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Animal models for the study of innate immunity: protozoan infections in fish
Published in G. F. Wiegertjes, G. Flik, Host-Parasite Interactions, 2004
Maaike Joerink, Jeroen P.J. Saeij, James L. Stafford, Miodrag Belosevic, Geert F. Wiegertjes
Recently, in goldfish, we showed that transferrin cleavage products act as macrophage-activating factor (MAF) by stimulating macrophages to produce large amounts of nitric oxide (Stafford and Belosevic, 2003; Stafford et al., 2001b). Possibly, neutrophilic granulocytes, that are generally the first immune cells recruited to the site of inflammation, initiate the cleavage of transferrin via the production of neutrophil-derived proteases (Miller et al., 1996). Likewise, activation by recognition of a proteolytic fragment from a self-protein has also been found in Drosophila (a proteolytically processed product of the spätzle gene activates Toll) (Michel et al., 2001). The recognition of endogenous ‘danger’ signals (e.g. molecules produced by stressed cells, or products that are usually found inside a healthy cell) by the immune system is the basis of the ‘Danger model’ (Matzinger, 1998). At this moment research on a putative goldfish macrophage receptor able to detect these transferrin cleavage products is ongoing.
An update on the ‘danger theory’ in inhibitor development in hemophilia A
Published in Expert Review of Hematology, 2019
Sarah J. Schep, Marianne Boes, Roger E.G. Schutgens, Lize F.D. van Vulpen
In order to answer these questions, Matzinger conceived the danger model, which challenged the central paradigm in immunology by claiming that the immune system is more concerned with damage than with foreignness and that immune cells become activated by alarm signals from injured tissues rather than the recognition of non-self [10,44]. Hereby the context in which the antigen contact takes place, dictates the immune response. Local alarm or danger signals from this micro-environment activate APCs, which in turn are able to induce T-cells by providing the necessary co-stimulation. These danger signals can arise from both exogenous (PAMPs) as well as endogenous sources. The endogenous ‘alarmins’ are mostly associated with host cells in distress and necrotic cell death [51]. These so-called DAMPs include heat-shock proteins, uric acid, and DNA associated proteins like high mobility group box 1 (HMGB1) [52–55]. As proposed by Seong and Matzinger, PAMPs and DAMPs share similar conserved hydrophobic portions on their respective molecules, which enable them to bind to the same PRRs and therefore to induce comparable inflammatory responses [56]. Importantly these endogenous and exogenous alarm molecules are not necessary directly related to the antigen, which could explain why the immune system not only reacts to ‘dangerous’ non-self infectious agents, like bacteria, but also to self-antigens from healthy cells during autoimmune diseases or to FVIII as is the case with inhibitor development in hemophilia A.
Immunotargeting and therapy of cancer by advanced multivalence antibody scaffolds
Published in Journal of Drug Targeting, 2020
Vala Kafil, Amir Ata Saei, Mohammad Reza Tohidkia, Jaleh Barar, Yadollah Omidi
It should be articulated that the initiation of immune surveillance or tolerance against malignancies is yet to be fully understood. Based on the ‘danger model’, Ag-presenting cells (APCs) are activated by danger/alarm signals from injured cells that can, in turn, activate various functions of the immune system [62]. The immunity/tolerance can mainly be driven through the factors related to (i) the structural properties of Ag (e.g. concentration, morphology, composition, size, charge and stability) and (ii) the host immune system such as effector/regulatory cells and macrophages, cytokines (i.e. IL-10, TGFβ in terms of tolerance or IL-4, TNF in terms of immunity), complement system, Abs and inflammation [63].
The effect of radioiodine treatment on the diseased thyroid gland
Published in International Journal of Radiation Biology, 2019
Andrew S. Riley, Gordon A. G. McKenzie, Victoria Green, Giuseppe Schettino, R. James A. England, John Greenman
It has previously been postulated that cell death in response to I131 occurs through both apoptosis and necrosis. Apoptosis, first described by Kerr and colleagues, is an energy dependent, programmed form of cell death first associated with cellular elimination during biological events such as embryonic development and healthy tissue turnover (Kerr et al. 1972). The process of apoptosis is strictly controlled in order to minimize local inflammation; cells are ‘marked’ for phagocytosis by translocation of the phospholipid phosphatidylserine (PS) onto the outer leaflet of the cellular plasma membrane and retain both plasma membrane integrity and some degree of metabolic activity until they are cleared by phagocytic cells (efferocytosis; Green et al. 2016). The immunological quiescence of apoptosis is further maintained by the release of anti-inflammatory cytokines, however in vitro studies have demonstrated a transition of end-stage apoptotic cells toward a necrotic morphotype in the absence of cells with phagocytic abilities in a process termed ‘secondary necrosis’ (Vanden Berghe et al. 2010). Necrosis is a passive, unprogrammed form of cell death that results from environmental perturbations causing loss of membrane integrity and thus the uncontrolled release of inflammatory cellular contents (Galluzzi et al. 2018). These components, also known as damage-associated molecular patterns (DAMPs), represent a heterogeneous group of cellular molecules which, according to the ‘danger model’ proposed by Matzinger (1994), are immuno-stimulatory. Furthermore, the immune-stimulatory effects characterizing necrotic cell death are also evident with secondary necrosis, underpinned by the release of DAMPs (Sachet et al. 2017).