Skip to main content
NCBI home page
Mediators of Inflammation logoLink to Mediators of Inflammation
. 1999;8(2):69–75. doi: 10.1080/09629359990559

Inhibitors of complement activity in human breast-milk: a proposed hypothesis of their physiological significance.

M O Ogundele 1
PMCID: PMC1781790  PMID: 10704143

Abstract

Several natural components abundant in the fluid phase of human breast-milk have been shown to be inhibitors of complement activation in vitro, particularly the classical pathway. These include lysozyme, lactoferrin, lactalbumin alpha and other ligand chelators, complement regulator proteins and other specific soluble inhibitors of complement activation. Their physiological significance probably resides in their ability to restrict in vivo complement activation to specialized (compartmentalized) sites on the cellular membrane structures in human milk, represented by the abundant surface area of the milk fat globule membranes. This would serve to prevent inflammatory-induced tissue damage of the delicate immature gastrointestinal tract of the newborn as well as the mammary gland itself. A number of recognized and potential inhibitors of complement activity in human milk and other biological fluids are hereby reviewed, with a proposal of their physiological significance.

Full Text

The Full Text of this article is available as a PDF (149.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ajusi J. D., Onyango F. E., Mutanda L. N., Wamola Bacteriology of unheated expressed breast milk stored at room temperature. East Afr Med J. 1989 Jun;66(6):381–387. [PubMed] [Google Scholar]
  2. Aramini J. M., Drakenberg T., Hiraoki T., Ke Y., Nitta K., Vogel H. J. Calcium-43 NMR studies of calcium-binding lysozymes and alpha-lactalbumins. Biochemistry. 1992 Jul 28;31(29):6761–6768. doi: 10.1021/bi00144a016. [DOI] [PubMed] [Google Scholar]
  3. Ballow M., Donshik P. C., Mendelson L. Complement proteins and C3 anaphylatoxin in the tears of patients with conjunctivitis. J Allergy Clin Immunol. 1985 Sep;76(3):473–476. doi: 10.1016/0091-6749(85)90729-8. [DOI] [PubMed] [Google Scholar]
  4. Ballow M., Fang F., Good R. A., Day N. K. Developmental aspects of complement components in the newborn. The presence of complement components and C3 proactivator (properdin factor B) in human colostrum. Clin Exp Immunol. 1974 Oct;18(2):257–266. [PMC free article] [PubMed] [Google Scholar]
  5. Barriga C., Pombero I., Duran J., Forner A., Cardesa J., Rodriguez A. B. Serum hemolytic and bactericidal activity in breast and formula-fed infants. Rev Esp Fisiol. 1995 Dec;51(4):213–218. [PubMed] [Google Scholar]
  6. Björkstén B., Burman L. G., De Château P., Fredrikzon B., Gothefors L., Hernell O. Collecting and banking human milk: to heat or not to heat? Br Med J. 1980 Sep 20;281(6243):765–769. doi: 10.1136/bmj.281.6243.765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cole F. S., Schneeberger E. E., Lichtenberg N. A., Colten H. R. Complement biosynthesis in human breast-milk macrophages and blood monocytes. Immunology. 1982 Jun;46(2):429–441. [PMC free article] [PubMed] [Google Scholar]
  8. Crago S. S., Prince S. J., Pretlow T. G., McGhee J. R., Mestecky J. Human colostral cells. I. Separation and characterization. Clin Exp Immunol. 1979 Dec;38(3):585–597. [PMC free article] [PubMed] [Google Scholar]
  9. France G. L., Marmer D. J., Steele R. W. Breast-feeding and Salmonella infection. Am J Dis Child. 1980 Feb;134(2):147–152. doi: 10.1001/archpedi.1980.02130140021007. [DOI] [PubMed] [Google Scholar]
