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The following are additional sections that are part of the article:
Passively acquired antibodies
Normal mechanism of B cell activation
What this means for vaccines
Lymphocyte subsets
Innate and T-cell immune responses
References
Passively acquired antibodies:
The newborn infant exhibits a physiological immunodeficiency manifested by a marked deficit in
endogenous antibodies. This is partly compensated for by maternal IgG which crosses the placenta and
provides protection for the neonate. Breast milk also contains various immunological mediators such
as IgA, lysozyme and lactoferrin which protect the infants immature gut. As opposed to antibodies,
maternal lymphocytes do not usually cross the placenta (reviewed by Cant et al., 2003)
Placental transfer of immunoglobulin is a late event in gestation and therefore preterm infants show
reduced antibody levels. After birth, levels of maternal antibodies fall due to catabolism while endogenous
antibody production in the infant rises. The point at which the neonate has the lowest total antibody
levels (decreased maternal antibody levels with no great rise yet in endogenously produced antibody)
occurs at 3-6 months of age. Adult levels of IgM are reached by 4-5 years and IgG by 7-8 years. Levels
of IgA rise only very slowly and only reach adult levels in the teenage years (reviewed by Cant et al.,
2003)
In general, the infant can mount a good IgG response to protein vaccines, such as tetanus toxoid, by
2 months of age. Maternally derived antibody can in some circumstances prevent optimal response to
certain vaccines – this seems to depend on the ratio of maternal antibody to vaccine antigen. (Jaspen
et al., 2006)
In order to better understand the primary differences in B cell responses of children compared with
adults, it is a good idea to review the different ways in which B cells can be stimulated to produce antigen.
As we will see, the chemical structure of the antigen (protein versus polysaccharide) critically influences
the type of immune response that will be produced.
Normal mechanisms of B cell activation:
As with T cell stimulation, B cell stimulation requires 2 signals. The first signal is provided by the B cell
receptor (a surface linked antibody molecule) binding to its antigen of interest. If this is a protein antigen,
the second signal is provided by a T helper cell (Thymus dependent). T helper cells bind via their T cell
receptor to peptide fragments presented by HLA II/ MHC II. (See figure 1).
CD4+ T helper
lymphocyte
Effector
Peptide HLA II / B lymphocyte
MHC II 1st signal
CD4
TCR
Protein
antigen
BCR
CD40-L
2nd signal CD40
st
1 signal is B cell receptor binding to peptide antigen.
nd
2 signal is CD40-L binding to CD40.
Thymus dependent antigens:
It is of interest that the B cell will internalise antigen via its B cell receptor and process it into small
peptides. It is these small peptides, derived from the larger antigen, that will be presented via MHCII
to T helper cells. Therefore the T cell that provides help for the B cell may not have a T cell receptor
specific for the exact peptide for which the B cell receptor is specific. As long as the T cell receptor is
specific for one of the peptide fragments derived from degradation of the antigen, the B cell will get the
required help. This help allows the B cell to undergo clonal proliferation and produce antibodies of the
IgG1 and IgG3 subclasses. (See figure 2).
Figure 2: B cell activation by a protein antigen
(Thymus dependent)
CD4+ T helper
lymphocyte
Peptide Effector
HLA II / B lymphocyte 1st signal
CD4 MHC II
TCR
Protein
antigen
BCR
CD40-L
2nd signal CD40
st
1 signal is B cell receptor binding to peptide antigen.
nd
2 signal is CD40-L binding to CD40.
Note: The peptide to which the T cell receptor binds is not necessarily identical to the
protein to which the B cell receptor binds.
Thymus independent antigens:
Polysaccharide antigens induce a T cell-independent response. Thus the first signal is again the B cell
receptor binding to the antigen. The second signal in this case is either provided by a receptor of the
innate immune system, such as a toll-like receptor (TI-1 response) or by extensive cross-linking of the
surface antibody by an antigen with repeating epitopes. (TI-2 response). (Cross-linking is an effective
mechanism only in mature B cells, not immature B cells).
It is noteworthy that TI-1 responses can sometimes be caused by mitogens, that is antigen that binds
to the B cell receptor as the first signal but NON-SPECIFICALLY. This means that the same antigen,
such as lipopolysaccharide, could bind to many different B cell receptors on different B cells.
