Immunology & Immunological Disorders Poster Session
Discussion and Conclusion
MFGM is known to possess peculiar adhesive properties. Previous studies have confirmed the ability of MFGM to aggregate and bind to fimbriated strains of certain pathogenic bacteria (37). Similar binding capacities are presently also implicated for activated Cp components. The studies furter suggest the contribution of Cp products of activation in their bacterial-adhesive role. Though the nature of the structures and forces involved are not fully known, the peculiar glycocalyx filaments of human MFGM (8) might be involved.
The ability of MFGM to bind activated Cp products, and thereby enhance its sequestration of bacteria on the surface, has been observed. The requirement of intact MFGM for the sequestration of bacteria as well as its binding and activation of Cp proteins are probably closely related. Previous studies with cow's milk have shown that at least C1q was deposited on certain unidentified milk components in preference to solid-phase killed bacteria (32). This might also be the explanation for the deposition of less C3 fragments on bacteria by clarified milk samples, compared to whole-milk, when diluted in the same buffer. It is therefore postulated that the MFGM bind to the native Cp components, and in the presence of bound particulate antigens, such as bacteria, with or without the presence of specific antibodies, support the activation of the Cp reaction cascade, via the classical and alternative pathways respectively. The resulting activated Cp fragments remaining bound to the MFGM, in turn adhere to other antigens in suspension, thereby enhancing the sequestration of these antigens by MFGM.
Furthermore, the experiments with the deposition of activated C3 fragments solid-phase bacteria have shown that the binding of these fragments to the MFGM could be reversed by the detergent buffer (PBS-Tw), leading to increased measurable levels of these molecules deposited on bacteria by whole-milk diluted in PBS-Tw compared to that in PBS, GVB++ or Mg++EGTA (Table 1).
Possible mechanisms for the interaction between native and split Cp components and the MFGM might include surface binding by physicochemical forces. This could involve either non-covalent hydrostatic interactions between polycationic proteins, such as C3a and C5a (15), or highly amphiphilic proteins such as C3b and terminal complement complexes-C5b-9 (TCC), or through the attachment to specific receptors, such as C3R or C5aR. C3 fragments have the ability to bind to membrane surfaces in the vicinity of ongoing complement activation, and thereby promote opsonization of particulate antigens and the generation of further C3/C5 convertase enzymes (17). While polycationic molecules like C5a, could have bound more avidly to one of the glycoprotein components of the MFGM, C3 fragments might have been bound to the lipid fraction of the membranes.
It is further proposed that the MFGM might serve an indispensable role in the physiological activation of HBM complement in-vivo. It might represent the major site on which the Cp is activated and comes into contact with particulate antigens either in the mammary gland or in the intestines of the suckling infant. The presence of such a wide variety of potent inhibitors of Cp activity in the fluid phase of human breast-milk, particularly of the classical pathway, which prevent the optimal activities of the Cp system, would be effectively by-passed, by the reaction taking place on the surface of the MFGM. The presence of protectin (CD59), a membrane surface Cp regulatory molecule, expressed on the MFGM, might suggest a physiological mechanism of protecting the MFGM in-vivo in the presence of ongoing antigen-induced Cp activation, without leading to a secondary damage of the MFGM.
These inhibitors of Cp activity identified in the HBM include Factor H (26), a cell-surface complement regulatory protein, Protectin or CD59 (19), some anti-microbial milk proteins, such as lactoferrin, (28) and IgA Fab fractions (36). Human alpha lactalbumin, lysozyme and low molecular-weight ligands, such as citrates and phosphates, having high affinity binding sites for calcium, acting as inhibitors of complement indirectly, by chelating the divalent ions required for complement activation (1). Moreover, properdin, a stabiliser of fluid-phase alternative pathway convertases, has been reported to be either absent in the HBM, or only present in minute quantities less than 1µg/ml (25). Most milk-borne macrophages are found to be laden with fat vacuoles which they have ingested in-vivo (5,38). A plausible explanation for this finding might lie in the fact that either C3 fragments or IgG having been deposited on the MFGM, have opsonized them and facilitated their phagocytosis by macrophages, together with their enclosed fat contents.
The ability of the MFGM to bind C3-opsonins, thereby enhancing its phagocytosis and ultimate degradation by phagocytes, might account for at least one of the mechanisms by which it is ultimately destroyed along the intestinal of the suckling infant. The adhesive role of MFGM in blocking the attachment of pathogenic organisms to the mucosal wall, presently discovered to be enhanced in the presence of activated Cp fragments, constitute one of the mechanisms by which HBM protect the nursing infants against gastro-intestinal and respiratory infections. This finding coupled with the observed capacity of the breast-milk Cp to be activated by a strain of one of the commonest neonatal pathogens, E. coli, not only in-vitro, but also in-vivo (as evidenced by presence of activated Cp products in fresh milk), suggest that the mutual interaction of these two breast-milk components, complement the anti-microbial functions of each other, for the benefit of the both the baby and the mother.
AREAS OF FURTHER RESEARCH
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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|