and ASM catalytic bioactivity, respectively.Publication Disordered Purinergic Signaling and Abnormal Cellular Metabolism are Associated with Development of Liver Cancer in Cd39/Entpd1 Null Mice(Wiley, 2013-01) Sun, Xiaofeng; Han, Lihui; Seth, Pankaj; Bian, Shu; Li, Linglin; Csizmadia, Eva; Junger, Wolfgang; Schmelzle, Moritz; Usheva, Anny; Tapper, Elliot B.; Baffy, Gyorgy; Sukhatme, Vikas; Wu, Yan; Robson, SimonLiver cancer is associated with chronic inflammation, which is linked to immune dysregulation, disordered metabolism and aberrant cell proliferation. CD39/ENTPD1 is an ectonucleotidase that regulates extracellular nucleotide/nucleoside concentrations by scavenging nucleotides to ultimately generate adenosine. These properties inhibit anti tumor immune responses and promote angiogenesis, being permissive for the growth of transplanted tumors. Here, we show Cd39 deletion promotes development of both induced and spontaneous autochthonous liver cancer in mice. Loss of Cd39 results in higher concentrations of extracellular nucleotides, which stimulate proliferation of hepatocytes, abrogate autophagy and disrupt glycolytic metabolism. Constitutive activation of Ras-MAPK and mTOR-S6K1 pathways occurs in both quiescent Cd39 null hepatocytes in vitro and liver tissues in vivo. Exogenous ATP boosts these signaling pathways, while rapamycin inhibits such aberrant responses in hepatocytes. Conclusions Deletion of Cd39 and resulting changes in disordered purinergic signaling perturb hepatocellular metabolic/proliferative responses, paradoxically resulting in malignant transformation. These findings might impact adjunctive therapies for cancer. Lastly, our studies indicate that the biology of autochthonous and transplanted tumors is quite distinct.Publication The Mitochondrial Uncoupling Protein-2 Promotes Chemoresistance in Cancer Cells(American Association for Cancer Research (AACR), 2008-04-15) Derdak, Zoltan; Mark, Nicholas M.; Beldi, Guido; Robson, Simon; Wands, Jack R.; Baffy, GyorgyCancer cells acquire drug resistance as a result of selection pressure dictated by unfavorable microenvironments. This survival process is facilitated through efficient control of oxidative stress originating from mitochondria that typically initiates programmed cell death. We show this critical adaptive response in cancer cells to be linked to uncoupling protein-2 (UCP2), a mitochondrial suppressor of reactive oxygen species (ROS). UCP2 is present in drug-resistant lines of various cancer cells and in human colon cancer. Overexpression of UCP2 in HCT116 human colon cancer cells inhibits ROS accumulation and apoptosis post-exposure to chemotherapeutic agents. Tumor xenografts of UCP2-overexpressing HCT116 cells retain growth in nude mice receiving chemotherapy. Augmented cancer cell survival is accompanied by altered N-terminal phosphorylation of the pivotal tumor suppressor p53 and induction of the glycolytic phenotype (Warburg effect). These findings link UCP2 with molecular mechanisms of chemoresistance. Targeting UCP2 may be considered a novel treatment strategy for cancer.Publication Role of P2X4 Receptor in Mouse Voiding Function(Nature Publishing Group UK, 2018) Yu, Weiqun; Hill, Warren; Robson, Simon; Zeidel, MarkPurinergic signalling plays an important role in the regulation of bladder smooth muscle (BSM) contractility, and P2X4 receptor is expressed in the bladder wall, where it may act by forming heteromeric receptors with P2X1, the major purinergic force-generating muscle receptor. To test this hypothesis, we examined mouse BSM contractile properties in the absence and presence of selective P2X1 (NF449 & NF279) and P2X4 antagonists (5-BDBD). These drugs inhibited BSM purinergic contraction only partially, suggesting the possibility of a heteromeric receptor. However, carefully controlled co-immunoprecipitation experiments indicated that P2X1 and P2X4 do not form physically linked heteromers. Furthermore, immunofluorescence staining showed that P2X4 is not present in mouse BSM per se, but in an unknown cellular structure among BSM bundles. To investigate whether deletion of P2X4 could impact voiding function in vivo, P2X4 null mice were characterized. P2X4 null mice had normal bladder weight and morphology, normal voiding spot size and number by voiding spot assay, normal voiding interval, pressure and compliance by cystometrogram, and normal BSM contractility by myography. In conclusion, these data strongly suggest that P2X4 is not present in mouse BSM cells, does not affect smooth muscle contractility and that mice null for P2X4 exhibit normal voiding function.