Elsevier

Immunobiology

Volume 217, Issue 2, February 2012, Pages 176-186
Immunobiology

Review
Off to a slow start: Under-development of the complement system in term newborns is more substantial following premature birth

https://doi.org/10.1016/j.imbio.2011.07.027Get rights and content

Abstract

Complement represents a keystone to the innate immune system, with three activation pathways that utilise foreign microbial pattern recognition as well as activation by the host's specific antibodies. However, innate immunity is not synonymous with neonatal immunity. The complement system in healthy term (38–42 weeks gestation) newborns is under-developed and, with only a few exceptions (e.g. C7 and factor D), the circulating complement component concentrations are between 10 and 80% of adult levels. Complement activation is tightly regulated and the circulating regulator levels are also low relative to adults, sometimes at almost undetectable levels (e.g. C4b-binding protein). For premature newborns, these relative deficiencies are even more marked. Newborns are known to be more susceptible to infection, and the importance of complement, not only through its decreased ability to directly lyse bacteria with the common terminal pathway, but also its reduced ability to recruit (chemotaxis) innate and adaptive leukocytes to sites of microbial invasion and reduced ability to enhance phagocytosis (opsonisation) will be discussed. Complement also holds a key role in enhancing and directing refinement of the specific antibody response to pathogens (as an adjuvant) that likely plays a role in the well-known under-performance of the humoral immune response in newborns.

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

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