Background, biology and significance of human granzymes

The human granzymes (Grz) are a highly conserved group of potent peptidases that are found, together with a pore forming protein-perforin in specialized granules of cytotoxic cells such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Granule exocytosis (perforin/Grz) pathway is used by these cells to defend organism against virus-infected and tumor cells by inducing them to undergo apoptosis. While the pro-apoptotic functions of Grz have been well established, it has recently become apparent that Grz also possess important extracelular activities which are now being extensively investigated. Soluble Grz are found extracellularly in normal plasma suggesting their constitutive secretion in healthy individuals via a granule independent biosynthetic pathway. The potent activities of extracellular Grz appear to be controlled by highly abundant plasma derived serine peptidase inhibitors. However, unregulated activities of proteolytic Grz have been shown to result in disease pathology especially, in the absence of their corresponding inhibitors. To date, most of the studies have concentrated on the structure and function of granzyme A (GrA) and GrB while very little work has been done on the remaining Grz which include GrM, GrH and GrK in humans. In this report, we discuss the current knowledge of Grz biochemistry, biology, functions, activity regulation and their role in human pathology with special emphasis on the significance of human GrK in this field

BIOCHEMICAL AND BIOLOGICAL CHARACTERIZATION OF GRANZYME K AND ITS BIOLOGICAL ROLE IN SYSTEMIC INFLAMMATION / SEPSIS

U ovom je radu razvijen kompetitivni Granzim K (GrK) specifični imunotest s ciljem da se istraži uloga te proteaze u sistemskoj upali/sepsi. Utvrđeno je značajno povećanje koncentracije GrK u plazmi pacijenata hitnog odjela s pretpostavljenom dijagnozom sepse, dok je u plazmi pacijenata uključenih u klinički pokus s dijagnosticiranom sepsom utvrđeno značajno smanjenje koncentracije GrK, u usporedbi s kontrolnom skupinom. Slobodni GrK s molekulskom težinom od ~26 kDa uočen je samo u plazmi pacijenata sa sepsom. Rezultati upućuju da bi GrK mogao biti dio patofiziologije sepse te na potencijalnu mogućnost njegova korištenja kao dijagnostičkog biomarkera za stupnjevanje sepse. U radu je započeta i karakterizacija GrK kako bi se razjasnila biološke uloga te moćne proteaze u sistemskoj upali/sepsi.The aim of this study was to investigate the potential role of Granzyme K (GrK) in systemic inflammation/sepsis and therefore a novel GrK-specific immunoassay was developed. The plasma levels of GrK were found increased in patients admitted to the emergency department with a putative diagnosis of sepsis while decreased in patients with severe sepsis enrolled in a clinical trial, compared to healthy subjects. The free GrK as a 26 kDa protein appeared only in patients with sepsis. The results indicate that plasma GrK levels could serve as a useful diagnostic marker to stage sepsis and may play a functional role in the development of sepsis. Characterization of human GrK was also initiated in order to elucidate biological function(s) of this potent serine protease in inflammatory responses/sepsis

BIOCHEMICAL AND BIOLOGICAL CHARACTERIZATION OF GRANZYME K AND ITS BIOLOGICAL ROLE IN SYSTEMIC INFLAMMATION / SEPSIS

U ovom je radu razvijen kompetitivni Granzim K (GrK) specifični imunotest s ciljem da se istraži uloga te proteaze u sistemskoj upali/sepsi. Utvrđeno je značajno povećanje koncentracije GrK u plazmi pacijenata hitnog odjela s pretpostavljenom dijagnozom sepse, dok je u plazmi pacijenata uključenih u klinički pokus s dijagnosticiranom sepsom utvrđeno značajno smanjenje koncentracije GrK, u usporedbi s kontrolnom skupinom. Slobodni GrK s molekulskom težinom od ~26 kDa uočen je samo u plazmi pacijenata sa sepsom. Rezultati upućuju da bi GrK mogao biti dio patofiziologije sepse te na potencijalnu mogućnost njegova korištenja kao dijagnostičkog biomarkera za stupnjevanje sepse. U radu je započeta i karakterizacija GrK kako bi se razjasnila biološke uloga te moćne proteaze u sistemskoj upali/sepsi.The aim of this study was to investigate the potential role of Granzyme K (GrK) in systemic inflammation/sepsis and therefore a novel GrK-specific immunoassay was developed. The plasma levels of GrK were found increased in patients admitted to the emergency department with a putative diagnosis of sepsis while decreased in patients with severe sepsis enrolled in a clinical trial, compared to healthy subjects. The free GrK as a 26 kDa protein appeared only in patients with sepsis. The results indicate that plasma GrK levels could serve as a useful diagnostic marker to stage sepsis and may play a functional role in the development of sepsis. Characterization of human GrK was also initiated in order to elucidate biological function(s) of this potent serine protease in inflammatory responses/sepsis