11/10/2023 0 Comments Scaffold protein perforinGranzymes are a family of conserved serine proteases stored within the cytotoxic granules of cytotoxic lymphocytes (CLs) whose functions were once believed to be primarily involved in immune-targeted cell death. This review examines, for the first time, the multiple roles of GrB in disease pathogenesis. The implications of sustained elevations of intracellular and extracellular GrB in chronic vascular, dermatological, and neurological diseases, among others, are developing. Given that GrB retains its activity in the blood, can cleave extracellular matrix, and its levels are often elevated in chronic inflammatory diseases, this protease may be an important contributor to certain pathologies. To the latter, an emerging immune-independent role for GrB has been forwarded due to recent discoveries that GrB may be expressed in nonimmune cells such as smooth muscle cells, keratinocytes, and chondrocytes in certain disease states. Long known to be a pro-apoptotic protease expressed by cytotoxic lymphocytes and natural killer cells, it is now accepted that GrB can be expressed in other cell types of immune and nonimmune origin. This review focuses on GrB, the most characterized of the granzyme family, in disease. However, in recent years, emerging clinical and biochemical evidence has shown that the latter approach may have overlooked a critical perforin-independent, pathogenic role for these proteases in disease. As there are 5 granzymes in humans and 11 granzymes in mice, many studies used perforin knockout mice as an initial screen to evaluate the role of granzymes in disease. Although originally proposed to have intracellular and extracellular functions, upon the discovery that perforin, in combination with GrB, could induce apoptosis, other potential functions for this protease were, for the most part, disregarded. HLH Hashimoto's disease SLE autoimmune diseases cytolytic granules granzyme type 1 diabetes.The cytotoxic granzyme B (GrB)/perforin pathway has been traditionally viewed as a primary mechanism that is used by cytotoxic lymphocytes to eliminate allogeneic, virally infected and/or transformed cells. Better understanding of the role of these molecules in health and disease will open a new field of research with possible therapeutic implications. Also, in this review we discuss the problem of abnormal perforin production in diseases such as: hemophagocytic lymphohistiocytosis (HLH), leukemias and lymphomas, infectious diseases and autoimmune diseases. This review will focus on mechanisms of action and structure of perforin. In consequence, the channels disrupt protective barrier of cell membrane and destroy integrity of the target cell. Polymerized perforin molecules form channels enabling free, non-selective, passive transport of ions, water, small-molecule substances and enzymes. However, CD4-positive T-cells are also able to express a low amount of perforin, when classic cytotoxicity is ineffective or disturbed. Natural killer (NK) cells and CD8-positive T-cells are the main source of perforin. In addition, perforin is involved in the pathogenesis of autoimmune diseases and allogeneic transplant rejection. Many research groups focus on the role of perforin in various diseases, immune response to bacterial and viral infections, immune surveillance and immunopathology. Perforin is able to polymerize and form a channel in target cell membrane. Perforin is a glycoprotein responsible for pore formation in cell membranes of target cells.
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