Innate and Adaptive Immune Components in Human Breast Milk and Their Role in Early-Life Immunity
Main Article Content
Human breast milk is a uniquely complex biological fluid renowned for delivering essential nutrients to newborns. Beyond its nutritional value, it also contains important immunological components that play a fundamental role in infant health and development. This review explores the immunological characteristics of breast milk, highlighting its diverse array of immune cells and bioactive molecules, including secretory IgA, cytokines, and chemokines. These components actively contribute to the maturation of the infant’s immune system, strengthen defenses against infections, and facilitate the development of a balanced gut microbiome. This discussion also explores how the immune components in breast milk function to benefit infants, examining their protective mechanisms and developmental impacts. Additionally, it addresses how storage conditions—such as freezing, refrigeration, or pasteurization—may alter the integrity and effectiveness of these vital immune factors. Furthermore, the influence of external environmental factors, including maternal diet, stress, and exposure to pollutants, is considered for their potential effects on the immunological quality of breast milk. For this literature review, relevant studies were systematically searched across multiple academic databases, including PubMed, ScienceDirect, Google Scholar, ResearchGate, and Elsevier. The search was limited to publications from the past ten years. Emerging research underscores the adaptive nature of breast milk and its profound impact on early-life immunity, offering valuable insights for optimizing infant feeding practices and potential clinical applications.
Keywords:
Breast Milk
Cytokine
Immune Cells
Innate
Adaptive
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2. Hatmal MM, Al-Hatamleh MAI, Olaimat AN, Alshaer W, Hasan H, Albakri KA, et al. Immunomodulatory Properties of Human Breast Milk: MicroRNA Contents and Potential Epigenetic Effects. Biomedicines. 2022;10(6):1219.
3. Boronat-Catalá M, Montiel-Company JM, Bellot-Arcís C, Almerich-Silla JM, Catalá-Pizarro M. Association between duration of breastfeeding and malocclusions in primary and mixed dentition: a systematic review and meta-analysis. Sci Rep. 2017;7(1):5048.
4. Belfort MB. The Science of Breastfeeding and Brain Development. Breastfeeding Medicine. 2017;12(8):459–61.
5. Quitadamo PA, Comegna L, Cristalli P. Anti-Infective, Anti-Inflammatory, and Immunomodulatory Properties of Breast Milk Factors for the Protection of Infants in the Pandemic From COVID-19. Front Public Health. 2021;8:589736.
6. Toscano M, De Grandi R, Grossi E, Drago L. Role of the Human Breast Milk-Associated Microbiota on the Newborns’ Immune System: A Mini Review. Front Microbiol. 2017;8:2100.
7. American Pregnancy Association. Breastfeeding Overview. American Pregnancy Association. 2022. Available from: https://americanpregnancy.org/healthy-pregnancy/breastfeeding/breastfeeding-overview/
8. Núñez-Delgado A, Mizrachi-Chávez VM, Welti-Chanes J, Macher-Quintana ST, Chuck-Hernández C. Breast milk preservation: thermal and non-thermal processes and their effect on microorganism inactivation and the content of bioactive and nutritional compounds. Front Nutr. 2024;10:1325863.
9. Yi DY, Kim SY. Human Breast Milk Composition and Function in Human Health: From Nutritional Components to Microbiome and MicroRNAs. Nutrients. 2021;13(9):3094.
10. Ballard O, Morrow AL. Human Milk Composition: Nutrients and Bioactive Factors. Pediatric Clinics. 2013;60(1):49–74.
11. Witkowska-Zimny M, Kaminska-El-Hassan E. Cells of human breast milk. Cell Mol Biol Lett. 2017;22(1):11.
12. Zheng Y, Corrêa-Silva S, de Souza EC, Maria Rodrigues R, da Fonseca FAM, Gilio AE, et al. Macrophage profile and homing into breast milk in response to ongoing respiratory infections in the nursing infant. Cytokine. 2020;129:155045.
13. Trend S, Jong E de, Lloyd ML, Kok CH, Richmond P, Doherty DA, et al. Leukocyte Populations in Human Preterm and Term Breast Milk Identified by Multicolour Flow Cytometry. PLOS ONE. 2015 Aug 19;10(8):e0135580.
