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Are granulocyte inhibitory proteins contributing to enhanced susceptibility to infections in uraemia?
1Department of Medicine, University of Vienna, Austria.
Abstract:
Infectious complications are still a major cause of morbidity and mortality in patients undergoing regular dialysis treatment. This increased morbidity and mortality of patients with uraemia has been attributed to the dysfunction of polymorphonuclear leukocytes (PMNLs). Uraemia contributes to impaired PMNL function by means of disarrangements in cellular biochemistry and biology. Reduced chemotaxis, adherence, oxidative activity, and glucose consumption in response to phagocytic challenge have been reported. Several compounds present in uraemic serum have been isolated and characterized to inhibit the biological activity of PMNLs. A first granulocyte inhibitory protein (GIP I) responsible for the PMNL dysfunction in uraemia has been isolated and characterized. The polypeptide, with a molecular weight of 28 000 Da, inhibits the uptake of deoxyglucose, chemotaxis, oxidative metabolism, and intracellular bacterial killing by PMNLs. A second granulocyte inhibitory protein (GIP II), with a molecular weight of 9500 Da, has been isolated from plasma ultrafiltrates obtained from haemodialysis patients. It interferes with similar functions of PMNLs. GIP I displays homology with light chain protein and GIP II with beta 2-microglobulin, respectively. Both proteins were also isolated from peritoneal dialysis effluents. Isolated kappa and lambda light chain monomers and dimers from haemodialysis and peritoneal dialysis patients also inhibit several PMNL functions. Recently, a PMNL degranulation inhibiting protein (DIP) was purified from plasma ultrafiltrates obtained from patients undergoing regular haemodialysis therapy. DIP shows homology with angiogenin and inhibits spontaneous as well as stimulated PMNL degranulation. These proteins may explain at least in part the enhanced susceptibility to infections in haemodialysis and peritoneal dialysis patients.
Insights
Uremic serum contains inhibitory proteins that impair polymorphonuclear leukocyte (PMNL) function, increasing infection risk in dialysis patients. These proteins, including GIP I, GIP II, and DIP, disrupt crucial immune responses.
Area of Science:
- Nephrology
- Immunology
- Biochemistry
Background:
- Infectious complications are a significant cause of morbidity and mortality in patients undergoing dialysis.
- Uremia is associated with impaired polymorphonuclear leukocyte (PMNL) function, contributing to increased infection susceptibility.
- Previous studies reported reduced PMNL chemotaxis, adherence, and oxidative activity in uremic patients.
Purpose of the Study:
- To identify and characterize proteins in uremic serum that inhibit PMNL biological activity.
- To elucidate the role of these inhibitory proteins in the enhanced susceptibility to infections in dialysis patients.
Main Methods:
- Isolation and characterization of granulocyte inhibitory proteins (GIP I and GIP II) from plasma ultrafiltrates of hemodialysis patients.
- Analysis of protein homology with known molecules like light chain protein, beta 2-microglobulin, and angiogenin.
- Investigation of PMNL degranulation inhibiting protein (DIP) in hemodialysis patient plasma ultrafiltrates.
Main Results:
- GIP I (28 kDa) and GIP II (9.5 kDa) were isolated and shown to inhibit PMNL deoxyglucose uptake, chemotaxis, oxidative metabolism, and bacterial killing.
- Both GIP I and GIP II were also found in peritoneal dialysis effluents.
- Kappa and lambda light chain monomers and dimers also inhibited PMNL functions.
- DIP was purified and inhibits PMNL degranulation, showing homology with angiogenin.
Conclusions:
- Specific inhibitory proteins, including GIP I, GIP II, and DIP, present in uremic serum and dialysis effluents contribute to PMNL dysfunction.
- These proteins likely explain, at least in part, the increased risk of infections observed in patients undergoing hemodialysis and peritoneal dialysis.