Immunoglobulin A in Bovine Milk: A Potential Functional Food

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Journal of Agricultural and Food Chemistry

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Immunoglobulin A in Bovine Milk: a Potential Functional Food?

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Julie A. Cakebread, Rex Humphrey, Alison J. Hodgkinson.

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AgResearch, Ruakura Research Centre, Hamilton, New Zealand

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Corresponding author:

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Julie Cakebread,

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Food and Bio-based products

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Ruakura Research Centre

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10, Bisley Street

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Private Bag 3123

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Hamilton 3240

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New Zealand,

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Tel: +64(0)7 838 5317

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Fax: +64(0)7 838 5628

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Authors: Cakebread, J.A; Humphrey, R; Hodgkinson, A.J.

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Acknowledgments: We thank Dr. Tom Wheeler for his useful comments.

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Total words: 1 Figure, 1 Table, no supplementary material

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Running title: sIgA and functional foods

E-mail: [email protected]

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ACS Paragon Plus Environment


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Abstract

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IgA is an anti-inflammatory antibody that plays a critical role in mucosal immunity. It is

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found in large quantities in human milk, but there are lower amounts in bovine milk. In

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humans, IgA plays a significant role in providing protection from environmental pathogens at

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mucosal surfaces and is a key component for the establishment and maintenance of intestinal

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homeostasis via innate and adaptive immune mechanisms. To-date, many of the dairy-based

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functional foods are derived from bovine colostrum, targeting the benefits of IgG. IgA has a

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higher pathogenic binding capacity and greater stability against proteolytic degradation when

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ingested, compared with IgG. This provides IgA-based products greater potential in the

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functional food market that has yet to be realised.

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Keywords : Immunoglobulin A, Free secretory component, Milk, Colostrum, Glycosylation

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1. Introduction

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Milk provides the sole source of nutrition for mammalian offspring until they are able to

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digest food from other sources. Different from other mammals, humans continue to drink

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milk into adulthood; a practice established following the domestication of animals, with the

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earliest dates linked to cattle herding in the Near East and southeastern Europe 1. Milk is an

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excellent source of protein, fat, carbohydrates and minerals as well as many

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immunomodulatory components, including immunoglobulins (Ig). In human milk and

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colostrum, the major Ig is IgA. IgA is also present in bovine milk, although IgG predominates

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2

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microbiota, populations of commensal bacteria that colonise the gastrointestinal tract. And

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conversely, the microbiota is important for the development and function of the immune

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system, as demonstrated by the perturbed immune system of germfree mice 3. On-going

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maintenance of homeostasis and health requires a co-operative interplay between the host

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immune system and resident microbiota.

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. In the infant, milk-derived IgA is important for the establishment and maintenance of the

Diet plays an important role in this process. Functional foods, i.e foods that provide

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health benefits additional to nutrition, are increasingly sought by health-conscious consumers.

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There are many dairy-based functional food products including colostrum-based products

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valued for their high IgG content. In this review, we examine the activities and functions of

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bovine milk-derived IgA and appraise its application as a functional food. We propose that

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IgA from bovine milk could provide consumers many health benefits and is an untapped

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resource that could be utilised in products for the growing health-food market.

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2. Secretory IgA

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IgA is produced in the body in several forms; monomeric (m)IgA, dimeric (d)IgA and

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secretory (s)IgA. In tissues, IgA is formed as a dimer consisting of two Ig units connected

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tail-to-tail at the heavy chain regions (Fc) and covalently bound by a small glycoprotein



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known as J chain 4, 5. As a dimer, IgA has four potential antigenic binding sites (Fab) in

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contrast to two binding sites for monomer Ig isotypes such as IgG. From the tissue-based site

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of production, dIgA is actively transported across the epithelial cell into mucosal secretions

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by the polymeric immunoglobulin receptor (pIgR), expressed on the baso-lateral surface of

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the cell. At the apical membrane pIgR is cleaved by proteolysis to release sIgA into the

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mucosal lumen along with a portion of pIgR, termed secretory component (SC) (see review

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by Kaetzel 2005 6).

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Bound to the Fc portions of the IgA molecule, SC acts to protect sIgA against

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proteolytic degradation 7, 8 and stabilizes its quaternary structure 9. This helps sIgA retain its

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activity in enzymatic environments, such as the gastrointestinal lumen 10. In the absence of

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dIgA, there is constitutive production and transport of pIgR which results in secretion of Free

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Secretory Component (FSC). Bovine milk FSC, the first SC to be isolated in free form for

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any species 11, shows close similarity to the amino acid composition of human FSC 12.

