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11. The contribution of the Fc RIIB immunoreceptor tyrosine-based inhibitory motif (ITIM) to the modulation of antibody immunotherapy

Author

Simpson, Alexander Patrick and Cragg, Mark

Abstract

Monoclonal antibodies (mAb) are an increasingly important therapeutic tool in the treatment of cancers and autoimmunity. Many mAbs elicit their efficacy through engagement of activatory Fc gamma receptors (Fc R), resulting in target cell depletion by immune effector cells. These activatory Fc Rs are negatively influenced by the single inhibitory Fc R, Fc RIIB. Fc RIIB has been shown to reduce the efficacy of mAbs through impairment of activatory Fc R function and upregulation of Fc RIIB has been identified as a resistance mechanism of mAb therapeutics in cancer. Fc RIIB contains an intracellular immunoreceptor-tyrosine-based inhibition motif (ITIM), which delivers inhibitory signalling. Whether the ITIM is required for all Fc RIIB-mediated inhibitory activities of therapeutic mAbs is not yet clear. To address this issue, we developed and characterised a novel transgenic mouse model (NoTIM), in which the endogenous inhibitory mouse (m)Fc RII is replaced with a non-signalling ITIM mutant of human (h)Fc RIIB. Cells from mice expressing the NoTIM receptor were no longer able to elicit phosphorylation of the Fc RIIB ITIM, mediate efficient internalisation of immune complexes or prevent anti-IgM-mediated calcium flux, confirming the expected phenotype. To understand how Fc RIIB inhibitory signalling impacted mAb-mediated depletion of target cells, NoTIM mice were treated with anti-mouse CD20 mAbs. The extent of depletion was compared to mice either lacking mFc RII or where mFc RII was replaced with a signalling competent hFc RIIB (hFc RIIB Tg). B cell depletion was reduced in both the NoTIM and hFc RIIB Tg mice compared to those lacking mFc RII. Subsequent experiments revealed this was not due to accelerated mAb internalisation nor enhanced clearance from the serum. Using a series of adoptive transfer models we determined that the NoTIM hFc RIIB was mediating inhibition, by competing with activatory Fc Rs on the surface of myeloid cells for the Fc of the direct targeting mAb. These findings were then assessed with respect to T regulatory cell and malignant murine B cell depletion. It was found that in both cases, depletion was negatively impacted by the expression of Fc RIIB at themyeloid surface rather than by its ability to signal. These data indicate that signalling through the ITIM is not critical for the ability of hFc RIIB to prevent mAb-mediated depletion of target cells, questioning current paradigms for its mechanism of action.

Published
2022

31. Evaluating the multiple sulfur isotope signature of Eoarchean rocks from the Isua Supracrustal Belt (Southwest‐Greenland) by MC‐ICP‐MS: Volcanic nutrient sources for early life

Author

Macdonald, Jane E., primary, Sugden, Patrick, additional, Dumont, Matthew, additional, Szilas, Kristoffer, additional, Glorie, Stijn, additional, Simpson, Alexander, additional, Gilbert, Sarah, additional, Burke, Andrea, additional, and Stüeken, Eva E., additional

Published
2024
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35. Evaluating the multiple sulfur isotope signature of Eoarchean rocks from the Isua Supracrustal Belt (Southwest-Greenland) by MC-ICP-MS:Volcanic nutrient sources for early life

Author

Macdonald, Jane E., Sugden, Patrick, Dumont, Matthew, Szilas, Kristoffer, Glorie, Stijn, Simpson, Alexander, Gilbert, Sarah, Burke, Andrea, Stüeken, Eva E., Macdonald, Jane E., Sugden, Patrick, Dumont, Matthew, Szilas, Kristoffer, Glorie, Stijn, Simpson, Alexander, Gilbert, Sarah, Burke, Andrea, and Stüeken, Eva E.

Abstract

On the anoxic Archean Earth, prior to the onset of oxidative weathering, electron acceptors were relatively scarce, perhaps limiting microbial productivity. An important metabolite may have been sulfate produced during the photolysis of volcanogenic SO2 gas. Multiple sulfur isotope data can be used to track this sulfur source, and indeed this record indicates SO2 photolysis dating back to at least 3.7 Ga, that is, as far back as proposed evidence of life on Earth. However, measurements of multiple sulfur isotopes in some key strata from that time can be challenging due to low sulfur concentrations. Some studies have overcome this challenge with NanoSIMS or optimized gas-source mass spectrometry techniques, but those instruments are not readily accessible. Here, we applied an aqua regia leaching protocol to extract small amounts of sulfur from whole rocks for analyses of multiple sulfur isotopes by multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS). Measurements of standards and replicates demonstrate good precision and accuracy. We applied this technique to meta-sedimentary rocks with putative biosignatures from the Eoarchean Isua Supracrustal Belt (ISB, >3.7 Ga) and found positive ∆33S (1.40–1.80‰) in four meta-turbidites and negative ∆33S (−0.80‰ and −0.66‰) in two meta-carbonates. Two meta-basalts do not display significant mass-independent fractionation (MIF, −0.01‰ and 0.16‰). In situ Re–Os dating on a molybdenite vein hosted in the meta-turbidites identifies an early ca. 3.7 Ga hydrothermal phase, and in situ Rb–Sr dating of micas in the meta-carbonates suggests metamorphism affected the rocks at ca. 2.2 and 1.7 Ga. We discuss alteration mechanisms and conclude that there is most likely a primary MIF-bearing phase in these meta-sediments. Our new method is therefore a useful addition to the geochemical toolbox, and it confirms that organisms at that time, if present, may indeed have been f

