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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.
The Role of Nanoparticles in Cancer Therapy through Apoptosis Induction
Published in Hala Gali-Muhtasib, Racha Chouaib, Nanoparticle Drug Delivery Systems for Cancer Treatment, 2020
Marveh Rahmati, Saeid Amanpour, Hadiseh Mohammadpour
When cells are infected by viruses, the perforin/granzyme apoptosis pathway is initiated by cytotoxic lymphocytes to remove the infected cells. Perforin, also known as cytoplasmic granule toxin, is a kind of protein with a pore-forming ability in mitochondrial membrane. Granzyme is a serine protease protein, which contains cytotoxic granules of cytotoxic lymphocytes (CLs). Although, Granzyme is required for triggering apoptosis, it should be delivered appropriately by perforin. In humans, there are numerous granzymes including A, B, H, K, and M, but the Granzymes A and B are the most abundant enzymes that are involved in apoptosis. This pathway is initiated when granzymes could enter into target cells. This internalization is facilitated by perforin. Granzyme B activates pro-apoptotic BH3-interacting domain death agonist Bid, leading to the activation of CASP-3. Activated CASP-3 is subsequently able to proceed with executive apoptosis. Granzyme B can also inactivate MCL-1, which is a member of the anti-apoptotic BCL-2 family [36]. The granzyme A pathway is also involved in apoptosis via activating a parallel, caspase-independent cell death pathway through single-stranded DNA damage [37].
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.
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.
Granzyme B as a therapeutic target for wound healing
Published in Expert Opinion on Therapeutic Targets, 2019
Christopher T. Turner, Sho Hiroyasu, David J. Granville
Although granzyme B was traditionally understood as being limited to this intracellular role in mediating apoptosis, a number of discoveries later challenged that notion. This involved a new appreciation that granzyme B is secreted extracellularly, often in the absence of perforin, and functions to cleave multiple substrates including extracellular matrix (ECM) proteins, cytokines, cell surface/cell junction proteins and proteoglycans. Furthermore, it was recognized that granzyme B can be expressed by other types of immune- and non-immune cells, many of which do not express perforin to facilitate internalization and/or do not form immune synapses required to direct granzymes toward the target cells in high concentrations (reviewed in Turner et al.) [12]. This led to the identification of new extracellular roles for granzyme B, and since extracellular concentrations are elevated in various diseases, it is now appreciated that granzyme B may exert important roles in chronic inflammatory, autoimmune and degenerative diseases.