Impaired function of neutrophils in uraemic patients.

BACKGROUND: Immunodeficiency explains the very high frequency of bacterial infections in patients with chronic renal failure (CRF), which leads to high mortality and morbidity, despite improved therapeutic interventions. Among several factors, the decreased functional capacity of phagocytic leucocytes appears to be responsible for the defective host defence mechanisms against infection in CRF. We evaluated both oxygen-dependent and oxygen-independent microbicidal activity of neutrophils isolated from uraemic patients. METHODS: Forty patients with CRF (20 with mild-to-moderate CRF and 20 with advanced CRF) along with 20 age- and sex-matched healthy controls were studied. The assessment of phagocytic capability, ability to produce superoxide (O2.-) anion and H2O2, myeloperoxidase and granule-specific hydrolytic enzymes such as acid phosphatase, cathepsin D and lysozyme activity of the patient's neutrophils were performed to study their bactericidal activity. RESULTS: The phagocytic index (PI) in the control group was found to be 50.38 (4.58). It was significantly reduced in both mild-to-moderate CRF and advanced CRF, as compared to controls. In mild-to-moderate and advanced CRF patients, O2.- production by resting polymorphonuclear neutrophils (PMN) was low. Also, on stimulation with PMA the O2.- production showed a relative reduction as compared to controls. H2O2 production by resting PMN from CRF patients was unaltered but on stimulation with PMA, the quantum of increase was significantly lower. A marked reduction in the level of intracellular myeloperoxidase activity in PMN was noted in CRF patients. Of the three intracellular lysosomal enzymes assayed, cathepsin D level was increased in the PMN of mild-to-moderate CRF patients; acid phosphatase level was elevated significantly in the PMN of both mild-to-moderate and advanced CRF patients. However, no change in lysozyme levels was observed. CONCLUSION: With increasing severity of uraemia, neutrophils from uraemic patients showed progressive impairment of phagocytic ability. Impairment of oxygen-dependent microbicidal mechanisms was indicated by a decrease in O2.- and H2O2 production. Increased activity of lysosomal enzymes such as cathepsin D and acid phosphatase suggest a state of neutrophil activation in uraemia. It is likely that the immunodeficiency state in uraemics is partly due to reduced bactericidal activity of the neutrophil cell population.

Modulation of Fc and C3b receptor activity of mouse peritoneal macrophages elicited by preformed immune complexes.

A study was undertaken to reveal the role of Fc and C3b receptor of mouse peritoneal macrophages (MPM) in the uptake of radiolabelled immune complexes. Large latticed preformed complexes consisting of human serum albumin (HSA)-anti HSA at equivalence (IC-Eq) and with antibody excess (IC-Ab) were observed to be avidly taken up by resident macrophages unlike small size complexes with antigen excess (IC-Ag). Macrophages elicited by thioglycollate (Tg) showed higher IC-binding capacity while IC-elicited MPM showed reduction in the same when compared to the resident cells. However, complement coated complexes were significantly taken up by these IC-elicited macrophages. Uptake studies were further extended to determine the expression of Fc and C3b receptor activity in MPM when elicited with preformed IC. Tg-elicited MPM were observed to bind greater number of IgG-coated erythrocytes (E-IgG) than resident MPM whereas IC-elicited MPM bound E-IgG poorly. When Fc receptors were blocked by in vitro IC treatment, poor binding of complement coated E-IgG [E(IgG)C] was recorded in resident MPM. The present complement medicated rosetting data tends to show enhanced expression of C3b receptors on IC-elicited macrophages.

Biochemical studies on stimulation of mouse peritoneal macrophages by interaction with preformed immune complexes.

Mouse peritoneal macrophages (MPM) were observed to be stimulated by both in vivo and in vitro interactions with preformed HSA-anti HSA immune complexes (IC) having different antigen-antibody ratios. This was indicated by cellular alterations in morphology, increase in cellular protein and lysosomal enzyme contents and a marked fall in 5' nucleotidase level. Analysis of cellular proteins of IC-elicited cells by SDS-polyacrylamide gel electrophoresis showed accumulation of 80, 47, 33, 28, 18 and 14 kDa proteins. Insoluble immune complexes at equivalence (IC-Eq) was found to be more effective in the stimulation process as compared to the soluble antigen excess complexes (IC-Ag). These IC-elicited cells secreted lesser amounts of lysosomal hydrolases when explanted in culture medium as compared to resting cells, whereas in vitro stimulation of resident MPM with IC resulted in enhanced lysosomal hydrolase release. IC-induced lysosomal secretion was time and dose dependent and varied with the nature of the complexes. Complement coated immune complexes (IC-CC) induced maximum enzyme secretion followed by IC-Eq and IC-Ag.

Effects of preformed immune complexes on liver enzymes & their serum clearance in mice.

Two different performed HSA-anti-HSA immune aggregates, insoluble complex at equivalence (IC-E) and soluble complex with 5 times antigen excess (IC-S)-were administered iv in experimental mice to study their interaction with liver cells. Both complexes produced no appreciable change in the levels of liver enzymes like acid phosphatase, cathepsin D and gamma-glutamyl transferase. However, marked reduction in the level of liver pseduocholinesterase (as much as 93%) was recorded in the treated animals under identical conditions of administration of both the complexes. Hepatic uptake studies revealed that within 5 min, maximal sequestration of IC occurred within the liver (10 to 18%) and the blood (70 to 82%) when computed in terms of total injected radioactive IC. After 4 h, radioactivity dropped to 3 per cent in liver and 50-40 per cent in blood. The liver seemed to be incapable of scavenging all the serum complexes at a time. Significant consumption of serum complement occurred, when freshly prepared complexes were administered to the animals, but the reduced complement level showed a tendency to reach normalcy after 2 h. The soluble and equivalence zone IC failed to exhibit identifiable discrimination facets with respect to handling by liver. The complexes IC-E and IC-S also behaved in a similar manner.

Influence of maternal, foetal and socio-economic factors on neonatal morbidity: a study on hospital born babies.

Present study revealed several significant associations. Firstly, two related variables, like duration of antenatal care and birth-weight of newborn were significantly associated with incidence of neonatal morbidity. Apart from these, attributes like mother's educational status and per capita family income were also found as important factors determining occurrence of illness during neonatal period. Moreover, children of working mothers suffered more from illness. However, it should be pointed out here that majority of the attributes discussed here, such as, occupation, literacy, income etc, are inter-dependant. So, to quantify correctly the relative risk and attributable risk of these factors in causing childhood disease needs cohort study with matched control to neutralise the effects of confounding variables.