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3. sIgA in milk

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Immunoglobulins in milk reflect the antigenic exposure of the mother. During late pregnancy

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differentiated B lymphocytes migrate from the intestine to the mammary glands under

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hormonal and cytokine control 13; these plasma cells produce IgA in situ which is then

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translocated and secreted into the milk as sIgA. The relationship between breast-feeding and

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infant health and wellbeing is well recorded 14 and due in large part to sIgA. SIgA in milk has

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been shown to support modulation and colonization of commensal bacteria in the neonate's

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intestinal mucosa and also assist the maturation of the immune system (Reviewed by Hanson

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and Korotkova) 15. A recent murine study supports the hypothesis that sIgA in breast milk

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promotes long term intestinal homeostasis through into adulthood 16. In human mammary

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secretions, sIgA represents 90% of total Ig compared with bovine colostrum and milk where

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IgA is only 10% if the total with 80% IgG (Table 1). This equates to approximately 0.1 g/L


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in bovine milk compared with 0.5–2 g/L in human milk 17, 18. These Ig ratios reflect the

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different events occurring in utero: infants are born with circulating maternal IgG transferred

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via the placenta 19, 20 while calves are born agammaglobulinemic. For this reason, bovine

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colostrum has very high levels of IgG, derived mainly from serum during the last few weeks

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of pregnancy. Calves are singularly dependent on ingesting maternal IgG in colostrum to

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provide them with protection against environmental pathogens until their own immune

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system matures 21. After this time, the major function of milk Igs in ruminants is a protective,

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developmental role in the intestinal lumen, as in humans 22.

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4. Glycosylation of sIgA

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The glycans (carbohydrates groups), attached to both the Fc and Fab regions of sIgA, play a

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key role in its protein structure and stability and ultimately its function 23-25. In humans (and

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higher primates) IgA has two isoforms; IgA1 and IgA2 which are produced in approximately

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equal amounts in human milk 26, 27. Most other species, including ruminants, have only one

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isoform that is similar to human IgA2 28, 29. There are differences in the glycosylation of the

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two isoforms. The hinge region of IgA1 is longer than that of IgA2, and has O- and N-

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glycosylation sites whereas IgA2 contains only N-glycosylation sites 30. Along the Fc portion

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of IgA2, there are a greater number of N-glycans compared with IgA1 30. SC is also heavily

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glycosylated, constituting between 15 and 24% of its whole molecular mass 31, with seven N-

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linked sites. In human milk, the presence and patterns of glycans on Igs vary with stage of

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lactation, with maternal genotype controlling expression of the glycosyl transferases 32.

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Glycosylation is important in the functional activities of sIgA and FSC. The diverse

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array of glycan epitopes are targets for lectins and bacterial adhesins 30. SC glycans can help

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anchor sIgA to the mucosal lining of the epithelium 33 where bacteria can be sequestered, thus

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increasing the bacterial binding capability of IgA 34. In addition, SC glycans non-specifically

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bind to Gram-positive commensal bacteria 24 as well as reducing virulence of Vibrio cholera



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(Gram-negative) so preventing pathogenic biofilm formation 35. FSC derived from milk has

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been shown to act as a non-specific microbial scavenger reducing the effects of Clostridium

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difficile toxins 36, inflammatory cytokine IL-8 37 and preventing adhesion of bacteria 38, 39 via

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interactions with its glycans 31. A recent study comparing the N-glycome of human and

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bovine milk observed species-specific variations in the glycan repertoire 40, however, the

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significance of these differences with regard to function has yet to be determined.

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Termed immune exclusion, the binding of IgA to microbes and microbial metabolic products

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and toxins, promotes bacterial aggregation, entrapment in mucus, and clearance from the

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gastrointestinal tract 41. SIgA purified from human milk has been shown to have a similar

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non-specific ‘exclusion’ function to that of intestinal derived sIgA. In a study using human

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buccal epithelial cells, sIgA from human colostrum inhibited adhesion of Escherichia coli

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(E.coli), a major agent of sepsis and meningitis in newborns 42. Adhesion of E.coli is often

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mediated by bacterial fimbriae which recognize specific receptors on the epithelial cells. The

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mechanism of inhibition in this instance was shown to involve specific interactions between

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sialyloligosaccharides on sIgA and the bacterial adhesins 43. Similarly bacterial toxins, such

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as the plant derived shiga-like toxin, ricin, have been shown to interact with human colostral

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sIgA 44.

