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Lars A. Hanson, Ursula Wiedermann, Rifat Ashraf, Shakila Zaman, Ingegräd Adlerberth, Ulf Dahlgren, Agnes Wold, and Fehmida Jalil
Human milk is a very complex fluid with a number of components and multiple functions. New functions are continually being identified. It is clear that human milk can affect the immune system of the breasfed infant. This results both in enhanced vaccine responses and, at times, down-regulation of other immune reactivities, such as transplant rejection and the risk of developing certain immunologic diseases, such as type I diabetes. Breastfeeding presumably gives the infant the possibility for an optimal immune response by providing good nutrition, including a decreased risk of vitamin A deficiency. The control of the intestinal flora and the anti-inflammatory effects of maternal milk also increase the possibilities for an adequate immune response in the infant. Further study is needed of the roles of idiotypic and anti-idiotypic antibodies, growth factors, cytokines, and various anti-inflammatory factors in the maternal milk in the infant's host defence.
Human milk is a very complex fluid with a multitude of proteins, cells, and other components. Knowledge is continually increasing about the effects of breastfeeding on the infant, including a number of direct and indirect effects on the immune system. Such influences are related to the fact that human milk is rich in various immunologically active factors, in particular the stable antibodies. Secretory IgA (SlgA) protects the mucous membranes of the infant's gastrointestinal and respiratory tracts, where most infections occur . Mother's milk also contains IgG and IgM antibodies, hormones, antioxidants, vitamins, cytokines, growth factors, complement factors, prostaglandins, granulocytes, macrophages, B and T Iymphocytes, and so forth. Many of these milk components not only participate in the support of the infant's host defence but also affect the normal microbiological flora in the gastrointestinal tract. In addition, other tissues and organs, including the immune system, are influenced.
Breastfeeding enhances vaccine responses in the infant and may affect transplantation outcome
A significantly higher salivary SlgA antibody response was obtained in breastfed than in nonbreastfed Italian infants after parenteral vaccination with diphtheria and tetanus toxoids and after oral poliovirus vaccination . Stool SlgA antibodies could not be used to measure the antibody response because of the presence of milk SlgA antibodies in the stool of breastfed infants. Instead, we analysed stool IgM, an isotype that is present at very low levels in maternal milk. The stool IgM response to parenteral tetanus toxoid and oral poliovirus vaccine was significantly higher in the breastfed group. These observations of the secretory antibody increases were obtained in infants 3 and 4 months of age. The infants had been vaccinated according to the ordinary vaccination schedule at 2, 3, and 12 months of age. Between the ages of 21 and 40 months, serum IgG antibodies to diphtheria toxoid and neutralizing serum antibodies to poliovirus were also significantly increased among the breastfed group compared with the formula-fed controls. These observations are in agreement with another study that determined the serum antibody response to the Haemophilus influenzae type b (Hib) polysaccharide capsule in breastfed and nonbreastled children who were vaccinated parenterally with an Hib protein conjugate vaccine .
The explanation for this effect of breastfeeding on the vaccine response is not entirely clear. We favour the hypothesis that at least some of the enhancing effect could be due to the anti-idiotypic antibodies (anti-antibodies) in human milk. We have shown the presence of such anti-antibodies against poliovirus in human milk . In the proper concentration, antiidiotypes can enhance immune responses . Nevertheless, it is not clear how milk immunoglobulins could be taken up by the child, and other explanations are possible. Thus, maternal milk contains nucleotides that might affect the infant's immune response by stimulating lymphocytes].
If breastfeeding is enhancing vaccine responses, one might expect long-term positive effects of breastfeeding on the host resistance of the breastfed infant. In fact, Silfverdahl et al.  found a long-term protective effect of breastfeeding against invasive H. influenzae infections such as meningitis and epiglottitis.
Several early studies suggested that tuberculin sensitivity was transferred via mother's milk [8, 9]. Even if the resulting tuberculin sensitivity in the infant was temporary, the observation suggested that T Iymphocytes present in milk could be transferred to the offspring. This may be the reason why vaccination against bacillus Calmette-Guérin seems to induce a stronger T-cell response in breastfed infants than in non-breastfed infants .
