Evolution of Immunologic Functions of the Mammary Gland and the Postnatal Development of Immunity

Goldman, Armond S.; Chheda, Sadhana; Garofalo, Roberto P.

doi:10.1203/00006450-199802000-00001

Cited by 115 publications

(70 citation statements)

References 102 publications

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“…In addition to transfer of immunoglobulin G to the fetus through the placenta, breastfeeding constitutes an important immunological support that the mammalian mother can provide to her relatively immunocompromised offspring against infections during the first months of life (2)(3)(4)(5)(6). The immune system in human milk includes secretory immunoglobulin A (sIgA), immunoglobulin G, free fatty acids, monoglycerides, proteins such as lactoferrin, lactalbumin, glycans, nonabsorbed oligosaccharides, exosomes, immunomodulators such as cytokines, nucleic acids, antioxidants, and immune cells such as macrophages, neutrophils, and lymphocytes (1,4,5,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

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confidence: 99%

Changes in immunomodulatory constituents of human milk in response to active infection in the nursing infant

et al. 2011

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INTRODUCTION:To investigate whether immunologic factors in breast milk change in response to nursing infants' infection. RESULTS: Total cD45 leukocyte count dropped from 5,655 (median and interquartile range: 1,911; 16,871) in the acute phase to 2,122 (672; 6,819) cells/ml milk after recovery with macrophage count decreasing from 1,220 (236; 3,973) to 300 (122; 945) cells/ml. Tumor necrosis factor-α (TNFα) levels decreased from 3.66 ± 1.68 to 2.91 ± 1.51 pg/ml. The decrease in lactoferrin levels was of borderline statistical significance. such differences were not recorded in samples of the controls. Interleukin-10 levels decreased in the sick infants' breast milk after recovery, but also in the healthy controls, requiring further investigation. secretory immunoglobulin a levels did not change significantly in the study or control group. DISCUSSION: During active infection in nursing infants, the total number of white blood cells, specifically the number of macrophages, and TNFα levels increase in their mothers' breast milk. These results may support the dynamic nature of the immune defense provided by breastfeeding sick infants. METHODS: Breast milk from mothers of 31 infants, up to 3 months of age, who were hospitalized with fever, was sampled during active illness and recovery. Milk from mothers of 20 healthy infants served as controls.T he increased sensitivity of the newborn infant to infections originates from the immaturity of the immune system (1). In addition to transfer of immunoglobulin G to the fetus through the placenta, breastfeeding constitutes an important immunological support that the mammalian mother can provide to her relatively immunocompromised offspring against infections during the first months of life (2-6). The immune system in human milk includes secretory immunoglobulin A (sIgA), immunoglobulin G, free fatty acids, monoglycerides, proteins such as lactoferrin, lactalbumin, glycans, nonabsorbed oligosaccharides, exosomes, immunomodulators such as cytokines, nucleic acids, antioxidants, and immune cells such as macrophages, neutrophils, and lymphocytes (1,4,5,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). All these immunologic milk constituents interact together and with the newborn's gut directly or indirectly (e.g., by changing the gut flora) to increase immunity against infection, and probably also contribute to the maturation and efficiency of the newborn immune system (5,6).Many studies in both industrialized and developing countries have shown that nursing infants are less vulnerable to infections during their first months of life, including gastroenteritis, respiratory infections, otitis media, urinary tract infections, and necrotizing enterocolitis in premature infants (3,(18)(19)(20)(21)(22)(23)(24)(25).The mechanisms involved in the immunity provided by human milk to the nursing infant are not fully understood. Until recently, it was believed that the changes in immunological constituents of breast milk were mostly related to the time that elapsed from delivery or, in some cases,...

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Changes in immunomodulatory constituents of human milk in response to active infection in the nursing infant

et al. 2011

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“…It is believed that these molecules contribute to decreased morbidity and mortality of infants who are fed breast milk (10,11). Recently, peptide antibiotics have been isolated from human milk, providing additional evidence that multiple molecules can be involved in the immune defense of this material (12,13).…”

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Expression and Secretion of Cathelicidin Antimicrobial Peptides in Murine Mammary Glands and Human Milk

