importance of breastmilk

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Mal J Nutr 16(1): 1 - 11, 2010

Breast Milk Immunoprotection and the Common MucosalImmune System: a Review

Prameela KK 1 & Mohamed AEK 2

1 Consultant Pediatrician, Clinical Department2 Professor of Immunology and Parasitology, Preclinical Department II

Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, 55100 Kuala Lumpur, Malaysia

ABSTRACT

It is universally known that breastfeeding provides a broad spectrum of nutritional and non-nutritional advantages to the developing infant. Non-nutritive protecting potentials of breast milk towards different infections andnon-infectious diseases are still attracting the attention of researchers in differentspecialties. The neonate, who is suddenly exposed to a wide variety of organisms,is in dire need of protection, enhancement and education of his immature immunesystem to encounter these organisms. The lactating mammary gland is an integralpart of the common mucosal immune system which stands as a sentinel incombating pathogens that enter the body via the mucosal route. The commonmucosal immune system also competently controls tolerance mechanisms toinnocent proteins and is involved in surveillance of carcinogensis. The diverse

roles of general mucosal immunity are nearly well established but the specialisedfunctions of breast tissue and breast milk in boosting the immune responsesneed more emphasis and highlighting. The detailed understanding andevaluation of breast milk as an immunological tool is reviewed within thedomain of the diverse activities of the common mucosal immune system.

Keywords: Breastfeeding, breastmilk, common mucosal immune system,immunity, lactating mammary gland

INTRODUCTION

Breastfeeding is globally recognised to be anexclusive nutrient for the first six months of the infants life and as a supportive nutrientfor a further eighteen months more. This is based on the fact that the immune andnutritive factors in breast milk conferimmediate and long term benefits which arefurther evidenced by the observation thatthose who had been deprived of

breastfeeding in infancy suffer many morbid

Correspondence author: Mohamed Adel El Kadi; Email: [email protected]

conditions in their adult life (Drash et al.1994)In spite of abundant information about theconstituents of breast milk, many facetsremain unclear and the precise role of lactating mammary glands in mucosalimmunity is actually understated andperhaps, understudied.

MUCOSAL PROTECTION

Mucosal surfaces or mucosae are organised

epithelial structures found throughout the


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Prameela KK & Mohamed AEK 2

body and formed by sheets of cells whichare continually bathed in a thick layer of mucus. They line the gastrointestinal,

respiratory and urogenital tracts and arefound in the pancreas, conjunctivae,lachrymal glands, salivary glands,mammary glands and body orifices.Mucosae cover, protect and provide secretoryand absorptive functions through moistmucoid surfaces. The nature of cells forminga particular mucous membrane reflects thespecialised functions of that tissue; howeverall mucosae share a common function of interaction between the internal andexternal environments of the body. Moreover,mucosae form the largest surface area of the body and a very important portal of entryfor pathogens during inspiration, uponingestion, or when in contact with theconjunctiva or the genitourinary mucosalsurfaces. Protection at the mucosal surfacesis a very intricate process which dependson a complex barrier of non-cellularcomponents and the integral structure of the

common mucosal immune system(Abraham, Sharon & Ofek , 1999; Nagler-Anderson, 2001) .

Non-cellular mucosal barriers aredifferent interrelated components withmucin representing the key structure. Mucinis a mixture of glycoproteins, proteoglycans,peptides and enzymes ( Lamont,1992) . Theglycoproteins of mucin line the surfaceepithelium from the oro-nasal cavity to therectum forming a thick barrier that traps theinvading bacteria and viruses to be expelledlater in a process called non- immuneexclusion (Belley et al.,1999).

Another significant non-cellularmucosal barrier is formed by gut enzymesfound throughout the length of the tract. Aset of active enzymes are produced by simpleand complex gland structures under tightcontrol of tactile stimulation of mucosa, localintrinsic nervous plexus reflexes, para-

sympathetic stimulation and group of autocrine hormones ( McNabb &Tomasi,1981) . Moreover, extraordinarily

stable small proteins known as trefoilfactors help to strengthen the barrierfunction of mucosa and promote its

