THE DEVELOPMENT OF MAMMARY SECRETORY IMMUNITY IN THE HUMAN NEWBORN

ABSTRACT. Yap, P. L., McKiernan, J., Mirtle, C. L. and McClelland, D. B. L. (MRC Unit of Reproductive Biology, 37 Chalmers Street, Edinburgh; University of Nottingham Department of Child Health; University of Edinburgh Department of Therapeutics and Clinical Pharmacology and the Blood Transfusion Service, Royal Infirmary, Edinburgh, Scotland). The development of mammary secretory immunity in the human newborn. Acta Paediatr Scand, 70:459,.–Milk protein concentrations were determined either by radioimmunoassay (IgA and IgG) or single radial immunodiffusion (IgM, lactoferrin, albumin and lysozyme) in single or serial samples of neonatal milk (witch's milk) obtained from 33 healthy newborns (seven of whom were light for dates), four ill newborns following major surgery and four newborns suffering from one of a variety of infections. In addition, paired neonatal milk and heel prick blood samples were collected from seven newborns, and paired neonatal milk and maternal milk samples were collected from a further seven neonates and their respective mothers. The concentrations of secretory IgA (11S IgA) in neonatal milk, although 300-fold lower than the corresponding IgA concentrations in maternal milk, when compared with neonatal serum IgA concentrations, were crfnsistent with local synthesis of IgA occurring in the neonatal mammary gland. Among the milk proteins studied, only 11S IgA concentrations increased significantly after birth in neonatal milk, the rise being unrelated to the gestational age of the newborn. As an entero-mammary circulation of IgA precursor lymphocytes exists in adults, it is suggested that the entry of foreign antigens into the neonatal gut after birth may be an important factor influencing the development of neonatal secretory immunity.     

Cytokine, chemokine and secretory IgA levels in human milk in relation to atopic disease and IgA production in infants

The relationship between breast-feeding, IgA production and development of atopic disease in children is a matter of controversy. Some of this controversy might be due to individual differences in the composition of breast milk. The aim of this study was to relate the levels of cytokines, chemokines and secretory (S)-IgA antibodies in breast milk to the development of atopic manifestation and salivary IgA production in infants. Cytokine, chemokine and SIgA levels, as measured with enzyme-linked immunosorbent assay (ELISA), in colostrum and mature milk were analyzed in relation to the development of positive skin-prick tests (SPT), allergic symptoms and salivary IgA antibody production during the first 2 years of life in 53 infants. There was no association between levels of IL-4, -5, -6, -8, -10, -13, -16, IFN-γ, TGF-β1, -β2, RANTES, eotaxin or SIgA levels in the breast milk with either SPT-positivity, development of allergic symptoms or salivary IgA levels during the first 2 years of life in the infants. Thus, differences in the composition of cytokines, chemokines and SIgA in breast milk did not, to any major degree, affect the development of a positive SPT, atopic symptoms, nor salivary IgA antibody production during the first 2 years of life.     

Plasma Antibodies to Cow's Milk Are Increased by Early Weaning and Consumption of Unmodified Milk, but Production of Plasma IgA and IgM Cow's Milk Antibodies Is Stimulated Even during Exclusive Breast-Feeding

ABSTRACT. We measured levels of cow's milk-specific (CM) antibodies of immunoglobulin classes G, A and M by enzyme-linked immunosorbent assay in plasma of 198 healthy infants; a variable number of samples taken at birth and at ages of 2, 4, 6, 9, 12 and 28 months were available (altogether 765 samples). The rise in the level of IgG CM antibodies was highest and most rapid in infants exposed to CM formula before the age of 1 month. The level fell by 9 months, but rose again by 12 months. This second rise was attributed to the introduction of dairy milk. Partially breast-fed and fully weaned infants had similar levels of IgG CM antibodies. The levels of IgG CM antibodies were unaffected by the infants' own atopy, their heredity for atopy, and the umbilical serum level of IgG CM antibodies. IgA and IgM CM antibodies were absent at birth. Their levels increased similarly in exclusively breast-fed infants and infants fed CM formula. We conclude that plasma IgG antibodies to cow's milk are increased by early weaning and by consumption of unmodified cow's milk. Production of plasma IgA and IgM antibodies to cow's milk is stimulated even during exclusive breast-feeding.     