et al. 2005

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Mammalian milk possesses inherent antimicrobial properties that have been attributed to several diverse molecules. Recently, antimicrobial peptides that belong to the cathelicidin gene family have been found to be important to the mammalian immune response. This antimicrobial is expressed in several tissues and increased in neonatal skin, possibly to compensate for an immature adaptive immune response. We hypothesized that the mammary gland could produce and secrete cathelicidin onto the epithelial surface and into milk. Human cathelicidin hCAP18/ LL-37 mRNA was detected in human milk cells by PCR. Quantitative real-time PCR demonstrated an increase in relative expression levels at 30 and 60 d after parturition. Immunohistochemistry of mouse breast tissue identified the murine cathelicidin-related antimicrobial peptide in lobuloacinar and ductules. Western blot analysis of human milk showed that LL-37 was secreted and present in the mature peptide form. The antimicrobial activity of LL-37 against Staphylococcus aureus, group A Streptococcus, and enteroinvasive Escherichia coli O29 in the human milk ionic environment was confirmed by solution colony-forming assay using synthetic peptide. These results indicate that cathelicidin is secreted in mammary gland and human milk, has antimicrobial activity against both Gram-positive and Gram-negative bacteria, and can contribute to the anti-infectious properties of milk. Antimicrobial peptides are found throughout nature and are important for the immune defense of plants, insects, and animals (1). Most of these molecules have a broad spectrum of antimicrobial activity against Gram-positive and Gram-negative bacteria, fungi, and viruses. In mammals, peptides from the cathelicidin family assist the antimicrobial efficacy of neutrophils, macrophages, and mast cells (2-6). In addition, antimicrobial genes of the defensin and cathelicidin families are produced by epithelia in response to injury of lung, gut, urinary bladder, oral mucosa, and skin (7-9). At the interface with the external environment, these molecules serve as a rapid first-line defense for inhibition of microbial proliferation and invasion.Human milk contains various anti-infectious materials such as immunoglobulins, cellular components, and cytokines. It is believed that these molecules contribute to decreased morbidity and mortality of infants who are fed breast milk (10,11). Recently, peptide antibiotics have been isolated from human milk, providing additional evidence that multiple molecules can be involved in the immune defense of this material (12,13). In other systems, the clinical consequences of antimicrobial peptide expression have been observed in patients who have atopic dermatitis and are susceptible to infection and also lack the ability to increase the cathelicidin LL-37 and human ␤-defensin (hBD-2) in response to inflammatory stimuli (14). Furthermore, patients with Kostmann syndrome, a rare inherited disorder characterized by frequent infections and neutrophil dysfunction, also have a deficien...

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“…The humid warm environment required for these eggs to hatch would be conducive to bacterial and fungal growth. On the other hand, a delay in immunological development in placental mammals may have developed both because the uterus protects the fetus from most pathogenic micro-organisms, and to avoid untoward immunological reactions to maternal tissue during pregnancy (131) . This protection does not result in infants developing as 'germ-free' animals; indeed, there are many factors that encourage the appropriate colonisation of the neonate with commensal and symbiotic micro-organisms during the lactation period.…”

Section: 'Altricial' Neonatal Metabolismmentioning

confidence: 99%

“…These components include lactoferrin, lysozyme, lactoperoxidase, xanthine oxidoreductase, oligosaccharides, glycoprotein, glycolipids, cytokines, growth factors, fatty acids, defensins, cathelicidins, lactadherin, antisecretory factor and leucocytes (neutrophils, macrophages and lymphocytes) that provide protection against pathogenic micro-organisms by either binding the microbes and preventing entry of the underlying tissues, engulfing and killing micro-organisms by phagocytosis, depriving microbes of essential nutrients or neutralising viruses and toxins. In addition some components function as anti-inflammatory factors (antioxidants, epithelial growth factors, cellular protective agents and enzymes that degrade mediators of inflammation), immunomodulators (nucleotides, cytokines and antiidiotypic antibodies) (131) and as prebiotics for symbiotic bacteria (132) .…”

Section: Protection From Pathogenic Micro-organismsmentioning

confidence: 99%

Evolution of lactation: nutritionv.protection with special reference to five mammalian species

2008

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The evolutionary origin of the mammary gland has been difficult to establish because little knowledge can be gained on the origin of soft tissue organs from fossil evidence. One approach to resolve the origin of lactation has compared the anatomy of existing primitive mammals to skin glands, whilst another has examined the metabolic and molecular synergy between mammary gland development and the innate immune system. We have reviewed the physiology of lactation in five mammalian species with special reference to these theories. In all species, milk fulfils dual functions of providing protection and nutrition to the young and, furthermore, within species the quality and quantity of milk are highly conserved despite maternal malnutrition or illness. There are vast differences in birth weight, milk production, feeding frequency, macronutrient concentration, growth rate and length of lactation between rabbits, quokkas (Setonix brachyurus), pigs, cattle and humans. The components that protect the neonate against infection do so without causing inflammation. Many protective components are not unique to the mammary gland and are shared with the innate immune system. In contrast, many of the macronutrients in milk are unique to the mammary gland, have evolved from components of the innate immune system, and have either retained or developed multiple functions including the provision of nourishment and protection of the hatchling/neonate. Thus, there is a strong argument to suggest that the mammary gland evolved from the inflammatory response; however, the extensive protection that has developed in milk to actively avoid triggering inflammation seems to be a contradiction.

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Evolution of Immunologic Functions of the Mammary Gland and the Postnatal Development of Immunity

Cited by 115 publications

References 102 publications

Changes in immunomodulatory constituents of human milk in response to active infection in the nursing infant

Changes in immunomodulatory constituents of human milk in response to active infection in the nursing infant

Expression and Secretion of Cathelicidin Antimicrobial Peptides in Murine Mammary Glands and Human Milk

Evolution of lactation: nutritionv.protection with special reference to five mammalian species

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