Published
2024

39. Neutralising deviance : the legitimation of harm and the culture of finance in the City of London

Author

Simpson, Alexander T. and Millington, Gareth

Subjects
301
Abstract

This research project is a profile of inverted social deviance that speaks to base issues of morality and justice in the organisation of economic life. Focusing on the City of London, the aim of the research project is to create a sociological snapshot of the organising interests and ideologies functioning within spaces and institutions of global finance. Engaging in the everyday routines, expectations assumptions of economic actors embedded within the financial services industry, this study contributes towards an enhanced understanding of how the cultural sensibilities that underpin a market based reality perpetuate gross social and economic inequalities through the shifting of negative market costs on vulnerable sections of society. Leading to a critical evaluation of the organising ideologies and taken-for-granted assumptions that function within the City of London, the principal findings detail the relational struggles, strategies and vested interests that dominate the field of finance life.

Published
2015

43. Medical Assistance in Dying for Mental Illness as a Sole Underlying Medical Condition and Its Relationship to Suicide: A Qualitative Lived Experience-Engaged Study: Aide Médicale à Mourir Pour Maladie Mentale Comme Seule Condition Médicale Sous-Jacente et Son Lien Avec le Suicide: Une Etude Qualitative Engagée Dans l'Expérience Vécue

Author

Hawke, Lisa D., Bastidas-Bilbao, Hamer, Cappe, Vivien, van Kesteren, Mary Rose, Stewart, Donna E., Gupta, Mona, Simpson, Alexander I. F., Campbell, Bartholemew H., Castle, David, and Stergiopoulos, Vicky

Subjects
ASSISTED suicide, MENTAL health services, PEOPLE with mental illness, SUICIDE, MENTAL illness
Abstract

Copyright of Canadian Journal of Psychiatry is the property of Sage Publications Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2024
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45. Copy Number Variation Analysis of Aggressive Behaviour in Schizophrenia.

Author

De Luca, Vincenzo, Chaudhary, Zanib, Al-Chalabi, Nzaar, Qian, Jessica, Xu, Xiaoguang, Gerretsen, Philip, Bani-Fatemi, Ali, Simpson, Alexander, Fischer, Corinne, Graff, Ariel, and Kolla, Nathan J.

Subjects
BEHAVIORAL assessment, SCHIZOPHRENIA, SUBSTANCE abuse, VIOLENCE
Abstract

Introduction: An increased proclivity towards violence is often associated with those diagnosed with schizophrenia (SCZ), despite contradictory findings from prior studies exploring the association between violence and SCZ. Evidence has shown that certain comorbidities, specifically the presence of a substance use disorders, can result in increased aggression in those with SCZ. Copy number variation (CNV) load has also previously been implicated in the genetic vulnerability of individuals with SCZ. For this study, we aimed to determine whether CNV load correlates with increased violence in SCZ. Methods: Community-dwelling patients diagnosed with SCZ spectrum disorders (n = 203) were recruited from a non-forensic population. The assessment for aggression was completed using a cross-sectional and retrospective design, and CNV analysis was conducted analysing genomic DNA using the Illumina Omni 2.5 array. Results: No correlation between the number of CNV events (either deletion or duplication) and the severity of the physical violence episode index was found. However, there was a significant association between larger deletion events across the violent behaviours under investigation. Discussion: These results need to be confirmed in more extensive studies using standardized tools developed for non-forensic populations, such as the Brown-Goodwin Scale of Aggression. [ABSTRACT FROM AUTHOR]

Published
2024
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46. Chronic Psychotic Disorders and Correctional Involvement: A Population-Based Matched Case-Control Study in Ontario, Canada.

Author

Vijh, Ruchi, Kouyoumdjian, Fiona G., Iwajomo, Tomisin, Simpson, Alexander I. F., Jones, Roland, Oliveira, Claire de, and Kurdyak, Paul

Subjects
PSYCHOSES, CRISIS intervention (Mental health services), EMERGENCY room visits, MENTAL health services
Abstract

Copyright of Canadian Journal of Psychiatry is the property of Sage Publications Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2024
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48. Copy Number Variation Analysis of Aggressive Behaviour in Schizophrenia

Author

De Luca, Vincenzo, primary, Chaudhary, Zanib, additional, Al-Chalabi, Nzaar, additional, Qian, Jessica, additional, Xu, Xiaoguang, additional, Gerretsen, Philip, additional, Bani-Fatemi, Ali, additional, Simpson, Alexander, additional, Fischer, Corinne, additional, Graff, Ariel, additional, and Kolla, Nathan J., additional

Published
2023
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