CHANGING PATTERN OF COW'S MILK INTOLERANCE: An Analysis of the Occurrence and Clinical Course in the 60s and mid-70s

ABSTRACT. Verkasalo, M., Kuitunen, P., Savilahti, E. and Tiilikainen, A. (Children's Hospital, University of Helsinki, Finland). Changing pattern of cow's milk intolerance. Acta Paediatr Scand, 70: 289, 1981.–The rapid changeover to commercial adapted infant formulae which took place in Finland between 1973 and 1975 was studied as a factor in the occurrence of severe intestinal cow's milk intolerance (CMI). Of infants treated for CMI in 1962-73, ninety-three percent (25/27) were on homemade or unadapted formulae. The admission rate for CMI in these years was 0.22/1 000 liveborn infants breast fed less than six months. During 1974-77 the corresponding figure was 0.56, with 85 % of the patients (18/26) on adapted cow's milk formulae. The patients treated before 1974 had a longer symptomatic period before admission, greater growth retardation and more severe intestinal damage than those seen during and after 1974. This is believed to reflect mainly the increasing awareness of CMI on the part of both laymen and the medical profession. In the history of 2/3 of the patients at least one of the following conditions was noted: non-breast feeding, infectious gastroenteritis, praematurity, 21-trisomy, prior intra-abdominal surgery, Hirschsprung's disease, and atopic disease in family members. The long follow-up averaging over four years revealed four patients with coeliac disease. In one of these the proximal jejunal mucosa was normal after two years on gluten-containing diet, but he showed a mucosal relapse as late as between 2 to 4 years on normal diet.     

Mucosal receptor for IgA in the breast-fed neonate

Immunoglobulin A from human milk binds to neonatal buccal cells. Pretreatment of the cells with anti-secretory component antiserum blocks this binding, suggesting that secretory component (SC) contributes to the adhesive process. The concentrations of SC in saliva of preterm neonates is lower than that of full-term infants. This may lower the effectiveness of mucosal immunity passively transferred from the mother.     

GASTRIC EMPTYING IN INFANTS FED HUMAN MILK OR INFANT FORMULA

ABSTRACT. Cavell, B. (Department of Paediatrics, University Hospital, Lund, Sweden). Gastric emptying in infants fed human milk or infant formula. Acta Paediatr Scand, 70:639,.–Gastric emptying of meals of human milk or infant formula was studied in 17 healthy infants aged 4 weeks to 6 months using a marker dilution technique. In the 24 studies performed gastric emptying followed a hiphasic pattern in 11 and a linear pattern in 12 studies. The average gastric half-emptying time for meals of human milk was 48 min, and for meals of infant formula 78 min. After 1 hour an average of 29.5 ml of human milk and 22.7 ml of infant formula per 0.1 m² of body surface area had emptied from the stomach.     

Incidence of Haemophilus influenzae in the throats of healthy infants with different feeding methods

BACKGROUND: Haemophilus influenzae is the major cause of otitis media and lower respiratory tract infection in childhood. In the presence of human milk, which contains numerous host defense factors, Haemophilus influenzae may be inhibited in attaching to and colonizing pharyngeal cells. We investigated the incidence of H. influenzae in the throats of 162 healthy infants with different feeding methods: 70 breast-fed, 49 mixed-fed and 43 formula-fed infants. METHODS AND RESULTS: Haemophilus influenzae was identified using standard microbiological procedures and the API NH system. The incidence of H. influenzae in breast-fed infants, mixed-fed infants and formula-fed infants was 0, 0 and 7.0% respectively. CONCLUSION: The results suggest that the colonization of H. influenzae in the throat was inhibited by the presence of breast milk.     

EFFECTS OF VARYING DEGREES OF HEAT TREATMENT ON MILK PROTEIN AND ITS NUTRITIONAL CONSEQUENSES

Schmidt, E. (Department of Paediatrics, University of Düsseldorf, GFR). Effects of varying degrees of heat treatment on milk protein and its nutritional consequences. Acta Paediatr Scand, Suppl. 296:41, 1982. — The loss of essential protein-nutrients by heat treatment of formula products has largely been eliminated by modern techniques employed by the food industry. Heat treatment of human milk reduces the biological activity of protein-like antimicrobial factors, but pasteurisation preserves most of the IgA-activity. Little is known about possible nutritional effects on low birthweight infants of heat treatment of human milk. In one study no impairment in nitrogen absorption or retention was observed.     

