Background: Increased prevalence of autoantibody Fab glycosylation has been demonstrated for several autoimmune diseases. Objectives: To study whether elevated Fab glycosylation is a common feature... Show moreBackground: Increased prevalence of autoantibody Fab glycosylation has been demonstrated for several autoimmune diseases. Objectives: To study whether elevated Fab glycosylation is a common feature of autoimmunity, this study investigated Fab glycosylation levels on serum IgG and its subclasses for autoantibodies associated with a range of different B cell- mediated autoimmune diseases, including rheumatoid arthritis, myasthenia gravis subtypes, pemphigus vulgaris, antineutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, anti-glomerular basement membrane glomerulonephritis, thrombotic thrombocytopenic purpura, and Guillain-Barre ⠁ syndrome. Methods: The level of Fab glycosylated IgG antibodies was assessed by lectin affinity chromatography and autoantigen-specific immunoassays. Results: In 6 of 10 autoantibody responses, in 5 of 8 diseases, the investigators found increased levels of Fab glycosylation on IgG autoantibodies that varied from 86% in rheumatoid arthritis to 26% in systemic lupus erythematosus. Elevated autoantibody Fab glycosylation was not restricted to IgG4, which is known to be prone to Fab glycosylation, but was also present in IgG1. When autoimmune diseases with a chronic disease course were compared with more acute autoimmune illnesses, increased Fab glycosylation was restricted to the chronic diseases. As a proxy for chronic autoantigen exposure, the investigators determined Fab glycosylation levels on antibodies to common latent herpes viruses, as well as to glycoprotein 120 in individuals who are chronically HIV-1-infected. Immunity to these viral antigens was not associated with increased Fab glycosylation levels, indicating that chronic antigen-stimulation as such does not lead to increased Fab glycosylation levels. Conclusions: These data indicate that in chronic but not acute B cell-mediated autoimmune diseases, disease-specific autoantibodies are enriched for Fab glycans. (J Allergy Clin Immunol 2023;151:16 46-54.) Show less
Amon, A.; Robertson, N.C.; Miyatake, H.; Heymans, C.; White, M.; DeRose, J.; ... ; Zhang, Y. 2023
Metastatic renal cell carcinoma (RCC) has a poor prognosis. Recent advances have shown beneficial responses to immune checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies. As only a subset of... Show moreMetastatic renal cell carcinoma (RCC) has a poor prognosis. Recent advances have shown beneficial responses to immune checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies. As only a subset of RCC patients respond, alternative strategies should be explored. Patients refractory to anti-PD-1 therapy may benefit from autologous tumor-infiltrating lymphocyte (TIL) therapy. Even though efficient TIL expansion was reported from RCC lesions, it is not well established how many RCC TIL products are tumor-reactive, how well they produce pro-inflammatory cytokines in response to autologous tumors, and whether their response correlates with the presence of specific immune cells in the tumor lesions. We here compared the immune infiltrate composition of RCC lesions with that of autologous kidney tissue of 18 RCC patients. Tcell infiltrates were increased in the tumor lesions, and CD8(+) Tcell infiltrates were primarily of effector memory phenotype. Nine out of 16 (56%) tested TIL products we generated were tumor-reactive, as defined by CD137 upregulation after exposure to autologous tumor digest. Tumor reactivity was found in particular in TIL products originating from tumors with ahigh percentage of infiltrated Tcells compared to autologous kidney, and increased CD25 expression on CD8(+) Tcells. Importantly, although TIL products had the capacity to produce the key effector cytokines IFN-gamma, TNF-alpha or IL-2, they failed to produce significant amounts in response to autologous tumor digests. In conclusion, TIL products from RCC lesions contain tumor-reactive Tcells. Their restricted tumor-specific cytokine production requires further investigation of immunosuppressive factors in RCC and subsequent optimization of RCC-derived TIL culture conditions. Show less
Asgari, M.; Lin, C.-A.; Joachimi, B.; Giblin, B.; Heymans, C.; Hildebrandt, H.; ... ; Valentijn, E. 2021
The androgen receptor (AR) is the master regulator of prostate cancer (PCa) development, and inhibition of AR signalling is the most effective PCa treatment. AR is expressed in PCa cells and also... Show moreThe androgen receptor (AR) is the master regulator of prostate cancer (PCa) development, and inhibition of AR signalling is the most effective PCa treatment. AR is expressed in PCa cells and also in the PCa-associated stroma, including infiltrating macrophages. Macrophages have a decisive function in PCa initiation and progression, but the role of AR in macrophages remains largely unexplored. Here, we show that AR signalling in the macrophage-like THP-1 cell line supports PCa cell line migration and invasion in culture via increased Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) signalling and expression of its downstream cytokines. Moreover, AR signalling in THP-1 and monocyte-derived macrophages upregulates IL-10 and markers of tissue residency. In conclusion, our data suggest that AR signalling in macrophages may support PCa invasiveness, and blocking this process may constitute one mechanism of anti-androgen therapy. Show less
