Skip to main content
Log in

Influence of breastfeeding versus formula feeding on lymphocyte subsets in infants at risk of coeliac disease: the PROFICEL study

  • Original Contribution
  • Published:
European Journal of Nutrition Aims and scope Submit manuscript

Abstract

Purpose

In addition to genetic risk, environmental factors might influence coeliac disease (CD) development. We sought to assess the effect of the interaction between milk-feeding practices and the HLA-DQ genotype on peripheral lymphocyte subsets and their activation markers in infants at familial risk for CD.

Methods

170 newborns were classified in 3 different genetic risk groups (high risk, HR; intermediate risk, IR; and low risk, LR) after DQB1 and DQA1 typing. Lymphocyte subsets were studied at the age of 4 months by flow cytometry analysis.

Results

79 infants were receiving exclusive breastfeeding (BF) and 91 partial breastfeeding or formula feeding (FF). Regarding genetic risk, 40 infants were classified in HR group, 75 in IR group and 55 in LR group. Two-way ANOVA did not show significant interactions between the type of milk feeding and genetic risk group on the lymphocyte subsets analysed. One-way ANOVA for milk-feeding practice alone showed that the percentage of CD4 + CD25+ cells was significantly higher in BF group than in FF group (BF, 10.92 ± 2.71; FF, 9.94 ± 2.96; p = 0.026), and absolute counts of CD4 + CD38+ cells were significantly higher in FF group than in BF group (FF, 2,881.23 ± 973.48; BF, 2,557.95 ± 977.06; p = 0.038). One-way ANOVA for genetic risk alone showed that absolute counts of NK cells were significantly higher in IR group than HR and LR groups (IR, 539.24 ± 340.63; HR, 405.01 ± 239.53; LR, 419.86 ± 262.85; p = 0.028).

Conclusion

Lymphocyte subset profiles in the early stages of life could be modulated by milk-feeding practices and genetic risk separately. Breastfeeding might have a positive immunomodulatory effect on lymphocyte subsets in infants at risk of CD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

Abbreviations

CD:

Coeliac disease

PCR-SPP:

Polymerase chain reaction-sequence-specific primers

HLA:

Human leucocyte antigen

Treg:

Regulatory T cells

NK:

Natural killer

LR:

Low genetic risk

IR:

Intermediate genetic risk

HR:

High genetic risk

BF:

Breastfeeding

FF:

Formula/mixture feeding

References

  1. Gianfrani C, Auricchio S, Troncone R (2005) Adaptive and innate immune responses in celiac disease. Immunol Lett 99(2):141–145. doi:10.1016/j.imlet.2005.02.017

    Article  CAS  Google Scholar 

  2. Dubois PC, van Heel DA (2008) Translational mini-review series on the immunogenetics of gut disease: immunogenetics of coeliac disease. Clin Exp Immunol 153(2):162–173. doi:10.1111/j.1365-2249.2008.03704.x

    Article  CAS  Google Scholar 

  3. Kagnoff MF (2007) Celiac disease: pathogenesis of a model immunogenetic disease. J Clin Invest 117(1):41–49. doi:10.1172/JCI30253

    Article  CAS  Google Scholar 

  4. Bourgey M, Calcagno G, Tinto N, Gennarelli D, Margaritte-Jeannin P, Greco L, Limongelli MG, Esposito O, Marano C, Troncone R, Spampanato A, Clerget-Darpoux F, Sacchetti L (2007) HLA related genetic risk for coeliac disease. Gut 56(8):1054–1059. doi:10.1136/gut.2006.108530

    Article  Google Scholar 

  5. Karell K, Louka AS, Moodie SJ, Ascher H, Clot F, Greco L, Ciclitira PJ, Sollid LM, Partanen J (2003) HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European genetics cluster on celiac disease. Hum Immunol 64(4):469–477

    Article  CAS  Google Scholar 

  6. Nova E, Pozo T, Sanz Y, Marcos A (2010) Dietary strategies of immunomodulation in infants at risk for celiac disease. Proc Nutr Soc 69(3):347–353. doi:10.1017/S0029665110001825

    Article  CAS  Google Scholar 

  7. Westerbeek EA, van den Berg A, Lafeber HN, Knol J, Fetter WP, van Elburg RM (2006) The intestinal bacterial colonisation in preterm infants: a review of the literature. Clin Nutr 25(3):361–368. doi:10.1016/j.clnu.2006.03.002

