- Passively acquired antibodies
- Normal mechanisms of B cell activation
- Thymus dependent antigens
- Thymus independent antigens
- What this means for vaccines
- Lymphocyte subsets
- Innate and T cell immune response
It is a well–known medical maxim that “children are more than just small adults” and nowhere is this more relevant than in the paediatric immune system. We know that babies are susceptible in their first three months of life to infections that are not common in older individuals (such as Streptococcus agalactiae) and that infants rely on maternal antibody for the first few months of life. Infants do not respond to certain vaccines in the same way as adults and do not make effective antibodies to polysaccharide antigens until around 5 years of age. The immune system grows and develops with the child and does not fully resemble that of an adult until puberty, when sex hormones may be responsible for the full maturation of the child’s immune system.
We will start by discussing the most obvious difference in the immune system of a child – the fact that most of the neonate’s antibodies are derived from the mother.
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). If you remember – T helper cells bind via their T cell receptor to peptide fragments presented by MHC II (See figure 1).
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).
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 – see figure 3) or by extensive cross-linking of the surface antibody by an antigen with repeating epitopes. (T1-2 response – see figure 4). (Cross-linking is an effective mechanism only in mature B ells, not immature B cells).
It is noteworthy that T1-1 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 18months – 2years 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).
What this means for vaccines:
The inability of infants to respond to polysaccharide antigens has important implications for vaccine design. It was found that responses to a polysaccharide vaccine (Pneumovax®) with polysaccharide antigens from 23 strains) designed to prevent Streptococcus pneumoniae infections elicited good responses in older children but poor responses in those less than 2 years of age. This problem has been largely resolved by conjugating the polysaccharide in the vaccine to a protein (Prevnar® with polysaccharides from only 7 strains). This allows elicitation of a T-cell dependent antibody response. The same is true of Haemophilus influenza type B vaccine, where polysaccharide from the organism has also been conjugated to a protein in order to make the polysaccharide more immunogenic.
The B cell has a B cell receptor specific for the polysaccharide, which is now conjugated to a protein. The B cell internalises the polysaccharide-protein complex. The protein is degraded to peptides and presented on the cell surface via MHC II. The polysaccharide cannot be presented via MHC molecules, which only present peptide. T helper cells with T cell receptors specific for the peptide bind to the peptide-MHC complex on the B cell. This brings the T cell in close contact with the B cell and allows the second signal to occur ie CD40L on the T cell binding to CD40 on the B cell. The B cell thus receives 2 signals (The B cell receptor binding to polysaccharide antigen and CD40L stimulation by the T cell) and can thus proliferate and secrete antibody against the polysaccharide.
This is also a mechanism by which haptens (small chemical groups, eg penicillin) can induce an immune response when attached to a carrier protein (See figure 5).
The reference ranges for lymphocyte subsets (eg CD4 T cells, CD8 T cells, B cells) are different for children compared with adults and clinical results should be interpreted in accordance with age specific reference ranges. This is particularly important for monitoring HIV infection in children. It is often more helpful to use a percentage rather than an absolute count as a guideline for initiating antiretroviral therapy, as the percentage of CD4 cells should always be above 25% of lymphocytes in a healthy infant regardless of the age of the child. (Please see paediatric management guidelines (CDC classification of paediatric staging) – for more specific guidelines on when to initiate antiretroviral therapy).
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-g production by lymphocytes as well as hyporesponsiveness of macrophages to activation by IFN-g. 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 feotal 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).
Arruvito, L., Sanz, M., Banham, A.H. and Fainboim, L. (2007) Expansion of CD4+CD25 Regulatory T cells during the follicular phase of the menstrual cycle: implications for human reproduction. Journal of Immunology 178:2572-2578.
Bondada S., Wu H., Robertson, D.A. and Chelvarajan R.L. (2000) Accessory cell defect in unresponsiveness of neonates and aged to polysaccharide vaccines.Vaccine 19(4-5):557-565.
Cant, A.J, Gibb, D.M., Davies, E.G., Cale, C. and Gennery, A.R. (2003) Immunodeficiency. Chapter 25 in Forfar and Arneil’s Textbook of Pediatrics. 6th ed (McIntosh, N., Helms, P. and Smyth, R.L. eds) Pp 1255-1271. Churchill Livingstone, Edinburgh.