restoration if any defect occurs (Wright,1993).The common mucosal immune system

is perfectly designed as an integratednetwork of lymphoid tissues, mucousmembrane associated cells and a collectionof effective molecules, existing alongside butseparate from the peripheral immune systemin the blood. It presents well-tuned defenseelements; the first is compact and localisedwhile the second is more diffuse anddisperse (Brandtzaeg, Baekkerold &Farsted,1999). The compact component isconcerned with selective picking of foreignantigens and introducing them intoexclusive antigen processing cells to initiatethe targeted responses while the seconddiffuse component is a collection of effectorB-and T lymphocytes, differentiated plasmacells, macrophages, dendritic cells,eosinophils, basophils and mast cells which

work together to accomplish more organisedhost protection (Conley & Delacroix,1987).Finally, the components of the mucosalimmune system interact together to produceeffective cell-mediated and humoralprotective responses, or under certainconditions, produce systemic anergy knownas mucosally introduced tolerance (Weiner,1997).

THE MUCOSA-ASSOCIATEDLYMPHOID TISSUE (MALT)

The mucosal surfaces in the adult areextensive, and require significant supportiveexpenditures of lymphoid tissues and othereffector molecules. These structures form thecore ingredient of the common mucosalimmune system and are collectively knownas mucosa-associated lymphoid tissueMALT (Langkamp-Henken, Glezer & Kudsk,

1992). MALT is not a single structure; thereare different divisions incorporating diverselocations which carry a key to their


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Breast Milk Immunoprotection and the Common Mucosal Immune System: a Review 3

functions. Thus, MALT comprises gut-associated lymphoid tissue (GALT), bronchial/tracheal-associated lymphoid

tissue (BALT), nasal-associated lymphoidtissue (NALT), vulvovaginal-associatedlymphoid tissue (VALT), larynx associatedlymphoid tissue (LALT), skin-associatedlymphoid tissue (SALT), conjunctiva-associated lymphoid tissue (CALT),mammary glands associated lymphoidtissue and the products of lactation (Krackeet al.,1997; Kelsall & Strober, 1999). Theorganised lymphoid follicles in the GALTand BALT are considered the principalinductive sites of mucosal immune responsein the body (Mc Ghee, Lamm & Strober,1999).Structurally, MALT is formed of intra-epithelial CD8+ lymphocyte repertoire, B-cells, dendritic cells, macrophages andmicrofold cells, (M-cells). M cells are of special interest as they are found in themucosal inductive sites in the intestinal andupper respiratory tract and stand assentinels to mucosal structures. They lack

microvilli and glycocalyx coating and exhibitmicrofolds on their luminal surface; thesecharacters suite their functions to absorb,transport, process and present antigens tosubepithelial lymphoid cells (Feather-stone,1997). Interestingly, the pathogenicreovirus, invasive salmonella and shigella

can gain entry via M-cells into deeper MALTstructures; some studies focus onidentification of the exact bacterial and viral

virulence factors associated with targetingM cells, like sigma protein of reovirus, aimingto develop effective vaccines and vaccinecomponents that could be delivered directlyinto mucosal inductive sites (Wolf et al.,1981).In the evolutionary process, different MALTstructures are developed at birth, withdiscrete T and B-cell populations apparentas early as 19 weeks gestation. Howeversecondary follicles with germinal centersreflecting B-cell activation do not appearuntil weeks after birth, reflecting theirdependency on exogenous stimuli(Brandtzaeg, 1998; Brandtzaeg,2003).

IMMUNOGLOBULIN A (IgA)

The remarkable magnitude of GALT as aninductive site for mucosal humoralimmunity is due to the fact that about 80% of all IgA-producing blasts and plasma cells

are located in the intestinal lamina propria,with a daily production of 3-5g of IgAflowing into the intestinal lumen (Cebra etal.,1977). IgA is the major humoralcomponent of mucosal immunity foundmainly associated with mucosal surfacesand expressed after B cells undergo class-

Figure 1. The molecular structure of sIgA (adapted from: Robyn Seipp, 2003)


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switching driven by cytokine stimulation(Van Cott et al.,1996). The secreted IgA is acomplex polypeptide dimer of two basic

heavy chains held to two light chains by Jchain. When IgA is transported across themucosal epithelium, it will acquire anadditional polypeptide component andpolymeric IgA (pIgA) is then formed. pIgA istransported by polymeric Ig receptor (pIgR)into mucosal secretions and extracellulardomain of pIgR will be bound to it to protectthe molecule from proteolytic enzymes in theharsh gastrointestinal tract environment(Kaetzel et al.,1991). In the end, secretory IgA(sIgA) synthesis comes as a net result of complicated molecular reactions betweenepithelial cells, IgA-committed B cells andTh cells (McIntyre & Strober, 1999).

