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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.
Oncology
Published in Rachel U Sidwell, Mike A Thomson, Concise Paediatrics, 2020
Rachel U Sidwell, Mike A Thomson
This may be: Primary (familial or sporadic). Mutations in the perforin gene found (10q21–22) in some cases (with absent perforin granules in cytotoxic lymphocytes), orSecondary (to infections, immunosuppression, metabolic disorders, fat infusions or malignancy)
Overview of Immune Tolerance Strategies
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Charles J. Hackett, Helen Quill
The gene that encodes perforin, a molecule that functions in the lytic mechanism of cytotoxic T-cells and natural killer cells, has recently been implicated in a homeostatic function. A disease called familial hemophagocytic lymphohistiocytosis (FHL) is associated with a genetic defect in the perforin molecule.23 High levels of activated T cells in the blood and tissues of FHL patients lead to the overproduction of inflammation-producing factors, resulting in severe organ damage, especially of the liver, spleen, and central nervous system. Only bone marrow transplantation can successfully treat the approximately 80 children born in the United States each year with this immune disorder. Mutations in at least three different genes each can give rise to FHL. Patients with one type of FHL were lacking or had an inactive perforin molecule. As expected, the perforin-deficient FHL patients are defective in cytotoxic cell function, and presumably lack an important molecule needed to regulate cellular immune responses.
A T-cell engaging bispecific antibody with a tumor-selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancer
Published in OncoImmunology, 2022
Brian C. Avanzino, Kirthana Prabhakar, Pranjali Dalvi, Sharon Hartstein, Hannes Kehm, Aarti Balasubramani, Andrew A. Boudreau, Ben Buelow, Karen Chang, Laura M. Davison, Suhasini Iyer, Vidyut Kalwit, Kristin Lewis Wilson, Harbani K. Malik-Chaudhry, Will Pierson, Geovanni Pineda, Udaya S. Rangaswamy, Sowmya Saiganesh, Ute Schellenberger, Harshad S. Ugamraj, Rodolfovan D. Yabut, Roland Buelow, Jocelyn Chapman, Nathan D. Trinklein, Katherine E. Harris
Fresh, de-identified, surgically removed ovarian tumor tissue (obtained under an MTA from Dr Chapman) was cut into small pieces, washed with PBS, and digested with 2.5 U/mL dispase II (STEMCELL Technologies) for 30 minutes at 37°C with manual agitation every 5 minutes. Dissociated cells were centrifuged and resuspended in DMEM with 10% FBS and 1% P/S at 0.4 × 106 cells/mL. Cells were incubated with the indicated antibodies for 48–72 hours. Cytotoxicity was measured using CytoTox 96 LDH substrate (Promega). Cytokines were measured as described above. Perforin and granzyme B were measured by ELISA (Cell Sciences and Thermo Fisher Scientific, respectively). T-cells were quantified, and the effector to target cell ratio in these samples was determined by measuring the subsets of live T-cells, positive for CD4 and CD8, vs. the target cells staining positive for FRα (CD4−/CD8−).
Intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): mechanisms of action and clinical and genetic considerations
Published in Expert Review of Neurotherapeutics, 2022
Marinos C. Dalakas, Norman Latov, Krista Kuitwaard
Perforin is a pore-forming protein found in cytotoxic T-lymphocytes and natural killer cells [64]. Perforin is responsible for creating pores in the cell membrane of target cells, triggering apoptosis [65]. Mutations leading to impairment of perforin function have been associated with autoimmune diseases [65]. SNPs in PRF1 were studied in 94 CIDP patients and 158 controls and were found to be more common in the CIDP patients (21.3%) than in controls (5.7%, OR 4.47, p < 0.0002) [66]. A relapsing disease course (70% vs. 37%) and axonal damage (85% vs 51%) were more frequently found in CIDP patients with PRF1 SNPs [66]. The most frequent variation found was the p.Ala91Val (OR 3.92) [66]. The p.Ala91Val variant was also found to be negatively associated with responsiveness to IVIg in a Dutch cohort of 157 CIDP patients [56].
Perforin affects regeneration in a mouse spinal cord injury model
Published in International Journal of Neuroscience, 2021
Igor Jakovcevski, Melitta Schachner
Perforin is a component of the immune system primarily expressed in natural killer (NK) cells and cytotoxic T-lymphocytes (CD8+) and is stored in cytoplasmic granules of these cells. It is pore-forming glycoprotein with sequence homology to the membrane attack component of complement C9 [17] and a major mediator for the cytotoxic properties of these cells [18–20]. Perforin participates in the induction of the rapid, apoptosis-like cell death of cells recognized as aberrant or foreign [21–23] and, secreted by NK-cells, CD8+ T-cells and CD4+ T-cells, it damages neurites in vitro [24] and contributes to neuronal degeneration in mouse models of multiple sclerosis [25–27], Parkinson’s disease [28] and stroke [29]. Additionally, perforin causes blood-brain barrier disruption, which could contribute to immune cell infiltration and increased inflammatory damage in several central nervous system disorders [30–33].