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5. sIgA and immune exclusion

Human milk sIgA also protects infants from specific pathogens (reviewed by Liu et al

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2013 45) via Fab epitopes. The Fab region of sIgA (Figure 1) interacts specifically with

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enteric toxins and pathogens that in turn impede the processes of early infection. Protection

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of infants against infections, including Vibrio cholera 46, Campylobacter jejuni 47, Shigella

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species 48, enterotoxigenic E.coli (ETEC) 49 and Giardia lamblia 50, relate to the specific sIgA

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content in human milk. In addition, human and animal studies have demonstrated that

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delivery of specific sIgA antibodies directly to mucosal surfaces can prevent, diminish or


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cure bacterial infections including Campylobacter jejuni 51, and Clostridium difficile 52

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(reviewed by Corthesy 2003 53.

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sIgA may also have a direct impact on the ability of microbial pathogens to secrete

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virulence factors required for invasion of intestinal epithelial cells. For example, Shigella

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flexneri usually enters intestinal epithelial cells via a type 3 secretion (T3S) system, however,

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when sIgA antibodies specific to the O-antigen of Shigella flexneri are present, entry is

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prevented 54. These data suggest milk-derived sIgA may have potential as an antidiarrheal

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agent for at risk populations. People with low IgA levels have been shown to have increased

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risk of inflammatory disorders of the gut 55. It is possible dietary supplementation with milk

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derived sIgA could reduce these inflammatory processes.

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Bacteria do not always exist singularly, but form complex structures called biofilms. A

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biofilm is defined as an aggregate of microorganisms that self-produce a matrix of

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extracellular polymeric substance (EPS), containing polysaccharides, proteins and DNA 56.

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There are two types of biofilms described in the literature: those where the biofilm matrix is

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produced by the bacteria themselves and those where the colonising bacteria depend to a

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lesser or greater extent on the host organism providing the extracellular matrix. Host

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supported biofilms can be utilized by the resident microbes for support and nutrition 57-59. In

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turn the biofilm and its residents provide a barrier against other invading pathogens, and

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provide metabolites which are of use to the host 57-59. This is of benefit if the colonising

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bacteria are commensals; however, 60-80% of human microbial infections are caused by

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pathogenic bacteria growing in biofilms. These ‘protected’ bacterial colonies are

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exceptionally resistant to environmental stresses, especially antibiotics 60 and this poses a

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major public health problem 61. In a recent study, specific IgA antibodies, produced in

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response to an anti- caries vaccine against Streptococcus mutans, were shown to inhibit the

6. Biofilms and sIgA



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formation of pathogenic bacterial biofilm formation in the mouth, by preventing the initial

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adherence , the first stage of biofilm formation 62, 63. This suggests another application for

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sIgA-based functional food products.

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7. sIgA and immune inclusion

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Seemingly at odds with the previous section, human sIgA can also facilitate biofilm

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formation 64. The hydrophilic glycosylated regions of sIgA allow the molecule to associate

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with both adhesins and lectin-like receptors expressed by the bacteria as well as the mucus

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lining on the mucosal surface 65. Microorganisms bound by sIgA are thereby more readily

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entrapped by the mucus 33 and this has been demonstrated in in vitro studies 66, 67.

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Furthermore, the glycans of sIgA facilitate adhesion of bacteria to both the gut epithelium

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and mucins 66, 68.

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Whilst the length of human gastrointestinal tract is populated with bacteria, the

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principle areas of permanent bacterial colonization are in the terminal ileum and the large

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intestine. This is primarily because of the passing of gastric acid and rapid food transit

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through the stomach and small intestine 69. Transit slows in the large bowel enabling

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ecosystems to develop 70 and bacteria can live freely, in microcolonies (biofilms) or on

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surfaces of particulate matter (food) 71. Milk derived sIgA could also play a role in promoting

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commensal biofilm formation. Studies have shown that sIgA from human milk can transit

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intact through the infant gut as it and be recovered from infant feces with retained activity 10.

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The presence of SC protects sIgA against proteolytic degradation 7, 8. Thus there is potential

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for milk derived sIgA to act in a prebiotic manner, aiding colonization of probiotic bacteria in

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the gut.