As sIgA is the main effector humoralcomponent of the mucosal immune system ,its molecular structure offers significantstability which fits its professional functionof mucosal protection (Woof & Mestecky,2005). In the mucosal lining, sIgA mediates

a variety of immune exclusion functions by interfer ing with bacter ia and virusadherence under tactical process known asintracellular neutralisation(Yan et al.,2002).

Because sIgA functions as an inhibitorof bacterial and viral attachment to themucosal epithelium and agglutinatesantigens, it is viewed as a benign antibodywhich fails to bind complement and in turn,unable to elicit an inflammatory response(Macpherson et al.,2001). sIgA is releasedinto serum in small amounts as a monomermolecule which may function as a secondline of defense by eliminating pathogens thathave breached the mucosal surface (Woof &Kerr, 2007).

The sIgA typically interacts with Fcreceptor (Fc R1) on the surface of theinvading pathogens triggering antibody-dependent-cell-mediated cytotoxicity

(ADCC) which offers additive protectionagainst many bacteria and viruses includingHIV-1 (Mantiset et al.,2007). Thus, it can be

concluded that the hallmark of the mucosalimmune response is the development of sIgAwith vital participation of other

immunoglobulin isotypes and cellularelements, including IgE, intraepitheliallymphocytes, dendritic cells, T-lymphocytessubsets, and a spectrum of immun-oregulatory and proinflammatory cytokinesand chemokines available locally in themucosa (Beagley & Elson, 1992).

BREAST MILK AND sIgA

In humans, the production and functions of sIgA are not optimum until four years of age,however breast milk is able to compensatethis when it confers sIgA passively to thesuckling infant, providing a robust localimmunity. sIgA in the breast milk, mainlycolostrum, is a developmental bridge untilthe infants intestines secrete its own . Theknown protective effects of colostrum againstdiarrheal diseases led some references todefine neonatal diarrhea as a colostrum

deficiency syndrome. This encouraged someresearchers to try therapeutic doses of colostrum (5 mg/kg daily) and found it ableto reduce neonatal Escherechia coliand otherviral diarrhea (Jelliffe & Jelliffe,1981). Theprofile of sIgA production in breast milk isfound to be influenced by maternal age,mood variables, immunological andinfectious factors, serum proinflammatoryand proimmune cytokines and cortisollevels. Older and stressed women showedlower sIgA while positive life events werecorrelated with higher breast milk sIgA levels(Groer, Davis & Steele,2004) . An importantcompensatory mechanism in IgA deficientinfants appears to be offered by IgM(Mellander et al.,1986). Investigations of human mucosa have shown that clonallyrelated IgM+ plasma cells probably secreteantibodies with similar specificities in thesame mucosal micromilieu (Mbawuike et

al. ,1999). Mucosal IgM-IgA interactionshave been studied in murine models andhave proven the presence of active switching


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from IgM to IgA in the gut mucosa micro-environment (Chapman et al.,1996 andFagarasan et al.,2001).

THE LACTATING MAMMARY GLANDAS A PART OF THE COMMONMUCOSAL IMMUNE SYSTEM

The lymphoid tissues found all over the bodyare classified into primary or central tissuesfound in hematopoietic bone marrow, andsecondary or peripheral tissues located inmost strategic points of the body namely thelymph nodes, spleen, MALT, GALT, BALT,NALT, SALT, VALT, urinary tract-associated lymphoid tissue, CALT andlactating mammary glands (Kunisawa,Fukuyama & Kiyono,2005; Randall,Carragher & Rangel-Moreno , 2008). Thesecondary lymphoid tissues havespecialised architecture and micro-environments that promote the controlledinteractions of immunocytes to elicit briskappropriate immune responses (Kunisawa

