Granzyme B and natural killer (NK) cell death

Abstract

Granzyme B is a unique serine protease, which plays a crucial role for target cell death. Several mechanisms of delivery of granzyme B to target cells have been recently identified. Granzyme B directly activates Bid, a specific substrate for granzyme B, resulting in caspase activation. Granzyme B efficiently cleaves many prominent autoantigens, and the hypothesis that autoantibodies arise when cryptic determinants are revealed to the immune system has been proposed. Some autoantibodies directed against granzyme B-specific neoepitopes are present in serum from patients with autoimmune diseases. In the tissues from autoimmune diseases, granzyme B might play an important role for disease progression (i.e., rheumatoid arthritis synovium) or inhibition (i.e., regulatory T cells). We have identified a novel type of activation-induced cell death (granzyme B leakage-induced cell death). Activation-induced natural killer (NK) cell death is accompanied by the leakage of granzyme B from intracellular granules into the cytoplasm, and it triggers apoptosis by directing Bid to mitochondrial membranes. An excess of "leaked" granzyme B over its inhibitor, serpin proteinase inhibitor 9, is a major determinant of cell death. The role of granzyme B in autoimmunity and its influence on NK cell death are discussed.

The root of many evils: indolent large granular lymphocyte leukaemia and associated disorders

“…Granule-mediated pathway can act on the activated LGL through endocellular or extracellular granule leakage, which triggers similar signaling pathways as in the target cells. [22, 23] Receptor-mediated pathway follows the same strategy. After activation, LGL express elevated death receptors, making themselves sensitive to the death ligands.…”

“…[16, 25] To ensure sufficient LGL activity prior to AICD, a delicate resistance system exists. [16, 22, 26] It enables the titration of AICD process and allows the elimination of LGL to occur only after antigen clearance.…”

A significantly impaired natural killer cell activity due to a low activity on a per-cell basis in rheumatoid arthritis

“…The killing activity of NK cells is regulated by signals from activating and inhibitory receptors [3,4]. Target cells expressing reduced levels of class I MHC molecules on transformed and virus-infected autologous cells deliver reduced levels of inhibitory signals to NK cells, thus resulting in the release of cytotoxic granules containing effector molecules (i.e., perforin, granzymes) which thus induce target cell death [5,6]. In addition, NK cells can participate in immune regulation by eliminating autoreactive T cells and B cells [7][8][9][10].…”

Rhaphidophora korthalsii modulates peripheral blood natural killer cell proliferation, cytokine secretion and cytotoxicity

“…This result carried the message that spontaneous leakage of granzyme B did not take place in all of the untreated and treated NK cells. Leakage of Granzyme B into cytosol and extracellular environment was found to induce NK cell self-apoptosis, which is termed “Granzyme B leakage-induced cell death” (GLCD) [29]. Thus, GLCD did not occur in all of the untreated or treated NK cells in this experiment as no significant leakage of Granzyme B was detected.…”