ReviewOff to a slow start: Under-development of the complement system in term newborns is more substantial following premature birth
Section snippets
Complement pathways and introduction
Complement is a central element of the innate immune system. It recognises microbial patterns (carbohydrate configurations uncommon to normal human physiology) to activate complement; it enhances the effectiveness of specific immunoglobulins in circulation (which includes maternally transferred IgG in newborns); it recruits leukocytes and lymphocytes to areas of inflammation and microbial invasion; it primes antigen presenting cells to aid in their maturation and influences the adaptive immune
Methods of measuring the complement system
Before we review the relative levels of complement components and function between adults, term neonates and preterm neonates, it is important to discuss the range of methods that have been used; including the benefits and shortfalls of each method.
Functional complement haemolysis assays
Measurement of the total functional capacity of complement is routinely assessed by the CH50 assay, which measures the lysis of rabbit-polyclonal antibody sensitised sheep erythrocytes. While it supposedly measures the classical and terminal pathway function, the assay is run under conditions where all pathways have the capacity to function. The AP50 assay in comparison is run under conditions that disable the classical and lectin pathways, and truly does measure the functional capacity of the
Concentrations of classical pathway components
Measurement of the classical complement pathway components was largely determined by RID (Table 2). Concentrations of C1 were often measured as individual C1q, C1r and C1s components and unexpectedly the ratio of subunits to adult values were not always equivalent. However, the choice of the adult serum used for comparison raises an important cautionary note at this point. In some investigations, the neonatal levels were compared to the maternal levels at birth, but two studies that compared
Concentrations of alternative pathway components
Similar to the studies above, measurement of the alternative complement pathway also largely relied on the RID method (Table 3). The alternative pathway shows similar correlation to the classical pathway, with complement activity and specific components being significantly lower in infants when compared to adult controls. Very few studies have been carried out on factor D; however, it appears to be one of the few components that is higher in normal term neonates than adults (Johnson et al., 1983
Concentrations of lectin pathway components
In contrast to the classical and alternative activation pathways, components of the lectin and ficolin pathways of complement activation are relatively recent discoveries. There is a large degree of overlap with the components of the classical pathway (C2, C4, and C3) that have already been detailed, and there is no universally accepted functional test similar to the CH50 or AP50 assays.
MBL is a collagenous C-type lectin which initiates complement activation upon interaction with appropriately
Concentration of C3
Many of the studies above have also examined C3 levels, but as this component is common to all the pathways we will summarise the findings listed in Table 2, Table 3. Some investigators found the levels of C3 in healthy term neonates almost equivalent to adult levels (e.g. Shapiro et al. (1981) at 97% and Johnson et al. (1983) at 87%), while other investigators found the term C3 levels to be 50–60% of adult levels (Arinola et al., 2003, Strunk et al., 1979, Yonemasu et al., 1978). Term neonatal
Concentrations of terminal pathway components
Measurement of terminal complement components in healthy term neonates has been performed by 3 (C8) to 6 (C5 and C9) different groups (excluding those that have compared neonatal to maternal levels) as shown in Table 4. Compared to adult levels the average term neonatal levels of C5 were 73%, C6 were 51%, C7 were 97%, C8 were 37.3%, and C9 were 29.4%. Although there are only 3 reports for C8 levels, the reported values were very close between 36 and 38% for term neonates. Term neonatal C6
Concentrations of serum complement regulators
Equally important to the activation of complement, the ability to modulate and control the activation to limit damage to the site of inflammation and infection is also important. There are a series of complement regulators that are present in the serum that have also been studied in neonates (Table 5). Factor I (fI) has the ability to cleave C4b and C3b blocking their ability to reform complement convertases, but the cleavage is greatly facilitated by the binding of soluble regulation
Inter-relation between complement, the innate and adaptive immune responses
Direct lysis of activating targets is not the only role complement plays in the immune system. Complement activation also releases small molecules that attract and influence immune cells as well as attaching ligands to pathogens to facilitate engulfment by phagocytes (Fig. 2). In the adult complement system, binding of IgM, IgG1 or IgG3 immunoglobulin isotypes to an antigen leads to activation of the classical pathway. This activation leads to covalent “tagging” of the activating surface with
Response of neonatal complement to bacteria
Since the activation of complement results in cleavage and/or structural alteration of the components, assays that recognise activation specific complexes or epitopes that are only present following activation have been developed. Irrespective of very low native complement protein levels, term and preterm babies can generate remarkable amounts of activation products of the complement cascade, as demonstrated during infection (Hogasen et al., 2000, Zilow et al., 1993, Zilow et al., 1997).