Daily Ingestion of Immunologic Components in Human Milk during the. First Four Months of Life

ABSTRACT. The amounts of lactoferrin, lysozyme, SIgA and SIgA antibodies to E. coli somatic antigens in human milk ingested per day and per kg per day by breast-fed infants were determined during the first four months of life. A gradual decline in the amounts of lactoferrin, SIgA, and SIgA antibodies ingested per day or per kg per day was found, whereas the quantities of lysozyme ingested by the infants rose during that period. These data suggest that the production and secretion of these immunologic factors by the mammary gland may be linked to the ontogeny of the production or catabolism of those components at mucosal tissues of the recipient infant.     

Food proteins and gut mucosal barrier. III. The influence of lactation and prolactin on the in vitro binding and uptake of bovine serum albumin and ovalbumin in the rat jejunum

The everted gut sac technique was used to study adaptive changes in small intestinal handling and uptake of radiolabeled bovine serum albumin and ovalbumin during lactation in rats. Binding and uptake of both proteins by the gut sacs of lactating animals were significantly less, compared to controls (p less than 0.001, after 30 min of incubation). This change was reversible after lactation ceased. The differences could not be explained by oral immunization since there were no specific antibodies found in sera, mucosal extracts, or breast milk; prior exposure to the protein did not alter the observed differences. No differences in mucosal breakdown of bovine serum albumin could be demonstrated by precipitation with trichloroacetic acid (10%); an increase in breakdown of ovalbumin in the lactating animals was shown under the same conditions. The injection of prolactin produced differences in bovine serum albumin binding and uptake similar to the ones observed in the lactating group (p less than 0.01, after 30 min of incubation, compared to solvent-injected controls). Since food protein antigen binding, breakdown and uptake are functions of the local intestinal host defense, these findings suggest that there are adaptive changes of the gut mucosal barrier during lactation which decrease the transfer of dietary antigens from mother to infant. The adaptation of the maternal intestinal host defense was shown to be influenced by prolactin.     

Bedside analysis of human milk for adjustable nutrition strategy

Aim: Mother's milk is optimum for preterm infants, but human milk fortifier is required at times, because some nutrients are sometimes insufficient for infant growth. It is important to measure the nutrients in breast milk at bedside so that the amount of nutrients that need to be supplemented can be determined. A human milk analyser (HMA, Miris®) is currently available. We examined if the macronutrient values measured by human milk analyser are comparable with those measured by conventional methods. We also sought to discover whether we could dilute the milk sample used for the human milk analyser measurement if the amount of milk available for testing was insufficient.
Subjects and Methods: First, the results of protein, fat and lactose content in breast milk samples obtained using the human milk analyser and conventional methods were compared. Second, we measured diluted samples and compared the values with nondiluted samples.
Results: When comparing the human milk analyser and conventional methods, all three nutrients exhibited a significantly positive correlation (p < 0.001); lactose content was reliable on the condition that it is 6–7 g/dL. The lactose content measured by the HPLC method was obtained by 3.05 × human milk analyser value − 13.4. When comparing diluted and nondiluted samples, fat and protein had expected values after dilution whereas lactose did not.
Conclusion: The human milk analyser can inform us about the amount of major nutrients in breast milk: fat, protein and lactose. However, when human milk is diluted, the lactose content measured by the human milk analyser is overestimated.     

Early induction of secretory immunity in infancy: specific antibody in neonatal breast milk.

Neonatal breast milk from 50 babies aged between 2 and 39 days was studied for the presence of antibody to the cows'' milk protein beta lactoglobulin. Specific IgA antibody and specific secretory antibody to beta lactoglobulin were detectable towards the end of the second week of life in milk secreted by neonates fed cows'' milk formula. Specific antibody concentrations were independent of total IgA concentrations. Babies receiving little or no cows'' milk protein did not produce antibody in neonatal breast milk. Antigen specific mucosal immune responses develop in tissues distant from the site of primary mucosal exposure by the end of the second week of life in term human neonates, suggesting that prophylactic immunisation against enteric or other mucosal pathogens within a few days of birth may provide antibody responses in secretions, which may protect against mucosal infection.     