    Article  Google Scholar 

  8. Williams AM, Bland PW, Phillips AC, Turner S, Brooklyn T, Shaya G, Spicer RD, Probert CS (2004) Intestinal alpha beta T cells differentiate and rearrange antigen receptor genes in situ in the human infant. J Immunol 173(12):7190–7199

    CAS  Google Scholar 

  9. Niers L, Stasse-Wolthuis M, Rombouts FM, Rijkers GT (2007) Nutritional support for the infant’s immune system. Nutr Rev 65(8 Pt 1):347–360

    Article  Google Scholar 

  10. Martin R, Langa S, Reviriego C, Jiminez E, Marin ML, Xaus J, Fernandez L, Rodriguez JM (2003) Human milk is a source of lactic acid bacteria for the infant gut. J Pediatr 143(6):754–758. doi:10.1016/j.jpeds.2003.09.028

    Article  CAS  Google Scholar 

  11. Schack-Nielsen L, Michaelsen KF (2007) Advances in our understanding of the biology of human milk and its effects on the offspring. J Nutr 137(2):503S–510S

    CAS  Google Scholar 

  12. de Vries E, de Bruin-Versteeg S, Comans-Bitter WM, de Groot R, Hop WC, Boerma GJ, Lotgering FK, van Dongen JJ (2000) Longitudinal survey of lymphocyte subpopulations in the first year of life. Pediatr Res 47(4 Pt 1):528–537

    Article  Google Scholar 

  13. Comans-Bitter WM, de Groot R, van den Beemd R, Neijens HJ, Hop WC, Groeneveld K, Hooijkaas H, van Dongen JJ (1997) Immunophenotyping of blood lymphocytes in childhood. Reference values for lymphocyte subpopulations. J Pediatr 130(3):388–393

    Article  CAS  Google Scholar 

  14. Panaro A, Amati A, di Loreto M, Felle R, Ferrante M, Papadia AM, Porfido N, Gambatesa V, Dell’Osso A, Lucivero G (1991) Lymphocyte subpopulations in pediatric age. Definition of reference values by flow cytometry. Allergol Immunopathol Madr 19(3):109–112

    CAS  Google Scholar 

  15. Shearer WT, Rosenblatt HM, Gelman RS, Oyomopito R, Plaeger S, Stiehm ER, Wara DW, Douglas SD, Luzuriaga K, McFarland EJ, Yogev R, Rathore MH, Levy W, Graham BL, Spector SA (2003) Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol 112(5):973–980. doi:10.1016/j.jaci.2003.07.003

    Article  Google Scholar 

  16. Jackson DG, Bell JI (1990) Isolation of a cDNA encoding the human CD38 (T10) molecule, a cell surface glycoprotein with an unusual discontinuous pattern of expression during lymphocyte differentiation. J Immunol 144(7):2811–2815

    CAS  Google Scholar 

  17. Carver JD, Pimentel B, Wiener DA, Lowell NE, Barness LA (1991) Infant feeding effects on flow cytometric analysis of blood. J Clin Lab Anal 5(1):54–56

    Article  CAS  Google Scholar 

  18. Cummins AG, Eglinton BA, Gonzalez A, Roberton DM (1994) Immune activation during infancy in healthy humans. J Clin Immunol 14(2):107–115

    Article  CAS  Google Scholar 

  19. Hawkes JS, Neumann MA, Gibson RA (1999) The effect of breast feeding on lymphocyte subpopulations in healthy term infants at 6 months of age. Pediatr Res 45(5 Pt 1):648–651

    Article  CAS  Google Scholar 

  20. Jeppesen DL, Hasselbalch H, Lisse IM, Ersboll AK, Engelmann MD (2004) T-lymphocyte subsets, thymic size and breastfeeding in infancy. Pediatr Allergy Immunol 15(2):127–132. doi:10.1111/j.1399-3038.2004.00032.xPAI032

    Article  Google Scholar 

  21. Donat E, Planelles D, Capilla-Villanueva A, Montoro JA, Palau F, Ribes-Koninckx C (2009) Allelic distribution and the effect of haplotype combination for HLA type II loci in the celiac disease population of the Valencian community (Spain). Tissue Antigens 73(3):255–261. doi:10.1111/j.1399-0039.2008.01191.x