  10. Franke W. W., Heid H. W., Grund C., Winter S., Freudenstein C., Schmid E., Jarasch E. D., Keenan T. W. Antibodies to the major insoluble milk fat globule membrane-associated protein: specific location in apical regions of lactating epithelial cells. J Cell Biol. 1981 Jun;89(3):485–494. doi: 10.1083/jcb.89.3.485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Goldman A. S., Goldblum R. M., Hanson L. A. Anti-inflammatory systems in human milk. Adv Exp Med Biol. 1990;262:69–76. doi: 10.1007/978-1-4613-0553-8_6. [DOI] [PubMed] [Google Scholar]
  12. Greenberg R., Groves M. L. Plasmin cleaves human beta-casein. Biochem Biophys Res Commun. 1984 Dec 14;125(2):463–468. doi: 10.1016/0006-291x(84)90563-1. [DOI] [PubMed] [Google Scholar]
  13. Götze O., Müller-Eberhard H. J. The alternative pathway of complement activation. Adv Immunol. 1976;24:1–35. doi: 10.1016/s0065-2776(08)60328-4. [DOI] [PubMed] [Google Scholar]
  14. Hakulinen J., Meri S. Shedding and enrichment of the glycolipid-anchored complement lysis inhibitor protectin (CD59) into milk fat globules. Immunology. 1995 Jul;85(3):495–501. [PMC free article] [PubMed] [Google Scholar]
  15. Iida K., Fujita T., Inai S., Sasaki M., Kato T. Complement fixing abilities of IgA myeloma proteins and their fragments: the activation of complement through the classical pathway. Immunochemistry. 1976 Sep;13(9):747–752. doi: 10.1016/0019-2791(76)90195-6. [DOI] [PubMed] [Google Scholar]
  16. Isaacs C. E., Kashyap S., Heird W. C., Thormar H. Antiviral and antibacterial lipids in human milk and infant formula feeds. Arch Dis Child. 1990 Aug;65(8):861–864. doi: 10.1136/adc.65.8.861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kijlstra A., Jeurissen S. H. Modulation of classical C3 convertase of complement by tear lactoferrin. Immunology. 1982 Oct;47(2):263–270. [PMC free article] [PubMed] [Google Scholar]
  18. Lavine M., Clark R. M. Changing patterns of free fatty acids in breast milk during storage. J Pediatr Gastroenterol Nutr. 1987 Sep-Oct;6(5):769–774. doi: 10.1097/00005176-198709000-00019. [DOI] [PubMed] [Google Scholar]
  19. Lewis-Jones D. I., Lewis-Jones M. S., Connolly R. C., Lloyd D. C., West C. R. Sequential changes in the antimicrobial protein concentrations in human milk during lactation and its relevance to banked human milk. Pediatr Res. 1985 Jun;19(6):561–565. doi: 10.1203/00006450-198506000-00012. [DOI] [PubMed] [Google Scholar]
  20. Long K. E., Yomtovian R., Kida M., Knez J. J., Medof M. E. Time-dependent loss of surface complement regulatory activity during storage of donor blood. Transfusion. 1993 Apr;33(4):294–300. doi: 10.1046/j.1537-2995.1993.33493242635.x. [DOI] [PubMed] [Google Scholar]
  21. Loos M. The classical complement pathway: mechanism of activation of the first component by antigen-antibody complexes. Prog Allergy. 1982;30:135–192. [PubMed] [Google Scholar]
  22. McClelland D. B., McGrath J., Samson R. R. Antimicrobial factors in human milk. Studies of concentration and transfer to the infant during the early stages of lactation. Acta Paediatr Scand Suppl. 1978;(271):1–20. [PubMed] [Google Scholar]
  23. Medof M. E., Walter E. I., Rutgers J. L., Knowles D. M., Nussenzweig V. Identification of the complement decay-accelerating factor (DAF) on epithelium and glandular cells and in body fluids. J Exp Med. 1987 Mar 1;165(3):848–864. doi: 10.1084/jem.165.3.848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Minta J. O., Jezyk P. D., Lepow I. H. Distribution and levels of properdin in human body fluids. Clin Immunol Immunopathol. 1976 Jan;5(1):84–90. doi: 10.1016/0090-1229(76)90152-5. [DOI] [PubMed] [Google Scholar]
  25. Morgan E. L., Thoman M. L., Hoeprich P. D., Hugli T. E. Bioactive complement fragments in immunoregulation. Immunol Lett. 1985;9(4):207–213. doi: 10.1016/0165-2478(85)90034-3. [DOI] [PubMed] [Google Scholar]