Transfer of milk cells may also result in immunologic tolerance (selectively reduced immune response) in the baby. Thus, a low response to paternal cells can be induced in newborn mice by letting them suckle a foster mother with the same transplantation antigens as their father . This phenomenon may explain why renal transplants from mothers survive longer in offspring they have breastfed than in those they have not breastfed . In premature infant baboons given radioactively labelled human colostral leucocytes, radioactivity accumulated in the gut wall, liver, and spleen . This suggests that the milk cells are really taken up and have the capacity to influence the immune system of the offspring. Such an influence might explain the finding that breastfeeding can decrease the risk of the offspring developing autoimmune type I diabetes later . The risk of type I diabetes determined by genetic factors is 30% to 40%. Nevertheless, the risk of inheritance from the father is two to three times greater than that from the mother. This difference may be at least partially explained by the effect of breastfeeding, which seems to halve the risk. In this connection, it may be added that breastfeeding seems to diminish the risk of developing Iymphomas  and Crohn's disease . This effect remains long after the breastfeeding has been terminated.
Breastfed infants respond to infections with respiratory syncytial virus with more interferon-y (IFN-y) than do non-breastfed infants . The breastfed infants also produce higher total levels of SlgA in the urine than their formula-fed counterparts .
Breastfeeding, nutrition, and immunity
A major cause of undernutrition in poor countries is the frequent infections resulting from inadequate hygiene, with contaminated water, lack of latrines, ineffective vaccination programmes, inefficient primary health care, lack of education, and the like. As shown by Howie  in this Workshop, breastfeeding can effectively prevent many of those infections.
Breastfed infants are usually given extra water during the hot season. Several studies have shown that this is totally unnecessary [20, 21]. Extra water makes babies less thirsty, which causes them to suck less, so that less milk is produced. Therefore, during the hot season, when the risk of infection is highest, the babies will get less milk. We have shown in a study from Pakistan that infants given water have more frequent diarrhoeal attacks and a significant reduction of weight and of head circumference compared with those who are exclusively breastfed . Whereas breastfeeding provides optimal nutrition to the infant, deficient or absent breastfeeding is clearly a risk factor for inadequate nutrition. The subsequent frequent infections add to the undernutrition, which can impair host defence in a number of ways. It is not always clear, however, that these disturbances of the immune system are of clinical relevance.
We have shown that vitamin A deficiency in rats causes a severe immunodeficiency, followed by a greatly reduced capacity to respond to vaccines and to resist infections, such as diarrhoea and septic arthritis [22, 23]. These animals also have severe protein-calorie undernutrition owing to the loss of appetite caused by the lack of vitamin A. When the vitamin deficiency is corrected by giving retinyl palmitate (vitamin A), their immune response normalizes, although their body weight remains some 30% less than normal.
Immunodeficiency in vitamin A-deficient rats is characterized by a 90% reduction of the intestinal SlgA antibody response to an oral cholera vaccine and a similar reduction of IgE antibody responses to soluble proteins. There is also a reduced IgM and IgG antibody production in response to T cell-dependent antigens. In addition, there is an upregulation of certain TH1 activities.
When these animals are colonized orally with a strain of Escherichia coli, the whole gut contains large numbers of bacteria, which translocate and are thus found in the local Iymph glands. The rats get diarrhoea and at the same time show increased levels of IgE antibodies to the colonizing bacteria and a normalization of the SIgA response, possibly owing to an adjuvant effect of the bacteria in the lymph nodes. These observations may be relevant to several unexplained problems with infection among non-breastfed infants in poor countries .
The most common cause of death between 3 and 28 days of age in poor populations in Pakistan is neonatal septicaemia . The causative bacteria most likely originate in the intestinal flora. The subclinical vitamin A deficiency may increase the risk of translocation of intestinal bacteria so that these bacteria reach the bloodstream. The major cause of death after 28 days of age is diarrhoea, and 84% of the deaths occur after prolonged diarrhoea. Again, early subclinical vitamin A deficiency may pave the way for prolonged diarrhoea.
In Pakistan 34% of the mortality in the first two years of life occurs in the first week and 90% in the first six months . Measures to protect infants during this sensitive period of life are therefore crucial. Vitamin A deficiency is common in mothers and infants in our study area in Pakistan (unpublished data), as in many other pans of the developing world. A significant reduction of this early mortality might be attained by giving the mothers vitamin A directly after delivery and ensuring that they start breastfeeding immediately, thus transferring most efficiently both vitamin A and SIgA antibodies.