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8. IgA versus IgG

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There are a plethora of immune products that are based on the functionality and content of

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IgG from mammalian milk. IgG antibodies act by fixing complement, opsonizing and


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agglutinating bacteria and neutralizing toxins and viruses. All these functions include

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inflammatory processes. In contrast, IgA antibodies are less inflammatory acting by

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agglutinating antigens, neutralizing bacterial toxins and viruses and preventing the adhesion

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of enteropathogenic bacteria to mucosal epithelial cells 72. Compared to IgG, sIgA has several

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advantageous capabilities. For example, it has greatly increased non-specific bacterial

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binding capacity via its glycosylated regions 34. It has greater stability against proteolytic

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degradation 7-9 helping sIgA retain its activity for prolonged periods in hostile environments,

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such as the gut lumen 10. The anti-inflammatory profile of sIgA makes it attractive for

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development as a functional food product that may benefit sufferers of intestinal

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inflammatory disorders. However, the amount of IgA required to give a health benefit is an

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important question that has not been adequately answered to date. Data on naturally occurring

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mucosal IgA titre range are also lacking. These questions will need to be addressed to

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evaluate the feasibility of IgA enriched foods.

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9. Effects of Food Processing on Igs

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Milk is processed at industrial scale into a wide range of consumer products, including liquid

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milks, yoghurts, cheeses, ice cream, milk powders. As with all manufactured food products,

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consumer safety is of paramount importance. For milk products this is assured primarily

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through the use of heat treatments, with various temperature and time combinations

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prescribed to inactivate the spoilage and pathogenic bacteria in raw milk 73. Milk is also

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subjected to heating during other processing operations for example, separation, thermal

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evaporation and spray drying, depending on the product being manufactured.

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However, immunoglobulins are among the more thermo-labile milk proteins.

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Exposure to processing operations involving heat, pressure or pH change can affect the

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conformation of these proteins and ultimately their antibody activity (reviewed in Hurley et

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al 74). Indeed, the exclusion of colostrum from dairy processing plants as part of regular milk



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supply is, in part, based on the high proportion of Igs and their different physicochemical

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properties such as lower stability to heat compared with the major milk proteins.

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Denaturation of these heat-sensitive proteins during thermal processes can result in

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aggregation, precipitation and consequent fouling of equipment, particularly of heat

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exchangers, limiting processing run times and increasing cleaning frequencies 75 . Using

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lower temperatures and longer retention times is an effective way of improving quality of

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human heat-treated milk 75, whilst high pressure processing has been used for human breast

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milk with apparent minimal effect on IgA 76. Methods aiming to identify markers of heat

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damage to milk products have been investigated77 Other alternative methods, that retain

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bioactivity of milk whilst meeting product safety requirements, are being developed. This

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will create an opportunity for the manufacture of bovine bioactive sIgA-enriched milk.

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In summary, the role of IgA in mucosal homeostasis could be exploited using bovine milk-

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derived sIgA. Glycobiology, an emerging area of immunology, may reveal new opportunities

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for heavily glycated proteins such as sIgA, for application in novel functional food products.

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Recent developments in extraction and processing techniques, to retain functionality, will

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help realize the opportunity for the untapped resource of sIgA in bovine milk. A key question

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to address is the amount of IgA required to observe functional health benefit. This is not

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known and needs to be better defined in order to evaluate the feasibility of sIgA in functional

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products. Potential applications for sIgA have been illustrated throughout this review but

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understanding how exogenous bovine sIgA could benefit the gastrointestinal environment to

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provide health benefits to the consumer, is an area waiting to be further explored.

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Tables Table 1: Comparison of the amount of the various classes of immunoglobulins in serum and mammary secretions for humans and cows Species

Ig

Concentration (g/l)

Human

IgG IgA IgM

Serum 12.10 2.50 0.93

Cowb

IgG1 IgG2 IgA IgM

11.20 9.20 0.37 3.05

a

% of total Ig

Colostrum 0.43 17.35 1.59

Milk 0.04 1.00 0.10

Serum 78.0 16.0 6.0

Colostrum 2.0 90.0 8.0

46.40 2.87 5.36 6.77

0.58 0.06 0.08 0.09

47.0 38.6 1.6 12.8

75.5 4.7 8.8 11.0

Ig – immunoglobulin a (Butler 1974) b (Butler 1983)


Milk 3.0 87.0 10.0 71.6 7.4 9.9 11.1

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Figure Captions Figure 1

A schematic representation of the structure of sIgA showing the heavy and light

chains, the antigen binding sites (Fab), effector (Fc) regions, the hinge region and glycosylation sites (glycans). Secretory component binds the dimerised IgA molecule, composed of two monomeric IgA molecules, that are joined by the J chain. Diagram adapted from Woof and Russell 78.



Figure 1


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For Table of Contents only


Immunoglobulin A in Bovine Milk: A Potential Functional Food

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