Tize, C.; Berckmoes, L.; Jong, J. de; Reis, R. 2020
This paper examines responses to the 2015 terror attack on Charlie Hebdo, a French satirical magazine, amongst students in a secondary school in Berlin-Neukolln, Germany. The Charlie Hebdo attack... Show moreThis paper examines responses to the 2015 terror attack on Charlie Hebdo, a French satirical magazine, amongst students in a secondary school in Berlin-Neukolln, Germany. The Charlie Hebdo attack occurred in the final weeks of a 19-month ethnographic study in the community. By analyzing the responses in the school to this critical event, we identify what is at stake for Muslim students. Students presented many explanations for why the attack happened, and opinions on whether the attackers' actions were justified. Staff were alarmed about students' viewpoints that they considered "extreme". These dynamics resulted in conflicts and misunderstandings amongst students, and between students and staff. Yet, we show that, rather than the violence itself, or questions about its legitimacy, it was everyday processes in students' lives - e.g., bullying, peer pressure and discrimination, and feelings of being misrepresented and misunderstood - that were central to students' reactions to the event. We suggest that to understand students' reactions, both the immediate and the broader socio-political contexts must be considered, particularly rising xenophobia and processes of polarization in Germany and Europe at large. We thus conclude that to understand young people's reactions to terrorist acts, we need to look beyond initial statements and explore ethnographically how wider contexts shape the actions, reactions, and future orientations of young Muslims in Europe. Show less
Drees, M.; Huisman, C.; Jong, J. de; Olde Keizer, M.; Rodenboog, S.D.; Tongeren, P.E. van; ... ; Wolf, M.J.F. van der 2020
Anion binding to a receptor based on stiff‐stilbene, which is equipped with a urea hydrogen bond donating group and a phosphate or phosphinate hydrogen bond accepting group, can be controlled by... Show moreAnion binding to a receptor based on stiff‐stilbene, which is equipped with a urea hydrogen bond donating group and a phosphate or phosphinate hydrogen bond accepting group, can be controlled by light. In one photoaddressable state (E isomer) the urea binding site is available for binding, while in the other (Z isomer) it is blocked because of an intramolecular interaction with its hydrogen bond accepting motif. This intramolecular interaction is supported by DFT calculations and 1H NMR titrations reveal a significantly lower anion binding strength for the state in which anion binding is blocked. Furthermore, the molecular switching processhas been studied in detail by UV/Vis and NMR spectroscopy. The presented approach opens up new opportunities toward the development of photoresponsive anion receptors. Show less
Holwerda, B.W.; Kelvin, L.; Baldry, I.; Lintott, C.; Alpaslan, M.; Pimbblet, K.A.; ... ; Wright, A. 2019
In 1797 and 1798 the first steps were taken in the Netherlands towards the development of a democratic system. In 1796-1797 a written Constitution was drafted for the Batavian Republic, as the... Show moreIn 1797 and 1798 the first steps were taken in the Netherlands towards the development of a democratic system. In 1796-1797 a written Constitution was drafted for the Batavian Republic, as the Netherlands was called at the time. This Constitution was in 1797 submitted in a national referendum for a vote of the people, but it was rejected. A new draft was written and again submitted the following year. This time the Constitution was adopted. Very little is known about these referenda. Extensive archival research has been necessary in order to understand how these steps in democracy were taken. It has been possible to produce a dataset of results for 948 cities, villages and rural districts. Based on the voting results, the public support for a democratic constitution has been analyzed after a description of the voting system. The voting results are examined along two cleavages structures. First, major distinctions existed between cities and rural districts and secondly between Catholics and Protestants. As a partial explanation the religious preferences are important to understand the turnout by the two referenda. Above all, the results of the two referenda show a deeply divided society of religious minorities. Show less