Cutolo, M., Sulli, A., Capellino, S., Villaggio, B., Montagna, P., Seriolo, B. and Straub, R.H. (2004) Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus (2004) 13:635-638.
Chang, C., Satwani, P., Oberfield, N., Vlad, G., Simpson, L.L. and Cairo, M.S. (2005) Increased induction of allogeneic-specific cord blood CD4+CD25+ regulatory T (Treg) cells: A comparative studyof naive and antigenic-specific cord blood Treg cells. Experimental Hematology 33:1508-1520.
Farooqi, I.S., Matarese, G., Lord, G.M., Keogh, J.M., Lawrence, E., Agwu, C., Sanna, V., Jebb, S.A., Perna, F., Fontana, S., Lechler, R.I., DePaoli, A.M. and O’Rahilly, S. (2002) Beneficial effects of leptin on obesity, T cell hyporesponsiveness and neuroendocrine/metabolic dysfunation of human congenital leptin deficiency. Journal of Clinical Investigation 110:1093-1103.
Godfrey, W.R., Spoden, D.J., Ge, Y.G., Baker, S.R., Liu, B., Levine, B.L., June, C.H., Blazar, B.R. and Porter, S.B. (2005) Cord blood CD4+CD25+ derived T regulatory cell lines express FoxP3 protein and manifest potent suppressor function. Blood 105(2):750-758.
Goldman, D.L., Khine, H. Abadi, J, Lindenberg, D.J., Pirofski, L.Niang, R and Casadevall, A. (2001) Serological evidence for Cryptococcus neoformans infection in early childhood. Pediatrics 107(5):e66.
Janeway, C.A., Travers, P, Walport, M. and Shlomchik, M.J (2005) The Humoral Immune Response. Chapter 9 in Immunobiology. Pg 367-406. Garland Science, New York.
Jaspen, H.B., Lawn, S.D., Safrit, J.T. and Bekker, L.G. (2006) The maturing immune system: implications for development and testing HIV-1 vaccines for children and adolescents. AIDS 20:483-494.
Marchant, A. and Goldman, M (2005) T cell-mediated immune response in human newborns: ready to learn? Clinical and Experimental Immunology 141:10-18.
Marodi, L. (2006) Innate cellular immune responses in newborns. Clinical Immunology 118:137-144.
Otero, M., Lago, R., Lago, F., Casanueva, F.F., Dieguez, C., Gomez-Reino, J.J. and Gualillo, O (2005) Leptin, from fat to inflammation: old questions and new insights. FEBS Letters 379:295-301.
Ozata, M., Ozdemir, C. and Licinio, J. (1999) Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin and spontaneous correction of leptin-mediated defects. Journal of Clinical Endocrinology and Metabolism 84:3686-3695.
Peelman, F., Waelput,W., Iserentant, H., Lavens, D., Eyckerman, S., Zabeau, L and Tavernier, J. (2004) Leptin: linking adipocyte metabolism with cardiovascular and autoimmune diseases. Progress in Lipid Research 43:283-30.
Prescott, S.L. (2003) Early origins of allergic disease: a review of processes and influences during early immune development. Current Opinion in Allergy and Clinical Immunology 3:125-132.
Reinke, E. and Fabry, Z. (2005) Breaking or making immunological privilege in the central nervous system: The regulation of immunity by neuropeptides. Immunology Letters 104:102-109.
Salem, M.L. (2004) Estrogen, A double-edged sword: Modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. Current Drug Targets – Inflammation and Allergy 3:97-104.
Sternberg, E.M. (2001) Neuroendocrine regulation of autoimmune/inflammatory disease. Journal of Endocrinology 169:429-435.
Tanriverdi, F., Silveira, L.F.G., MacColl, G.S. and Bouloux, P.M.G. (2003) The hypothalamic-pituitary-gonadal axis: immune function and autoimmunity. Journal of Endocrinology 176:293-304.
Teitelbaum, J.E. and Walker, W.A. (2005) The development of mucosal immunity. European Journal of Gastroenterology and Hepatology 17:1273-1278.
Vassiliadou, N., Tucker, L. and Anderson, D.J. Progesterone-induced inhibition of chemokine receptor expression on peripheral blood mononuclear cells correlates with reduced HIV-1 infectability in vitro. Journal of Immunology; 1999, 162:7510-7518.
Dr Melinda Suchard
BSc (Wits), FCPath(SA)Clin, DTM&H(Wits)