14. Molès JP, Tuaillon E, Kankasa C, Bedin AS, Nagot N, Marchant A, et al. Breastmilk cell trafficking induces microchimerism-mediated immune system maturation in the infant. Pediatric Allergy and Immunology. 2018;29(2):133–43.
15. Khudri G, Sukmawati D, Barasila A, Suryandari D. Association between Macrophage’s Cell Number and Maternal Factors in Human Milk. Makara Journal of Science. 2024;28(2):7.
16. Lokossou GAG, Kouakanou L, Schumacher A, Zenclussen AC. Human Breast Milk: From Food to Active Immune Response With Disease Protection in Infants and Mothers. Front Immunol. 2022;13:849012.
17. Twigger AJ, Küffer GK, Geddes DT, Filgueria L. Expression of Granulisyn, Perforin and Granzymes in Human Milk over Lactation and in the Case of Maternal Infection. Nutrients. 2018;10(9):1230.
18. Mezu-Ndubuisi OJ, Maheshwari A. Role of macrophages in fetal development and perinatal disorders. Pediatr Res. 2021;90(3):513–23.
19. Zhang F, Xia Y, Su J, Quan F, Zhou H, Li Q, et al. Neutrophil diversity and function in health and disease. Sig Transduct Target Ther. 2024;9(1):343.
20. Yu JC, Khodadadi H, Malik A, Davidson B, Salles É da SL, Bhatia J, et al. Innate Immunity of Neonates and Infants. Front Immunol. 2018;9:1759.
21. Dixon DL, Forsyth KD. Leukocytes in expressed breast milk of asthmatic mothers. Allergologia et Immunopathologia. 2017;45(4):325–32.
22. Hassiotou F, Geddes DT. Immune Cell–Mediated Protection of the Mammary Gland and the Infant during Breastfeeding. Advances in Nutrition. 2015;6(3):267–75.
23. Marischen L, Englert A, Schmitt AL, Einsele H, Loeffler J. Human NK cells adapt their immune response towards increasing multiplicities of infection of Aspergillus fumigatus. BMC Immunol. 2018;19(1):39.
24. Li S, Zhang L, Zhou Q, Jiang S, Yang Y, Cao Y. Characterization of Stem Cells and Immune Cells in Preterm and Term Mother’s Milk. J Hum Lact. 2019;35(3):528–34.
25. Fernández L, Langa S, Martín V, Maldonado A, Jiménez E, Martín R, et al. The human milk microbiota: Origin and potential roles in health and disease. Pharmacological Research. 2013;69(1):1–10.
26. Caba-Flores MD, de la Soledad Lagunes-Castro M, López-Monteon A, Viveros-Contreras R, Kuri JGN, Huerta-Morales D, et al. Analysis of the presence of natural killer cell subpopulations in preterm human milk: A first approach. Journal of Reproductive Immunology. 2024;166:104394.
27. Pighi C, Rotili A, De Luca M, Chiurchiù S, Calò Carducci FI, Rossetti C, et al. Characterization of Natural Killer Cell Profile in a Cohort of Infected Pregnant Women and Their Babies and Its Relation to CMV Transmission. Viruses. 2024;16(5):780.
28. Demers-Mathieu V, Underwood MA, Beverly RL, Nielsen SD, Dallas DC. Comparison of Human Milk Immunoglobulin Survival during Gastric Digestion between Preterm and Term Infants. Nutrients. 2018;10(5):631.
29. Henrick BM, Yao XD, Nasser L, Roozrogousheh A, Rosenthal KL. Breastfeeding Behaviors and the Innate Immune System of Human Milk: Working Together to Protect Infants against Inflammation, HIV-1, and Other Infections. Front Immunol. 2017;8:1631.
30. Pedersen SH, Wilkinson AL, Andreasen A, Kinung’hi SM, Urassa M, Michael D, et al. Longitudinal analysis of mature breastmilk and serum immune composition among mixed HIV-status mothers and their infants. Clinical Nutrition. 2016;35(4):871–9.
31. Moylan DC, Pati SK, Ross SA, Fowler KB, Boppana SB, Sabbaj S. Breast Milk Human Cytomegalovirus (CMV) Viral Load and the Establishment of Breast Milk CMV-pp65-Specific CD8 T Cells in Human CMV Infected Mothers. The Journal of Infectious Diseases. 2017;216(9):1176–9.