Lipopolysaccharide associating with Toll-like receptor 4 would provide the second signal in all these
cells. (Janeway et al., 2005; Bondada et al., 2000)
Thymus independent antigens lead to production of IgG2 as the predominant IgG subclass. Why all
of this is important to know is that neonates cannot mount a thymus independent response (particularly
a TI-2 response). (Janeway et al., 2005; Bondada et al., 2000). This is very relevant to many common
bacteria with polysaccharide capsules such as Streptococcus pneumoniae, Streptococcus agalactiae,
Neisseria menigitidis and Haemophilus influenzae.
The reason that newborns cannot adequately make antibodies to repeating polysaccharide epitopes
is only partially elucidated. The reasons may be due to immaturity of receptors in the innate immune
system. It may also be due to most of their B cells being immature and unable to respond to B cell
receptor crosslinking (Janeway et al., 2005). The ability to respond to polysaccharide antigens is
developed by 18 months – 2 years of age.
It is critical to understand more about thymus independent antigens particularly in view of potential HIV
vaccines as HIV gp120 is a highly glycosylated protein and therefore a thymus-independent antigen.
(Jaspan et al., 2006). (See figures 3 & 4).
Figure 3: B cell activation by a polysaccharide antigen:
Thymic Independent Type-1 (TI-1)
CD4+ T helper
lymphocyte
Effector 1st signal
B lymphocyte
CD4
BCR
TCR
Polysaccharide
antigen
CD40-L
CD40
Toll-like 2nd signal
receptor
bound to
an antigen
st
1 signal: B cell receptor binds antigen.
Note: This may be in a NON-SPECIFIC way eg. via a mitogen such as lipopolysaccharide – can bind
to many different B cell receptors!
nd
2 signal provided by Toll-like receptor.
CD4+ T helper
lymphocyte BCR
Polysaccharide
CD4 antigen
Effector
B lymphocyte
TCR
CD40-L
2nd signal
CD40
st
1 signal: B cell receptor binds antigen.
nd
2 signal provided by clustering of B cell receptors.
CD4+ T helper
lymphocyte
Peptide Effector
HLA II / B lymphocyte
CD4 MHC II
TCR
The polysaccharide antigen does not get presented on the B cell surface.
The T cell provides help to the B cell via CD40L binding to CD40.
As would be expected, there is also higher proportion of naïve T lymphocytes (lymphocytes that
have never met their cognate antigen) in children compared with adults. These naïve T cells can
be identified on flow cytometry by expression of the marker CD45RA (compared with CD45RO found
on memory cells) (reviewed by Marchant and Goldman, 2005).
Innate and T-cell Immune Response:
Immune responses in the neonate are skewed away from a Th1 profile towards a Th2 profile. (Jaspan
et al., 2006, Cant et al., 2003). There is decreased IFN- production by lymphocytes as well as
hyporesponsiveness of macrophages to activation by IFN-. There is also decreased production of Th1
cytokines (such as IL-1 and IL-12) by mononuclear phagocytes. This may be a follow-up to the skewing
of foetal immunity towards Th2 and anti-inflammatory direction. A range of mediators produced by the
placenta (including IL-10 and progesterone) are thought to down-regulate Th1 in order to prevent
rejection of the foetus (reviewed by Marodi, L., 2006; Prescott, S.L., 2003).
Toll-like receptor signalling may also be impaired in young children. While TLR-4 (the receptor for
lipopolysaccharide, seems to be found at similar levels, an adaptor protein (MyD88) involved in TLR
signalling may be deficient (reviewed by Marodi, L., 2006).There is also a relative deficiency of CD40L
on neonatal T cells which improves with age.
Despite these differences, vaccines such as BCG and whole cell pertussis are able to induce a potent
Th1 type of immune response in very young children. This may be related to the potent ability of these
vaccines to stimulate dendritic cells. BCG has in fact been shown to increase the cytokine and antibody
responses to unrelated vaccine antigens! (Reviewed by Marchant and Goldman., 2005).
As the child grows the cytokine milieus shifts according to environmental exposures and infections.
In developing countries helminth infections bias the cytokine milieu towards a Th2 profile (see Jaspan
et al., 2006).
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