Hogasen
Protective effect of low complement levels in neonatal pathology
While it would be easy to suggest that correcting complement levels to adult concentrations to increase newborn bactericidal activity would be beneficial, particularly for C9, complement's contribution to pathophysiology to ischemia-reperfusion injury and respiratory pathology are also well known. For newborn infants and particularly premature neonates, the importance of low C9 levels for protection against CNS pathology and decreased risk of intracerebral haemorrhage following hypoxic-ischemia
Conclusions
The direct role for under-development of the complement system in term newborns, and more so in premature newborns, to enhanced susceptibility to bacterial infection is obvious. Simple supplementation of C9 has been shown to correct the bactericidal activity and functional haemolytic capacity in term neonatal serum. However, low concentrations of effector components may be required when some of the circulating complement regulator concentrations, particularly C4BP, are so low. Further low
References (73)
- et al.
Activity of the alternative pathway of complement in the newborn infant
J. Pediatr.
(1978) - et al.
New perspectives on mannan-binding lectin-mediated complement activation
Immunobiology
(2007) - et al.
The role of ficolins in the lectin pathway of innate immunity
Int. J. Biochem. Cell Biol.
(2011) - et al.
Complement component C9 enhances the capacity of beta-lactam antibiotics to kill Escherichia coli in vitro and in vivo
Am. J. Med. Sci.
(1998) - et al.
P35, an opsonic lectin of the ficolin family, in human blood from neonates, normal adults, and recurrent miscarriage patients
Immunol. Lett.
(1999) The role of complement in neonatal hypoxic-ischemic cerebral injury
Clin. Perinatol.
(2004)Regulation of B lymphocyte activation by complement C3 and the B cell coreceptor complex
Curr. Opin. Immunol.
(2005)- et al.
Complement component 9 activation, consumption, and neuronal deposition in the post-hypoxic-ischemic central nervous system of human newborn infants
Neurosci. Lett.
(2005) - et al.
Serum complement and immunoglobulin values in small-for-gestational-age infants
J. Pediatr.
(1981) - et al.
Association of low levels of mannan-binding protein with a common defect of opsonisation
Lancet
(1989)
Ficolins and FIBCD1: soluble and membrane bound pattern recognition molecules with acetyl group selectivity
Mol. Immunol.
The role of mannose-binding lectin in health and disease
Mol. Immunol.
Transplacental transport of IgG antibodies to preterm infants: a review of the literature
Early Hum. Dev.
Human complement C7 and C9 in fetal and newborn sera
Arch. Dis. Child.
Synthesis of two components of human complement, beta 1H and C3bINA, during fetal life
Acta Paediatr. Scand.
Complement levels and leukocyte phagocytosis in newborn babies
Afr. J. Med. Med. Sci.
The role of complement in B cell activation and tolerance
Adv. Immunol.
Evaluation of complement activation in premature newborn infants with hyaline membrane disease
Eur. J. Pediatr.
Serum complement levels in infancy: age related changes
Pediatr. Res.
Low serum levels of mannose binding lectin are a risk factor for neonatal sepsis
Pediatr. Res.
Ontogeny of complement regulatory proteins - concentrations of factor H, factor I, C4b-binding protein, properdin and vitronectin in healthy children of different ages and in adults
Scand. J. Immunol.
The complement system of the newborn infant
Biol. Neonate
The role of mannose-binding lectin in susceptibility to infection in preterm neonates
Pediatr. Res.
The alternative pathway of complement activation in the neonate
Pediatr. Res.
Serum haemolytic classical and alternative pathways of complement in infancy: age-related changes
Acta Paediatr. Scand.
Development of human complement system
J. Immunol.
High prevalence of mannose-binding lectin (MBL) deficiency in premature neonates
Clin. Exp. Immunol.
Low mannose-binding lectin (MBL) levels in neonates with pneumonia and sepsis
Clin. Exp. Immunol.
Collectin 11 (CL-11
CL-K1) is a MASP-1/3-associated plasma collectin with microbial-binding activity. J Immunol
Host defence lectins in preterm neonates
Acta Paediatr.
The analysis of the complement activation product SC5 b-9 is applicable in neonates in spite of their profound C9 deficiency
J. Perinat. Med.
Complement components in 100 newborns and their mothers determined by electroimmunoassay
Acta Pathol. Microbiol. Immunol. Scand. C
Complement in the newborn infant
Pediatrics
Complement factor 9 deficiency in serum of human neonates
J. Infect. Dis.
Supplemental complement component C9 enhances the capacity of neonatal serum to kill multiple isolates of pathogenic Escherichia coli
Pediatr. Res.
Mannose-binding protein in preterm infants: developmental profile and clinical significance
Clin. Exp. Immunol.
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