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Basics of Allergy
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Rafeul Alam, Dipa K Sheth, Magdalena M Gorska
CD8 T cells have two distinct mechanisms of cytotoxicity: perforin and Fas ligand (Fig. 1.3) (Russell and Ley 2002). Perforin is a membrane pore-forming molecule, which allows release of granular enzymes directly into the cytosol of the target cell. Granzyme B induces rapid apoptosis of the target cell through caspase-dependent and caspase-independent manners.
Tissue injury and repair
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
It is now recognized that there are other ways to stimulate the initiation pathway. We know, for example, that cytotoxic T lymphocytes release compounds such as granzyme B, which lead to the executioner phase without the involvement of a transmembrane death receptor complex or mitochondrial changes. Radiation and free radicals can also set the pathways in motion by inducing DNA damage and activating the tumour-suppressor TP53 gene, which codes for the p53 protein. p53 has been termed the ‘guardian of the genome’, arresting the cell cycle under these circumstances to allow time for DNA repair. If there is no repair, p53 induces apoptosis by upregulating the pro-apoptotic signals Bax and Apaf-1.
Hemophagocytic lymphohistiocytosis
Published in Biju Vasudevan, Rajesh Verma, Dermatological Emergencies, 2019
Aradhana Sood, Deep Kumar Raman, Pankaj Das
Elevated soluble IL2 receptor alpha, reduced cell surface expression of CD107-α, elevated sCD163; and reduced perforin, SAP, or XIAP are consistent with a diagnosis of HLH. Peripheral blood T-cell subsets normal helper/suppressor ratio of peripheral T cells, with low B cells and variable immunoglobulin levels are seen [21]. Elevated granzyme B has been found and is a marker of lymphocyte activation.
Engaging natural killer cells for cancer therapy via NKG2D, CD16A and other receptors
Published in mAbs, 2023
Kerry A. Whalen, Kavya Rakhra, Naveen K. Mehta, Alexander Steinle, Jennifer S. Michaelson, Patrick A. Baeuerle
Among immune cells, NK cells are most closely related to cytotoxic T cells. The latter encompasses T cell subsets, including CD8+ and CD4+ T cells, gamma-delta T cells, and natural killer T (NKT) cells, all of which contain cytotoxic granules filled with cysteine proteases, called granzymes, and a pore-forming protein called perforin. NK cells, NKT cells and gamma-delta T cells belong to the innate immune system and serve as a first line of defense against pathogens, while CD8+ and CD4+ T cells are elements of the adaptive immune system, which are highly specific for pathogenic antigens, but first need to be primed, selected, and expanded in response to peptide antigen stimuli.11 Like T cells, NK cells are cytotoxic by virtue of having secretory granules filled with the same granzymes and a variant of perforin.12 Once delivered into a cytolytic synapse formed between NK cell and target cell, perforin forms a pore in the target cell membrane that enables transmembrane delivery of granzymes. Inside the target cell, granzyme B activates pro-caspases 3 and 7, eliciting programmed cell death, or apoptosis, while other granzymes such as granzyme A, H, K and M cleave numerous other protein substrates, causing target cell damage.13 Like T cells, NK cells also release inflammatory cytokines and chemokines upon activation.14
Immunotoxins and nanobody-based immunotoxins: review and update
Published in Journal of Drug Targeting, 2021
Mohammad Reza Khirehgesh, Jafar Sharifi, Fatemeh Safari, Bahman Akbari
For further deimmunising, human endogenous cytotoxic enzymes such as Granzyme B and RNase have been used in IT development. Granzyme B secretes from activated cytotoxic T-cells and natural killer cells. Translocation of Granzyme B into target cells leads to apoptosis induction [121–124]. Another strategy to reducing the immunogenicity of ITs is PEGylation, attaching polyethylene glycol to the target molecules. However, ITs PEGylation leads to reduced binding affinity and increased size [125,126]. Vascular leak syndrome (VLS) is one of the common side effects and dose-limiting toxicity of ITs. VLS is characterised by increased vascular permeability accompanied by extravasation of fluids and proteins, resulting in interstitial edoema and organ failure [127]. The conserved motif exists in RTA, PE and IL2 that induces VLS via binding to the endothelial cells [128]. Removing the motif may prevent VLS induction in IT therapy.
B7-H3 inhibits the IFN-γ-dependent cytotoxicity of Vγ9Vδ2 T cells against colon cancer cells
Published in OncoImmunology, 2020
Huimin Lu, Tongguo Shi, Mingyuan Wang, Xiaomi Li, Yanzheng Gu, Xueguang Zhang, Guangbo Zhang, Weichang Chen
A growing body of evidence indicates that activated γδ T cells exert cytotoxic effects against tumor cells through the granzyme B/perforin pathway.37 We further explored whether the role of B7-H3 in modulating the cytotoxic potential of Vδ2 T cells is perforin/granzyme B pathway-dependent. ELISA showed that the expression levels of perforin and granzyme B were significantly increased in Vδ2 T cells after B7-H3 siRNA treatment (Figure 6A). Treatment with CMA, a V-H+-ATPase inhibitor that blocks perforin release, reversed the B7-H3 knockdown-induced increase in the killing functions of Vδ2 T cells (Figure 6B–D, Supplementary Fig. 6A and B). Furthermore, BCL-2, a granzyme B inhibitor, also abrogated this effect (Figure 6B–D, Supplementary Fig. 6A and B). Meanwhile, 4H7 treatment obviously downregulated the expression of perforin and granzyme B in Vδ2 T cells (Figure 6E). Moreover, the addition of recombinant human granzyme B significantly rescued the impaired antitumor ability of Vδ2 T cells stimulated with 4H7 (figure 6F–H, Supplementary Fig. 6 C and D).