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New Insights into the Role of Milk Fat Globule Membrane in the Sequestration of Particulate Antigens: Interactions with the Complement System

Contact Person: Michael O. Ogundele (mogundel@yahoo.com)


Efforts have been directed in the past few years to identify various immune-active substances in the human breast-milk (HBM). These include specific anti-viral antibodies, anti-bacterial antibodies, non-specific IgG, IgA, IgM, lactoferrin, lysozyme, different cytokines, lymphocytes, polymorphonuclear leucocytes, and macrophages (2-5,7,9,11,18,20,22,29,31,35). Little is known about the role and contribution of the milk fat globule membrane (MFGM) in the protection of both the maternal mammary gland and the nursing infant. Though the exact peculiar histochemical and biochemical structures of the MFGM have been unravelled, in comparison to similar structures in the milk of other mammals, its physiological functions remain largely unresolved (39). The present observation of its interactions with the complement (Cp) system helps to clarify the central role of the MFGM in its contribution to the antibacterial effects of human breast-milk. It further highlights the significance of another hitherto underestimated host defence factor in HBM, the bactericidal effects of the Cp system. There is a conclusive body of evidence that breast-feeding protects the infant against a wide range of infectious and other diseases, especially in the developing world communities (12,21).

It has generally been argued that the Cp system activity in the breast-milk was insignificant because of the relatively low levels of most of the individual components, the presence of several anti-inflammatory systems and many other specific "anti-complementary" factors present in the breast-milk (16,19,26,28). While the mechanisms of its activation in the presence of such an overwhelmingly inhibitory environment, present studies have pointed out some pertinent physiological functions of the milk Cp, in relationship with the MFGM. Non-immune mechanisms of Cp activation have been demonstrated in the mucosal secretions of the lachrymal gland (3), suggesting that the inhibition of classical pathways of Cp activation at these mucosal sites could still be circumvented, to enable some of the physiological role of the Cp to be realised. Apart from the Cp and FFA, most of the available antimicrobial agents in HBM are bacteriostatic. Since bactericidal FFA are also present in the artificial formula feeds, and it does not seem to contribute to the protection of the formula-fed infants (20), the Cp system should therefore be regarded as a potentially source of significant contribution to the increased resistance of breast-fed infants against infection.

The serum Cp system consist of at least 19 proteins, mostly in pre-activated enzymatic forms, activated in a multi-step cascade reaction via either the classical or alternative pathways. The classical pathway is activated mainly by antigen-antibody complexes (IgG or IgM mostly) starting with C1q, C1r, C1s, C4 and C2, and eventually leading to the activation of C3 by cleavage into C3a and C3b (23). The alternative pathway (APC) utilizes active sites (such as are present on zymosan, yeast, cobra venom, most gram-negative bacteria, sheep erythrocytes and human cells deficient in the expression of membrane regulatory molecules) in the presence of properdin, serum factors B and D, to activate C3. This step unifies the two pathways and proceeds uniformly thereafter to the formation of (C5b-9) membrane attack complexes (MAC), capable of inserting into biological membranes and producing cell lysis and death. APC activating surfaces are characterized by possession of structures which restrict access to inhibitory factor H to deposited C3b, thereby amplifying the formation of further C3b in the presence of factor B (17).

HBM is a complex biological fluid consisting of up to 95% water suspension of diverse proteins, sugar and cellular elements i.e. macrophages, neutrophils, lymphocytes, as well as secretory and other epithelial cells (11). It contains 2-5% lipid fraction. The lipid fraction consists mainly of triglycerides enveloped in complete tri-laminar units of biological cell membranes, the milk fat globule membrane (MFGM) ranging from 4 to 20Ám in diameter. This membrane is derived from the apical region of the mammary gland epithelial cells and are budded off around the milk lipids as they are being secreted by the cells (13). The MFGM is similar to any other cell membrane of eukaryotic cells. It consists of (a) the proteinaceous coat innermost layer, (b) the biomembrane, and (c) the glycocalyx outer layer. The glycocalyx layer is rich in PAS-positive, highly negatively charged sialic acid-containing glycoproteins. Electron microscopic studies of the outer layer of the human MFGM has shown the presence of numerous thin filaments radially oriented around the membrane into the aqueous phase of milk, many of which appear branched. They are said to be absent from the MFGM of other mammals (39). However, their functions and physiological significance have not been clearly identified. It has been suggested that the filaments may protect the MFGM against degradation by milk proteases and in the digestive tract, and act to prevent the fusion of the globules to each other. Other proposed functions of the MFGM include transportation of milk lipid along the upper intestinal tract towards the site of enzymatic digestion in the stomach and small intesine, to prevent adhesion to the upper intestinal wall (8). The high molecular weight mucus components of MFGM have been implicated in preventing the adhesion of certain meningitis-causing bacterial strains in neonates to the buccal epithelial mucosa (37). The present study was conducted to examine further characteristics of the bacteria-adhesive role of the intact HBM fat globule membrane (MFGM) in relation to the activities of the Cp system in particular.

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Ogundele, M.O.; (1998). New Insights into the Role of Milk Fat Globule Membrane in the Sequestration of Particulate Antigens: Interactions with the Complement System. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Available at URL http://www.mcmaster.ca/inabis98/immunology/ogundele0176/index.html
© 1998 Author(s) Hold Copyright