Overview of Immune Tolerance Strategies
Richard K. Burt, Alberto M. Marmont in Stem Cell Therapy for Autoimmune Disease, 2019
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.
Tumor Suppression
John Melford in Pocket Guide to Cancer, 2017
As is the case for neutrophils, natural killer cells circulate in the blood ready to be summoned to infection sites in response to cytokine signals. They are different from macrophages and neutrophils in that they are not phagocytes, and they can kill abnormal cells, or normal cells infected with pathogens. Natural killer cells are armed with small granules in their cytoplasm that contain toxic chemicals and proteins, one of which is perforin. Upon release close to a target cell, perforin forms pores in its outer membrane through which other proteins enter. These proteins initiate apoptosis. Importantly, cell death by this means also kills resident viruses, thus preventing their release into the extracellular space. Apoptosis provides a relatively clean form of cell death that does not cause inflammation. In contrast, necrosis caused by trauma promotes inflammation. Natural killer cells also have an immunoregulatory role as they secrete several cytokines. Another important task carried out by natural killer cells is immunosurveillance.
Sertoli cell immune regulation within the testis
C. Yan Cheng in Spermatogenesis, 2018
In response to nonself antigens, B cells produce antibodies (IgM and IgG) that bind to these antigens and coat the target cells. This results in killing of the target cell through the following pathways (Figure 6.4a). Antibodies activate the complement cascade leading to formation of the membrane attach complex (MAC) on the cell membrane of the target cells, which leads to complement mediated cell lysis. Additionally, complement cascade activation causes the release of anaphylatoxins, specifically C4a, C3a, and C5a, which mediate acute inflammation by attracting immune cells. Lastly, natural killer (NK) cells can initiate antibody-dependent cellular cytotoxicity by binding to the IgG1 or IgG3 coated cells through their low affinity Fcy receptor. After binding, NK cells kill the target cells through several different mechanisms: (1) exocytosis of cytoplasmic granules containing perforin and granzymes, (2) releasing proinflammatory cytokines, or (3) TNF family death receptor signaling. Both the uptake of perforin and granzymes and TNF family death receptor signaling causes apoptosis of target cells.
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].
A novel homozygous disruptive PRF1 variant (K285Sfs*4) causes very early-onset of familial hemophagocytic lymphohystiocytosis type 2
Published in Pediatric Hematology and Oncology, 2020
F. Saettini, I. Castelli, M. Provenzi, G. Fazio, M. Quadri, G. Cazzaniga, S. Sala, F. Dell’Acqua, E. Sieni, M. L. Coniglio, L. Pezzoli, M. Iascone, F. Vendemini, A. C. Balduzzi, A. Biondi, C. Rizzari, S. Bonanomi
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory multisystemic disease. Familial hemophagocytic lymphohistiocytosis (FHL) represents a group of rare autosomal recessive disorders causing an impaired cytotoxicity of T-lymphocytes (CTL) and of natural killer cells (NK) due to an altered secretion of lytic granules. Five FHL (FHL 1-5) subtypes have been identified.1 Depending on ethnic origin,2 variants in the PRF1 gene (FHL2) account for almost half of the FHL cases. PRF1 gene encodes for the human perforin, an effector molecule of lymphocyte cytotoxicity involved in innate and adaptive immunity. Perforin is a pore-forming protein located in the granules of NK and CTL that allows the rapid killing of virus infected and tumor-derived cells, allowing the passage of granzymes to the target cell and therefore inducing apoptosis.3,4 We here report a case of FHL2 caused by the novel homozygous variant (p.K285Sfs*4) with very early-onset and fatal outcome.