    Article  CAS  Google Scholar 

  22. Berrington JE, Barge D, Fenton AC, Cant AJ, Spickett GP (2005) Lymphocyte subsets in term and significantly preterm UK infants in the first year of life analysed by single platform flow cytometry. Clin Exp Immunol 140(2):289–292. doi:10.1111/j.1365-2249.2005.02767.x

    Article  CAS  Google Scholar 

  23. Peters U, Schneeweiss S, Trautwein EA, Erbersdobler HF (2001) A case-control study of the effect of infant feeding on celiac disease. Ann Nutr Metab 45(4):135–142

    Article  CAS  Google Scholar 

  24. Ivarsson A, Hernell O, Stenlund H, Persson LA (2002) Breast-feeding protects against celiac disease. Am J Clin Nutr 75(5):914–921

    CAS  Google Scholar 

  25. Branski D, Fasano A, Troncone R (2006) Latest developments in the pathogenesis and treatment of celiac disease. J Pediatr 149(3):295–300. doi:10.1016/j.jpeds.2006.06.003

    Article  Google Scholar 

  26. Kimpimaki T, Erkkola M, Korhonen S, Kupila A, Virtanen SM, Ilonen J, Simell O, Knip M (2001) Short-term exclusive breastfeeding predisposes young children with increased genetic risk of Type I diabetes to progressive beta-cell autoimmunity. Diabetologia 44(1):63–69

    Article  CAS  Google Scholar 

  27. McLoughlin RM, Calatroni A, Visness CM, Wallace PK, Cruikshank WW, Tuzova M, Ly NP, Ruiz-Perez B, Kattan M, Bloomberg GR, Lederman H, Gern JE, Gold DR (2011) Longitudinal relationship of early life immunomodulatory T cell phenotype and function to development of allergic sensitization in an urban cohort. Clin Exp Allergy J Br Soc Allergy Clin Immunol. doi:10.1111/j.1365-2222.2011.03882.x

    Google Scholar 

  28. Brugman S, Visser JT, Hillebrands JL, Bos NA, Rozing J (2009) Prolonged exclusive breastfeeding reduces autoimmune diabetes incidence and increases regulatory T-cell frequency in bio-breeding diabetes-prone rats. Diabetes Metab Res Rev 25(4):380–387. doi:10.1002/dmrr.953

    Article  CAS  Google Scholar 

  29. Mosconi E, Rekima A, Seitz-Polski B, Kanda A, Fleury S, Tissandie E, Monteiro R, Dombrowicz DD, Julia V, Glaichenhaus N, Verhasselt V (2010) Breast milk immune complexes are potent inducers of oral tolerance in neonates and prevent asthma development. Mucosal Immunol 3(5):461–474. doi:10.1038/mi.2010.23

    Article  CAS  Google Scholar 

  30. Lan RY, Ansari AA, Lian ZX, Gershwin ME (2005) Regulatory T cells: development, function and role in autoimmunity. Autoimmun Rev 4(6):351–363. doi:10.1016/j.autrev.2005.01.007

    Article  CAS  Google Scholar 

  31. Admyre C, Johansson SM, Qazi KR, Filen JJ, Lahesmaa R, Norman M, Neve EP, Scheynius A, Gabrielsson S (2007) Exosomes with immune modulatory features are present in human breast milk. J Immunol 179(3):1969–1978

    CAS  Google Scholar 

  32. Perez-Cano FJ, Dong H, Yaqoob P (2010) In vitro immunomodulatory activity of Lactobacillus fermentum CECT5716 and Lactobacillus salivarius CECT5713: two probiotic strains isolated from human breast milk. Immunobiology 215(12):996–1004. doi:10.1016/j.imbio.2010.01.004

    Article  CAS  Google Scholar 

  33. Zhou YJ, Gao J, Yang HM, Yuan XL, Chen TX, He ZJ (2010) The role of the lactadherin in promoting intestinal DCs development in vivo and vitro. Clin Dev Immunol 2010:357541. doi:10.1155/2010/357541

    Article  Google Scholar 

  34. Newburg DS, Peterson JA, Ruiz-Palacios GM, Matson DO, Morrow AL, Shults J, Guerrero ML, Chaturvedi P, Newburg SO, Scallan CD, Taylor MR, Ceriani RL, Pickering LK (1998) Role of human-milk lactadherin in protection against symptomatic rotavirus infection. Lancet 351(9110):1160–1164

