Complement Utilization in Children with Severe Plasmodium falciparum Malaria

Yakoe, Nancy Kemuma (2008) Complement Utilization in Children with Severe Plasmodium falciparum Malaria. Masters thesis, Kenyatta University.

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Abstract

Complement system, an important component of the innate and adaptive immunity, is over activated during malaria infection. As a result, components of the cascade are utilized consumed and this has the potential to impair complement mediated host defense. Activation of complement also leads to production of potent pro-inflammatory mediators such as C3a and C5a, which could potentially account for cytokine deregulation that are seen in children with severe malaria. These events may drive the host immunological responses toward resolution or aggravation of malaria. The aim of this study was therefore to determine the extent of complement utilization in children with malaria. To do this, children presenting at Kisumu District Hospital with either severe malarial anemia or uncomplicated malaria were enrolled in a case control study. Complement utilization was assessed firstly by Complement Hemolytic Activity Assay (CH50) and secondly by Enzyme Linked Immunosorbent Assay for the stable metabolites of complement activation fragments (C3a-desArg, C4a-desArg and C5a-desArg) in plasma and functional activity of the three arms of complement system. In order to rule out the genetic components in complement deficiency, PCR was used to detect the frequency of the complement C4 null genes (C4AQO and C4BQO). The mean levels of complement hemolytic activity in children with severe malarial anemia (15.2 ±17.6 U/mL) were below normal (ranges from 34-70 U/mL) and were half the mean levels in controls (35.0± 23.3 U/mL, P < 0.0001, paired t Test), indicating excessive C3 utilization in the former. The % functional activity was greatly reduced in severe malaria for all the three pathways than the controls (P < 0.01, paired t Test). The levels ofC3a-desArg were 10 times higher than normal (normal ranges = 257-689.6 ng/mL) in both the severe malaria (mean = 3,188±733.9 ng/mL) and controls (3,577±644.6 ng/mL), indicating a high degree of complement activation in both groups. Similar trends were obtained for C4a-desArg in cases (1808±417.3 ng/mL) and controls (1621±512.6 ng/mL) compared to normal ranges (63.4-235.4 ng/mL). Unexpectedly, despite the significant difference in the utilization of complement between severe malarial anemia and controls (as reflected by CH50 levels), the levels of pro-inflammatory mediators (C3a, C4a and C5a) were not higher in severe malaria. This argues against the possibility of the high TNF-a commonly reported in cases of severe malarial anemia being attributable to formation of any of these proinflammatory toxins. C5a-desArg levels were markedly elevated in both groups (cases = 67±34.2 ng/mL, controls =95±50.2 ng/mL), compared to normal (ranges from 1.29-7.8 ng/mL) indicating significant intravascular hemolysis due to assembly of membrane attack complex (MAC). However, because levels of C5a in children with severe malarial anemia were not different from those with uncomplicated malaria, it is concluded that the anemia observed in severe malaria is not due to assembly of membrane attack complex. Five patients were homozygous for C4BQOnull allele (1 case and 4 controls), but C4AQO allele was wild type in both groups indicating that, while few patients may have genetic components, most of the hypocomplementemia is due to increased utilization of C3. Taken together, these results indicate: 1) Uncompensated utilization of C3 in patients with malarial anemia. 2) Complement deficiency observed in cases of severe malarial anemia is not associated with genetic defects. 3) All arms of complement contribute to excessive utilization but the classical and mannose binding lectin (MBL) pathways are more affected.

Item Type:	Thesis (Masters)
Subjects:	Q Science > QR Microbiology R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine R Medicine > RJ Pediatrics > RJ101 Child Health. Child health services
Divisions:	Africana
Depositing User:	Tim Khabala
Date Deposited:	09 Jan 2018 09:11
Last Modified:	09 Jan 2018 09:11
URI:	http://thesisbank.jhia.ac.ke/id/eprint/3061

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