32. MacGillivray DM, Kollmann TR. The Role of Environmental Factors in Modulating Immune Responses in Early Life. Front Immunol. 2014;5:434.
33. Wood H, Acharjee A, Pearce H, Quraishi MN, Powell R, Rossiter A, et al. Breastfeeding promotes early neonatal regulatory T-cell expansion and immune tolerance of non-inherited maternal antigens. Allergy. 2021;76(8):2447–60.
34. Cérbulo-Vázquez A, Hernández-Peláez G, Arriaga-Pizano LA, Bautista-Pérez P, Romero-Venado J, Flores-González JC, et al. Characterization of CD127− CD25++ Treg from human colostrum. American Journal of Reproductive Immunology. 2018;79(2):e12806.
35. Parigi SM, Eldh M, Larssen P, Gabrielsson S, Villablanca EJ. Breast Milk and Solid Food Shaping Intestinal Immunity. Front Immunol. 2015;6:415.
36. Moossavi S, Azad MB. Origins of human milk microbiota: new evidence and arising questions. Gut Microbes. 2020 Nov 9;12(1):1667722.
37. Collado MC, Santaella M, Mira-Pascual L, Martínez-Arias E, Khodayar-Pardo P, Ros G, et al. Longitudinal Study of Cytokine Expression, Lipid Profile and Neuronal Growth Factors in Human Breast Milk from Term and Preterm Deliveries. Nutrients. 2015 Oct;7(10):8577–91.
38. Vass RA, Kemeny A, Dergez T, Ertl T, Reglodi D, Jungling A, et al. Distribution of bioactive factors in human milk samples. Int Breastfeed J. 2019 Feb 11;14(1):9.
39. Centre for Disease Control and Prevention. Breast Milk Storage and Preparation. CDC. 2024. Available from: https://www.cdc.gov/breastfeeding/breast-milk-preparation-and-storage/handling-breastmilk.html
40. Eglash A, Simon L, The Academy of Breastfeeding Medicine. ABM Clinical Protocol #8: Human Milk Storage Information for Home Use for Full-Term Infants, Revised 2017. Breastfeeding Medicine. 2017;12(7):390–5.
41. Demers-Mathieu V, Huston RK, Dallas DC. Cytokine Expression by Human Macrophage-Like Cells Derived from the Monocytic Cell Line THP-1 Differs between Treatment with Milk from Preterm- and Term-Delivering Mothers and Pasteurized Donor Milk. Molecules. 2020;25(10):2376.
42. Putri DK, Syaidah R, Jusuf AA. The Effects of Different Storage Conditions on Leukocytes in Human Breast Milk. Sultan Qaboos Univ Med J. 2024;24(1):91–8.
2. Hatmal MM, Al-Hatamleh MAI, Olaimat AN, Alshaer W, Hasan H, Albakri KA, et al. Immunomodulatory Properties of Human Breast Milk: MicroRNA Contents and Potential Epigenetic Effects. Biomedicines. 2022;10(6):1219.
3. Boronat-Catalá M, Montiel-Company JM, Bellot-Arcís C, Almerich-Silla JM, Catalá-Pizarro M. Association between duration of breastfeeding and malocclusions in primary and mixed dentition: a systematic review and meta-analysis. Sci Rep. 2017;7(1):5048.
4. Belfort MB. The Science of Breastfeeding and Brain Development. Breastfeeding Medicine. 2017;12(8):459–61.
5. Quitadamo PA, Comegna L, Cristalli P. Anti-Infective, Anti-Inflammatory, and Immunomodulatory Properties of Breast Milk Factors for the Protection of Infants in the Pandemic From COVID-19. Front Public Health. 2021;8:589736.
6. Toscano M, De Grandi R, Grossi E, Drago L. Role of the Human Breast Milk-Associated Microbiota on the Newborns’ Immune System: A Mini Review. Front Microbiol. 2017;8:2100.