    Article  CAS  Google Scholar 

  35. Newburg DS (1999) Human milk glycoconjugates that inhibit pathogens. Curr Med Chem 6(2):117–127

    CAS  Google Scholar 

  36. Peterson JA, Scallan CD, Ceriani RL, Hamosh M (2001) Structural and functional aspects of three major glycoproteins of the human milk fat globule membrane. Adv Exp Med Biol 501:179–187

    Article  CAS  Google Scholar 

  37. Kvistgaard AS, Pallesen LT, Arias CF, Lopez S, Petersen TE, Heegaard CW, Rasmussen JT (2004) Inhibitory effects of human and bovine milk constituents on rotavirus infections. J Dairy Sci 87(12):4088–4096. doi:10.3168/jds.S0022-0302(04)73551-1

    Article  CAS  Google Scholar 

  38. Stene LC, Honeyman MC, Hoffenberg EJ, Haas JE, Sokol RJ, Emery L, Taki I, Norris JM, Erlich HA, Eisenbarth GS, Rewers M (2006) Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Am J Gastroenterol 101(10):2333–2340. doi:10.1111/j.1572-0241.2006.00741.x

    Article  CAS  Google Scholar 

  39. Guandalini S (2007) The influence of gluten: weaning recommendations for healthy children and children at risk for celiac disease. Nestle Nutr Workshop Ser Pediatr Program 60:139–151. doi:10.1159/0000106366 (Discussion 151–135)

    Article  Google Scholar 

  40. Chirdo FG, Rumbo M, Anon MC, Fossati CA (1998) Presence of high levels of non-degraded gliadin in breast milk from healthy mothers. Scandinavian J Gastroenterol 33(11):1186–1192

    Article  CAS  Google Scholar 

  41. Rumbo M, Chirdo FG, Anon MC, Fossati CA (1998) Detection and characterization of antibodies specific to food antigens (gliadin, ovalbumin and beta-lactoglobulin) in human serum, saliva, colostrum and milk. Clin Exp Immunol 112(3):453–458

    Article  CAS  Google Scholar 

  42. Ozkan T, Ozeke T, Meral A (2000) Gliadin-specific IgA antibodies in breast milk. J Int Med Res 28(5):234–240

    CAS  Google Scholar 

  43. Hall MA, Norman PJ, Thiel B, Tiwari H, Peiffer A, Vaughan RW, Prescott S, Leppert M, Schork NJ, Lanchbury JS (2002) Quantitative trait loci on chromosomes 1, 2, 3, 4, 8, 9, 11, 12, and 18 control variation in levels of T and B lymphocyte subpopulations. Am J Hum Genet 70(5):1172–1182. doi:10.1086/340090

    Article  CAS  Google Scholar 

  44. Amadori A, Zamarchi R, De Silvestro G, Forza G, Cavatton G, Danieli GA, Clementi M, Chieco-Bianchi L (1995) Genetic control of the CD4/CD8 T-cell ratio in humans. Nat Med 1(12):1279–1283

    Article  CAS  Google Scholar 

  45. Clementi M, Forabosco P, Amadori A, Zamarchi R, De Silvestro G, Di Gianantonio E, Chieco-Bianchi L, Tenconi R (1999) CD4 and CD8 T lymphocyte inheritance. Evidence for major autosomal recessive genes. Hum Genet 105(4):337–342

    Article  CAS  Google Scholar 

  46. Puglisi F, Capuano P, Simone M, Verzillo F, Laurentaci C (1999) T-cell activity in HLA-associated autoimmune diseases. Panminerva Med 41(4):315–317

    CAS  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge the assistance of the statistician Dr. Laura Barrios in the statistical analysis. Supported by grants AGL2007-66126-C03-01/ALI, AGL2007-66126-C03-02/ALI and AGL2007-66126-C03-03/ALI, from the Spanish Ministry of Science and Innovation and grants 200570F0091 and 200570F0093 from CSIC. T. Pozo and G. de Palma were recipients of a personal grant from the JAE/I3P Program of CSIC (Spain).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Esther Nova.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pozo-Rubio, T., Capilla, A., Mujico, J.R. et al. Influence of breastfeeding versus formula feeding on lymphocyte subsets in infants at risk of coeliac disease: the PROFICEL study. Eur J Nutr 52, 637–646 (2013). https://doi.org/10.1007/s00394-012-0367-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00394-012-0367-8

Keywords

Navigation