& Kiyono,2005). Secondary lymphoidtissues differ functionally, so while lymphnodes collect antigens and antigenpresenting cells from non-lymphoid organsthrough afferent lymphatics, other mucosalassociated lymphoid tissues acquireantigens directly across the mucosa.Secondary lymphoid tissues develop duringembryogenesis or in the first few weeks after birth according to highly coordinatedinteractions between new emerginghematopoietic cells and immature mesen-chymal or stromal cells. These interactionsare orchestrated by chemokines, cytokinesand growth factors that attract hema-topoietic cells to the sites of future lymphoidstructures and promote their survival anddifferentiation there (Baggiolini, Dewald &Moser,1997). The lactating mammary glandsare integral parts of the common mucosalimmune system as evidenced by the milk

composition of lymphocytes derived andmigrate from precursor immuno-competentcells present in breast-associated lymphoid

tissue and gut-associated lymphoid tissue.The local lymphocytes in the lactating breasttissues are mostly CD4 and CD8 T-cells with

less numbers of B lymphocytes. Chemokinesand cytokines of transforming growthfactor-beta (TGF-beta), interleukin-4 (IL-4)and intrleukin-10 (IL-10) promote B-cellswitching into IgA producing cells locallyin the lactating mammary glands(Hayward,1983) .

Breast milk is a complex mixture of interacting compounds that differ incomposition not only between women butalso within the lactation period. It is aspecies specific product which containsproteins, non-protein nitrogen compounds,carbo-hydrates, lipids, minerals andvitamins. Many of the milk components arenon-nutritive elements, designedparticularly to support immune-development, tolerance, and to regulateinflammation (Oddy, 2001).

NON-NUTRITIVE PROTECTIVE

VALUES OF BREAST MILKMilk is a communication vehicle between thematernal immune system and infant .Although infants have antibodies derivedfrom the maternal circulation, they remainunprotected when challenged with neworganisms. Breast milk can minimise this risk by supplying antibodies and by directingand educating the immune, metabolic, andmicroflora systems of the infant (Brandtzaeg,2003). The profile of passive immunitytransmitted by breast milk to the infant,reflects previous maternal exposures, whilethe sensitised lymphocytes derived from the breast associated lymphoid tissues showadaptive memory with production of morespecific immunoglobulins and cytokines(Bottcher et al., 2000). So, in nursing mothers,plasma cells migrate from activated B-cellsto home in the lactating mammary glands,

synthesise immuno-globulins, mainly sIgA,and to less extent IgD, IgM, IgE and IgE toprovide the suckling infant with an


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exceptionally active mucosal protectivefactors (Field, 2005).

More bioactive factors are also found in

the breast milk including lactoferrin,lysozymes, lactoperoxidase, free fatty acids,complement, vitamin B12 binding protein,folic acid-binding protein, bifidus factor,fibronectin, oligosaccharides, high mole-cular weight mucins and interferons. Theyhave no intrinsic memory but contribute inthe non specific protective values of breastmilk ( Newman, 1995 ).

Cellular defensive values of breast milkdepend on the phase and stage of lactation;varieties of leukocytes appear in colostrumand mature milk, with macrophages forming55-60% of total breast milk cells, neutrophils30-40% and lymphocytes 5-10% (Goldman,1993). Viable breast milk leukocytes have been isolated from the faeces of sucklinginfants with their key surface moleculesremaining antigenically intact. This could be of particular significance in relation tomucosal protective values of breast milk

(Goldman, 1993).Macrophages derived from breast milkmodulate the infants T and B cells throughtheir activation markers (CD11c) whichprovide phagocytic and immunoregulatoryfunctions . Moreover, these cells containengulfed sIgA which could be released oncein contact with bacteria in the gut (Rivas, ElMohandes & Katona,1994).

Neutrophils of breast milk demonstratedecreased adherence, polarity, motility andexpress high levels of CD11b and low levelsof L-selectin markers. These criteria areindicative of prior activation and limitedfunctional capacity once they are secretedinto milk (Kim et al., 2003).

Lymphocytes in the breast milk showhigher proportion of CD8+ and +expressed receptors. CD4+ cells expressingCD40L, sCD30 and CD45RO+ surfaceproteins are also found in the human milk

which signify active immunological memory(Eglinton, Roberton & Cummins,1994).Field (2005) found CD4+ cells from

maternal origin able to compensate the

immature functions of the defective neonatalT cells and promote their maturation.Cytokines in breast milk include IL-4, IL-10

and TGF-beta, which are produced bymucoepithelial cells and imply collaboration between neighboring lymphocytes andmucosal microenvironment of the breastassociated lymphoid tissues (Field , 2005).