In a pilot study in a Pakistani village, we have seen the effects of introducing a health programme that involves breastfeeding promotion, improved primary health care, and education of mothers. Infant modality, stunting, and the prevalence of diarrhoea were all decreased by 50% within two years (F. Jalil, personal communication, 1995). It will be of interest to see what supplementation of breastfeeding mothers with vitamin A might do in this setting.
Breastfeeding and the intestinal flora
Other kinds of indirect effects on the infant's host defence presumably follow from the effects of breastfeeding on the intestinal flora. Non-breastfed infants in poor areas are quickly colonized by several potentially pathogenic aerobic bacterial strains, which show a continuous flux in the gut. In contrast, exclusively breastfed Swedish infants show a stable, more slowly developing intestinal flora, dominated among the aerobes mostly by a single strain of E. coli or sometimes Klebsiella . This difference in the diversity of the enterobacterial flora in breastfed and non-breastfed infants has also been seen in other countries in Europe . Certain E. coli may be favoured by breastfeeding, and so is their expression of the adhesin called type 1 fimbriae ,* which, in contrast to other E. coli adhesins, is not associated with virulence. This may be due to the fact that type 1 fimbriae bind directly to mannose residues on phagocytes, which promote phagocytosis . Other adhesins that may function as virulence factors seem to be suppressed by breastfeeding.
It is obvious that various milk factors can prevent adhesion of certain E. coli to host tissues, presumably influencing the immune response. One example is shown in figure 1. Among such anti-adherence substances in milk are SlgA antibodies and various analogues to epithelial receptors that bind Vibrio cholerae, E. coli , V. cholerae enterotoxin , pneumococci, and H. influenzae . Recently, a milk component, presumably a glucosaminoglycan, has been shown to inhibit the binding of human immunodeficiency virus (HIV) to its CD4 receptor on lymphocytes . The continuous exposure of E. coli to milk components in the gut of the breastfed infant induces continuous changes of surface structures presumably tied to decreasing virulence .
Breastfed infants have higher counts of Staphylococcus aureus, S. epidermidis, and enterococci in the gut than nonbreastfed infants [35-37]. In contrast, breastfed infants do not have higher counts of bifido-bacteria, as is often presumed .
It seems likely that the immune response may differ in breastfed infants, who have a stable intestinal flora in which the aerobes are dominated by E. cold of little or no virulence, and non-breastfed infants, who have a variable flora containing various pathogens and who therefore are at high risk of diarrhoea and other infections. It could also be that various milk components modify the exposure to certain antigens or their presentation to the infant's immune system.
Human milk is anti-inflammatory
Mother's milk contains a number of anti-inflammatory factors with anti-oxidant activity that are able to block chemotaxis of granulocytes and inhibit production of free radicals, peroxidase, and so forth . It is possible that these functions may enhance the well-being of the neonate by preventing inflammation. The neonate is colonized with gram-negative bacteria producing endotoxins in the gut that may induce the production of inflammatogenic, catabolic, and appetite-reducing cytokines such as interleukin1 (IL-1), IL-6, and tumour necrosis factor-a (TNF-a). This cytokine production may be prevented by capacities of the breastmilk. which may be one explanation why non-breastfed infants lose significantly more weight during the first week of life than those exclusively breastfed . In this connection, it is interesting that human milk lactoferrin, a major milk protein, can block endotoxin-induced IL-6 release from human cells . On the other hand, a similar effect is obtained with undenatured bovine millk lactoferrin and its bactericidal peptide lactoferricin.
Human milk contains cytokines such as IL-1, TNF-a, IFN-g , IL-6, transforming growth factor-ß (TGF-ß). and IL-10 [42-44]. Cytokine production can be induced from milk cells as well. Thus, the milk T cells can produce IL-2, IL-3, IL-4, IL-10, IFN-g , and TNF-a , and the macrophages can produce IL-1a IL-1p, IL-lra (IL-1 receptor analogue), IL-6, IL-8, and IL-10. It is presently unknown whether all these cytokines, with capacities to strikingly influence immune responses, can also have such effects on the breastfed infant's immune reactivity. It is likely that their presence and potential activities are under strict control. The cytokine-modulating effect of lactoferrin mentioned above may be an example of such a control function.
Our studies have been supported by the Swedish Agency for Research Cooperation with Developing Countries and the Swedish Medical Research Council (no. 215).
A combined discussion of this paper and the paper by Victora can be found after Victora's paper on page 397.
FIG. 1. Diagram showing that defatted colostrum can prevent adherence of Escherichia cold strains with certain adhesins to a colonic epithelial cell line
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