Markers of inflammation in the feces of infants with cow's milk allergy

Growing evidence exists that exposure to cow's milk elicits inflammation in the gut of infants with cow's milk allergy, irrespective of symptoms. To demonstrate inflammation and increased protein leakage from the gut during a cow's milk elimination‐challenge test in fecal samples of infants presenting with different symptoms suggestive of cow's milk allergy, we measured the concentrations of α₁‐antitrypsin (AT), eosinophil cationic protein (ECP), immunoglobulin (Ig) A, and cow's milk‐specific IgA antibodies, in fecal samples of 208 infants with a mean age of 7 months. Prechallenge samples were collected after a mean 3‐week elimination period, and post‐challenge samples were obtained 4 days after starting the challenge. Fecal levels of prechallenge total IgA (p = 0.02) and post‐challenge AT (p = 0.001) were higher in infants with a positive challenge. Of these infants, pre‐ and post‐challenge levels of ECP were higher in those reacting after 24 h than in those reacting within 1 h (p = 0.006 and p = 0.045). Prechallenge levels of ECP were higher in those showing intestinal symptoms (p = 0.008), and both pre‐ and post‐challenge levels of total IgA were higher in those with an IgE‐mediated reaction to cow's milk (p = 0.04 and p = 0.008). Regardless of the challenge result, total IgA increased during the challenge (p < 0.001 for both challenge‐positive and ‐negative infants) and was higher in those breast‐fed until the challenge than in those fed formula only (p < 0.01). Hence, in infants reacting to the cow's milk challenge, higher prechallenge levels of fecal IgA indicate increased antigenic stimuli in the gut, and higher post‐challenge levels of AT reflect increased protein loss as a result of intestinal inflammation. In infants with slowly evolving gastrointestinal symptoms, increased fecal ECP may help in distinguishing patients from those who tolerate cow's milk. Individual serial follow‐up of fecal IgA and ECP can be used to estimate the degree of inflammation in the gut and an appropriate time for a challenge test, but are not diagnostic tools for cow's milk allergy.     

New World Health Organization guidance helps protect breastfeeding as a human right

Written by the WHO/UNICEF NetCode author group, the comment focuses on the need to protect families from promotion of breast‐milk substitutes and highlights new WHO Guidance on Ending Inappropriate Promotion of Foods for Infants and Young Children. The World Health Assembly welcomed this Guidance in 2016 and has called on all countries to adopt and implement the Guidance recommendations. NetCode, the Network for Global Monitoring and Support for Implementation of the International Code of Marketing of Breast‐milk Substitutes and Subsequent Relevant World Health Assembly Resolutions, is led by the World Health Organization and the United Nations Children's Fund. NetCode members include the International Baby Food Action Network, World Alliance for Breastfeeding Action, Helen Keller International, Save the Children, and the WHO Collaborating Center at Metropol University. The comment frames the issue as a human rights issue for women and children, as articulated by a statement from the United Nations Office of the High Commissioner for Human Rights.     

母乳库的医学应用

国外母乳库的发展已100 余年,曾于上世纪80 年代受艾滋病的影响导致大部分母乳库倒闭。随着对母乳成分及其优越性的重新认识,母乳库再次在全球迅速发展,并先后成立了北美母乳库协会以及欧洲母乳库协会,建立和修订了越来越完善的母乳库标准与指南。捐赠母乳对早产儿的临床疗效已不容质疑,欧洲儿科肝病、消化道疾病与营养学会明确指出：早产儿在无法获得生母母乳时,应推荐使用捐赠母乳。我国母乳库建立于2013 年,其临床意义和社会意义尚在进一步探讨之中。     