Lactoferrin is an iron-binding proteinwith a hundredfold higher activity thantransferrin, the major iron transport proteinin the body. The highest known concentra-tion of lactoferrin is 7 gram /liter which isfound in human colostrum only. Maturehuman milk contains about 1 gram/liter and bovine milk contains lesser amounts (Ward,Paz & Conneely , 2006). Lactoferrin hasdifferent biological activities, it inhibitsdifferent pathogenic bacteria, viruses,parasites and fungi, activates a variety of immune system cells, regulates normal cellgrowth and inhibits tumor cell division andspreads in experimental animals (Weinberg ,2002). In the breast milk, Lactoferrin helps

the infant to absorb more iron, and seemsessential factor for B- and T- lymphocytesgrowth (Valenti & Antonini, 2006).

Alpha-lactalbumin is a protein in breastmilk found to destroy cancer cells ( J ensen, &Lammi-Keefe, 2001). This may partly explainthe early report on childhood lymphoma being nine times higher in bottle-fed infants(Davis, Savitz & Grauford, 1988).

OTHER PROTECTIVE FACTORS

Prostaglandins in fresh breast milk are believed to protect the immature delicategastrointestinal mucosa of the newborn.Premature babies are partially protectedagainst necrotising enterocolitis (NEC) whenthey are breastfed (Bedrick, 1990 and Lucas& Cole, 1990). Lactadherin is a glycoproteinwhich attaches to rotaviruses and inhibitstheir settling on the gut wall (Newburg et

al.,1998). Interferons, found primarily incolostrum, have strong anti-viral activity(Bocci et al.,1993). Colostrum fibronectinsintensify phagocytes to attack bacteria


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aggressively even before being tagged byantibodies (Friss et al.,1988). Cortisol andother smaller proteins of epidermal growth

factor, nerve growth factor, insulin-likegrowth factor and somatomedin C, act toclose up the leaky mucosal lining of theinfant, making it relatively impermeable topathogens (Newman,1995 ).

BREAST MILK PROMOTES TOLERANCEAND PRIMING OF THE INFANTSIMMUNE SYSTEM

The mechanisms responsible forsensitisation, in particular within thegastrointestinal tract, are IgE-mediated aswell as of a non-IgE-mediated, immuno-logical origin. The phenomenon that is theopposite of sensitisation is the maintenanceof tolerance and is exemplified by oraltolerance. The cytokines transforminggrowth factor beta and interferon gammahave been shown to be key immuno-regulatory cytokines in oral tolerance

(Kalliomki et al., 1999). Lack of maturationof the infant immune system from a T helper2 to a T helper 1 type of immune responsemay be caused by less microbial challengeespecially in formula milk fed infants(Steffen,2001). Apart from the geneticconstitution of the individual, breastfeedingin infancy may be the most important singledeterminant for the development of clinicaltolerance. During breastfeeding, there is afine balance between antigen responses thatresults in tolerance, and the responses whichresult in sensitisation. Successful develop-ment of tolerance contributes to lowerincidences of food-related allergies in breast-fed infants (Van Odijk et al., 2003).

CONCLUSION

The impressive facts about breast milkshould consolidate firm efforts towards

continuous breast feeding in infants for upto two years. Feeding decisions are veryindividual, but the current knowledge aboutthe unique composition and indispensable

values of breast milk, makes it undoubtedlythe first choice. The mothers mature andmore effective immune system is represented

successfully in the lactating mammaryglands as an integral part of the commonmucosal immune system. Breast milk thenconfers passive and active immunities to thesuckling infant. Yet no artificiallyengineered formula can offer the completeset of breast milk ingredients. Furthermore,human breast milk as a species specificproduct cannot be equalised to any otheranimal milk. The biochemical, physiologicaland genetic backgrounds of breast milkcomponents should be further analysed andmore studies on mucosal associatedlymphoid tissues must focus on the lactatingmammary gland. It is hoped that furtherresearch in this area may improve theunderstanding of the complex strategies of mucosal immunity provided by breast milkwhich carries a special importance fornutritionists, immunologists andpediatricians alike.

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importance of breastmilk

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