  26. Nikolova E. B., Tomana M., Russell M. W. All forms of human IgA antibodies bound to antigen interfere with complement (C3) fixation induced by IgG or by antigen alone. Scand J Immunol. 1994 Mar;39(3):275–280. doi: 10.1111/j.1365-3083.1994.tb03371.x. [DOI] [PubMed] [Google Scholar]
  27. Ogundele M. O. A novel anti-inflammatory activity of lysozyme: modulation of serum complement activation. Mediators Inflamm. 1998;7(5):363–365. doi: 10.1080/09629359890893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Okamoto U., Horie N., Nagamatsu Y., Yamamoto J. I. Plasminogen-activator in human early milk: its partial purification and characterization. Thromb Haemost. 1981 Apr 30;45(2):121–126. [PubMed] [Google Scholar]
  29. Prentice A., Prentice A. M., Lamb W. H. Mastitis in rural Gambian mothers and the protection of the breast by milk antimicrobial factors. Trans R Soc Trop Med Hyg. 1985;79(1):90–95. doi: 10.1016/0035-9203(85)90245-7. [DOI] [PubMed] [Google Scholar]
  30. Rainard P., Poutrel B., Caffin J. P. Assessment of hemolytic and bactericidal complement activities in normal and mastitic bovine milk. J Dairy Sci. 1984 Mar;67(3):614–619. doi: 10.3168/jds.S0022-0302(84)81346-6. [DOI] [PubMed] [Google Scholar]
  31. Rainard P., Poutrel B. Deposition of complement components on Streptococcus agalactiae in bovine milk in the absence of inflammation. Infect Immun. 1995 Sep;63(9):3422–3427. doi: 10.1128/iai.63.9.3422-3427.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Reiter B., Brock J. H. Inhibition of Escherichia coli by bovine colostrum and post-colostral milk. I. Complement-mediated bactericidal activity of antibodies to a serum susceptible strain of E. coli of the serotype O 111. Immunology. 1975 Jan;28(1):71–82. [PMC free article] [PubMed] [Google Scholar]
  33. Russell M. W., Mansa B. Complement-fixing properties of human IgA antibodies. Alternative pathway complement activation by plastic-bound, but not specific antigen-bound, IgA. Scand J Immunol. 1989 Aug;30(2):175–183. doi: 10.1111/j.1365-3083.1989.tb01199.x. [DOI] [PubMed] [Google Scholar]
  34. Russell M. W., Reinholdt J., Kilian M. Anti-inflammatory activity of human IgA antibodies and their Fab alpha fragments: inhibition of IgG-mediated complement activation. Eur J Immunol. 1989 Dec;19(12):2243–2249. doi: 10.1002/eji.1830191210. [DOI] [PubMed] [Google Scholar]
  35. Sack R. A., Underwood A., Tan K. O., Morris C. Vitronectin in human tears--protection against closed eye induced inflammatory damage. Adv Exp Med Biol. 1994;350:345–349. doi: 10.1007/978-1-4615-2417-5_59. [DOI] [PubMed] [Google Scholar]
  36. Schroten H., Hanisch F. G., Plogmann R., Hacker J., Uhlenbruck G., Nobis-Bosch R., Wahn V. Inhibition of adhesion of S-fimbriated Escherichia coli to buccal epithelial cells by human milk fat globule membrane components: a novel aspect of the protective function of mucins in the nonimmunoglobulin fraction. Infect Immun. 1992 Jul;60(7):2893–2899. doi: 10.1128/iai.60.7.2893-2899.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Schroten H., Uhlenbruck G., Hanisch F. G., van Mil A. Unterschiedliche Phagozytoserate menschlicher Blutmonozyten und Muttermilchmakrophagen: Einfluss von Intralipid und Milchfettkügelchen. Monatsschr Kinderheilkd. 1987 Jan;135(1):36–40. [PubMed] [Google Scholar]
  38. Veerhuis R., Kijlstra A. Inhibition of hemolytic complement activity by lactoferrin in tears. Exp Eye Res. 1982 Feb;34(2):257–265. doi: 10.1016/0014-4835(82)90059-8. [DOI] [PubMed] [Google Scholar]
  39. Welsch U., Schumacher U., Buchheim W., Schinko I., Jenness P., Patton S. Histochemical and biochemical observations on milk-fat-globule membranes from several mammalian species. Acta Histochem Suppl. 1990;40:59–64. [PubMed] [Google Scholar]

Articles from Mediators of Inflammation are provided here courtesy of Wiley

RESOURCES