7. American Pregnancy Association. Breastfeeding Overview. American Pregnancy Association. 2022. Available from: https://americanpregnancy.org/healthy-pregnancy/breastfeeding/breastfeeding-overview/
8. Núñez-Delgado A, Mizrachi-Chávez VM, Welti-Chanes J, Macher-Quintana ST, Chuck-Hernández C. Breast milk preservation: thermal and non-thermal processes and their effect on microorganism inactivation and the content of bioactive and nutritional compounds. Front Nutr. 2024;10:1325863.
9. Yi DY, Kim SY. Human Breast Milk Composition and Function in Human Health: From Nutritional Components to Microbiome and MicroRNAs. Nutrients. 2021;13(9):3094.
10. Ballard O, Morrow AL. Human Milk Composition: Nutrients and Bioactive Factors. Pediatric Clinics. 2013;60(1):49–74.
11. Witkowska-Zimny M, Kaminska-El-Hassan E. Cells of human breast milk. Cell Mol Biol Lett. 2017;22(1):11.
12. Zheng Y, Corrêa-Silva S, de Souza EC, Maria Rodrigues R, da Fonseca FAM, Gilio AE, et al. Macrophage profile and homing into breast milk in response to ongoing respiratory infections in the nursing infant. Cytokine. 2020;129:155045.
13. Trend S, Jong E de, Lloyd ML, Kok CH, Richmond P, Doherty DA, et al. Leukocyte Populations in Human Preterm and Term Breast Milk Identified by Multicolour Flow Cytometry. PLOS ONE. 2015 Aug 19;10(8):e0135580.
14. Molès JP, Tuaillon E, Kankasa C, Bedin AS, Nagot N, Marchant A, et al. Breastmilk cell trafficking induces microchimerism-mediated immune system maturation in the infant. Pediatric Allergy and Immunology. 2018;29(2):133–43.
15. Khudri G, Sukmawati D, Barasila A, Suryandari D. Association between Macrophage’s Cell Number and Maternal Factors in Human Milk. Makara Journal of Science. 2024;28(2):7.
16. Lokossou GAG, Kouakanou L, Schumacher A, Zenclussen AC. Human Breast Milk: From Food to Active Immune Response With Disease Protection in Infants and Mothers. Front Immunol. 2022;13:849012.
17. Twigger AJ, Küffer GK, Geddes DT, Filgueria L. Expression of Granulisyn, Perforin and Granzymes in Human Milk over Lactation and in the Case of Maternal Infection. Nutrients. 2018;10(9):1230.
18. Mezu-Ndubuisi OJ, Maheshwari A. Role of macrophages in fetal development and perinatal disorders. Pediatr Res. 2021;90(3):513–23.
19. Zhang F, Xia Y, Su J, Quan F, Zhou H, Li Q, et al. Neutrophil diversity and function in health and disease. Sig Transduct Target Ther. 2024;9(1):343.
20. Yu JC, Khodadadi H, Malik A, Davidson B, Salles É da SL, Bhatia J, et al. Innate Immunity of Neonates and Infants. Front Immunol. 2018;9:1759.
21. Dixon DL, Forsyth KD. Leukocytes in expressed breast milk of asthmatic mothers. Allergologia et Immunopathologia. 2017;45(4):325–32.
22. Hassiotou F, Geddes DT. Immune Cell–Mediated Protection of the Mammary Gland and the Infant during Breastfeeding. Advances in Nutrition. 2015;6(3):267–75.
23. Marischen L, Englert A, Schmitt AL, Einsele H, Loeffler J. Human NK cells adapt their immune response towards increasing multiplicities of infection of Aspergillus fumigatus. BMC Immunol. 2018;19(1):39.
24. Li S, Zhang L, Zhou Q, Jiang S, Yang Y, Cao Y. Characterization of Stem Cells and Immune Cells in Preterm and Term Mother’s Milk. J Hum Lact. 2019;35(3):528–34.
25. Fernández L, Langa S, Martín V, Maldonado A, Jiménez E, Martín R, et al. The human milk microbiota: Origin and potential roles in health and disease. Pharmacological Research. 2013;69(1):1–10.
26. Caba-Flores MD, de la Soledad Lagunes-Castro M, López-Monteon A, Viveros-Contreras R, Kuri JGN, Huerta-Morales D, et al. Analysis of the presence of natural killer cell subpopulations in preterm human milk: A first approach. Journal of Reproductive Immunology. 2024;166:104394.