新生儿黄疸中碳氧血红蛋白检测的临床应用研究

为探讨常见新生儿黄疸中碳氧血红蛋白(COHb)检测的临床价值,以德国800系列生化血气分析仪附加的270-血氧仪检测动脉化毛细血管血COHb,同步取静脉血检测血清总胆红素(STB)。病例选自本院新生儿病房2001年7月～2002年6月收治的伴有常见黄疸原因的足月新生儿157例[新生儿溶血病75例、感染51例、晚发性母乳性黄疸31例]。对照组101例为日龄匹配无病理性黄疸者,其中≤7天者52例,检测不同日龄的COHb,共测120例次。结果对照组中COHb生后5天内较高,峰值在1～2天,一周后接近成人正常水平。COHb与STB无相关性;溶血组COHb及STB均显著高于对照组(P<0.001),感染、母乳性黄疸组COHb与对照组比较差异无显著性(P>0.05)。结果提示COHb可用于证实新生儿黄疸中有无胆红素产量的增多,有助于黄疸病因的诊断。     

早产母乳营养成分的分析

目的 探讨早产儿母亲乳汁营养成分的特点及动态变化。方法 收集2012 年11 月至2014 年1月在北京协和医院产科分娩产妇170 人的母乳339 份,用MIRIS 母乳分析仪检测母乳中宏量营养素及能量,比较各组母乳营养成分的差异。结果 （1）早产母乳中蛋白质含量：初乳> 过渡乳> 成熟乳（2.22±0.49 g/dL vs1.83±0.39 g/dL vs 1.40±0.28 g/dL;PPPPP+1~33+6 周组（2.11±0.25 g/dL）和≥ 34 周组（2.22±0.39 g/dL）比较差异有统计学意义（P+1~33+6 周（51±6 kcal/dL vs 58±8 kcal/dL,P+1~33+6 周组和≥ 34 周组（P+1~33+6 周成熟乳蛋白质显著高于≤ 30 周和≥ 34 周组（P结论 （1）早产初乳、过渡乳和成熟乳营养成分差异显著;（2）早产初乳蛋白质显著高于足月初乳,这种差异未能持续到成熟乳阶段;（3）不同孕周早产产妇母乳营养成分亦存在差异,以适应不同胎龄早产儿的营养需要。     

Daily Ingestion of Immunologic Components in Human Milk during the. First Four Months of Life

ABSTRACT. The amounts of lactoferrin, lysozyme, SIgA and SIgA antibodies to E. coli somatic antigens in human milk ingested per day and per kg per day by breast-fed infants were determined during the first four months of life. A gradual decline in the amounts of lactoferrin, SIgA, and SIgA antibodies ingested per day or per kg per day was found, whereas the quantities of lysozyme ingested by the infants rose during that period. These data suggest that the production and secretion of these immunologic factors by the mammary gland may be linked to the ontogeny of the production or catabolism of those components at mucosal tissues of the recipient infant.     

Scientific rationale and benefits of nucleotide supplementation of infant formula

The present review examines the role of dietary nucleotides in infants, and the scientific rationale and benefits of nucleotide supplementation of infant formula. The immunoprotective benefits of human milk, the biology of human milk nucleotides, and the immunological and gastrointestinal effects of dietary nucleotides in animal studies and in vitro experiments are examined. Clinical studies are reviewed, especially those examining the efficacy of nucleotide-supplemented infant formula in enhancing immunity and reducing the risk of sepsis. The presence of human milk cells, and a variety of immunoactive and trophic components of human milk, can explain the reduced incidence of sepsis in breastfed term and preterm infants. Nucleotides, believed to play an immunomodulatory role, are found in lower concentrations in infant formula. Animal studies have shown that dietary nucleotides enhance a number of immune responses and the growth, differentiation and repair of the gut. Several clinical studies have reported beneficial effects of nucleotide supplementation on gut microflora, diarrhoea and immune function, and one study has reported better catch-up growth in term infants with severe intrauterine growth retardation. More basic research studying the metabolism of nucleotides in neonates is encouraged. Additional randomized controlled trials are necessary to demonstrate the clinical benefits of nucleotide supplementation of infant formula, as it cannot be presumed that nucleotides produce the same benefits for the infant as human milk. Studies are especially necessary in high-risk neonatal situations, such as extreme prematurity, significant suboptimal nutrient intake before and after birth, and recovery from gut injury.