27. Pighi C, Rotili A, De Luca M, Chiurchiù S, Calò Carducci FI, Rossetti C, et al. Characterization of Natural Killer Cell Profile in a Cohort of Infected Pregnant Women and Their Babies and Its Relation to CMV Transmission. Viruses. 2024;16(5):780.
28. Demers-Mathieu V, Underwood MA, Beverly RL, Nielsen SD, Dallas DC. Comparison of Human Milk Immunoglobulin Survival during Gastric Digestion between Preterm and Term Infants. Nutrients. 2018;10(5):631.
29. Henrick BM, Yao XD, Nasser L, Roozrogousheh A, Rosenthal KL. Breastfeeding Behaviors and the Innate Immune System of Human Milk: Working Together to Protect Infants against Inflammation, HIV-1, and Other Infections. Front Immunol. 2017;8:1631.
30. Pedersen SH, Wilkinson AL, Andreasen A, Kinung’hi SM, Urassa M, Michael D, et al. Longitudinal analysis of mature breastmilk and serum immune composition among mixed HIV-status mothers and their infants. Clinical Nutrition. 2016;35(4):871–9.
31. Moylan DC, Pati SK, Ross SA, Fowler KB, Boppana SB, Sabbaj S. Breast Milk Human Cytomegalovirus (CMV) Viral Load and the Establishment of Breast Milk CMV-pp65-Specific CD8 T Cells in Human CMV Infected Mothers. The Journal of Infectious Diseases. 2017;216(9):1176–9.
32. MacGillivray DM, Kollmann TR. The Role of Environmental Factors in Modulating Immune Responses in Early Life. Front Immunol. 2014;5:434.
33. Wood H, Acharjee A, Pearce H, Quraishi MN, Powell R, Rossiter A, et al. Breastfeeding promotes early neonatal regulatory T-cell expansion and immune tolerance of non-inherited maternal antigens. Allergy. 2021;76(8):2447–60.
34. Cérbulo-Vázquez A, Hernández-Peláez G, Arriaga-Pizano LA, Bautista-Pérez P, Romero-Venado J, Flores-González JC, et al. Characterization of CD127− CD25++ Treg from human colostrum. American Journal of Reproductive Immunology. 2018;79(2):e12806.
35. Parigi SM, Eldh M, Larssen P, Gabrielsson S, Villablanca EJ. Breast Milk and Solid Food Shaping Intestinal Immunity. Front Immunol. 2015;6:415.
36. Moossavi S, Azad MB. Origins of human milk microbiota: new evidence and arising questions. Gut Microbes. 2020 Nov 9;12(1):1667722.
37. Collado MC, Santaella M, Mira-Pascual L, Martínez-Arias E, Khodayar-Pardo P, Ros G, et al. Longitudinal Study of Cytokine Expression, Lipid Profile and Neuronal Growth Factors in Human Breast Milk from Term and Preterm Deliveries. Nutrients. 2015 Oct;7(10):8577–91.
38. Vass RA, Kemeny A, Dergez T, Ertl T, Reglodi D, Jungling A, et al. Distribution of bioactive factors in human milk samples. Int Breastfeed J. 2019 Feb 11;14(1):9.
39. Centre for Disease Control and Prevention. Breast Milk Storage and Preparation. CDC. 2024. Available from: https://www.cdc.gov/breastfeeding/breast-milk-preparation-and-storage/handling-breastmilk.html
40. Eglash A, Simon L, The Academy of Breastfeeding Medicine. ABM Clinical Protocol #8: Human Milk Storage Information for Home Use for Full-Term Infants, Revised 2017. Breastfeeding Medicine. 2017;12(7):390–5.
41. Demers-Mathieu V, Huston RK, Dallas DC. Cytokine Expression by Human Macrophage-Like Cells Derived from the Monocytic Cell Line THP-1 Differs between Treatment with Milk from Preterm- and Term-Delivering Mothers and Pasteurized Donor Milk. Molecules. 2020;25(10):2376.
42. Putri DK, Syaidah R, Jusuf AA. The Effects of Different Storage Conditions on Leukocytes in Human Breast Milk. Sultan Qaboos Univ Med J. 2024;24(1):91–8.
