The effects of milk proteins on immunity: Mechanisms and implications RJJ van Neerven FrieslandCampina Research, Wageningen, The Netherlands Cellbiology and Immunology Group, Wageningen University, Wageningen, the Netherlands

Milk is a natural, complete food full of functional components It has two main functions: promoting development & growth and protection against infections

Paul Ehrlich: Transfer of immunity by milk Maternal immunization of animals and subsequent breastfeeding protected suckling mice against the toxins abrin and ricin (1892) Transfer of immunity by milk Paul Ehrlich ( ) Quote from : Kauffmann Nature Immunol 2008

Transfer of immunity by milk: factors involved Verhasselt, Mucosal Immunology 2010 Most of these factors are also present in cow’s milk !

Effects of farming on allergy development: Evidence from multiple epidemiological studies Effect on asthma, rhinitis and wheezing Effect of stable and animal exposure Effect of milk consumption Effect of heating of raw milk

Protective effect of exposure to milk and stables on development of allergy Riedler et al Lancet 2001

Epidemiological studies on the effect of farm milk consumption on allergies Adapted from von Mutius and Vercelli Nat. Rev. Immunol 2011

Heating status and milk protein levels are linked to the protective effect of farm milk on asthma Loss et al J Allergy Clin Immunol, 2011

Raw milk consumption is associated with fewer upper airway infections in early life -1 Pasture study: A prospective birth cohort of 1100 children in 5 countries * Statistically significant Loss et al JACI in press Reference group for milk types is UHT Shop milk.

Raw milk consumption is associated with fewer upper airway infections in early life -2 Pasture study: A prospective birth cohort of 1100 children in 5 countries Loss et al JACI in press Reference group for milk types is UHT Shop milk. * Statistically significant

Binding of bovine IgG to human airway pathogens

Specificity of bovine immunoglobulins: Agglutination of pathogenic bacteria

Human serum IgG (IV Ig) and bovine milk IgG (bIg) bind to human RSV and influenza Den Hartog et al Submitted IV Ig bIg

Bovine IgG can prevent in vitro infection of human cells by human RSV Concentration Ig (log(ug/ml)) Inhibition RSV (%) Den Hartog et al Submitted Therapeutic Ab Human serum Ig Bovine milk Ig

Functions of immunoglobulins Binding to bacteria, viruses and allergens Igs neutralise pathogens Igs induce phagocytosis and killing of pathogens Igs induce and enhance immune responses +

Bovine IgG promotes phagocytosis of pathogens by human MoDC Den Hartog et al Submitted

How can raw milk consumption protect against respiratory infection and allergy ? Adapted from van Neerven et al JACI 2012

RSV infections are linked to otitis and asthma

Acknowledgements WUR CBI: Huub Savelkoul Gerco den Hartog FrieslandCampina Laurien Ulfman Anouk Feitsma Elise van de Weg- Schrijver Talitha Eshuis Andre Groeneveld Margrethe Jonkman Rolf Bos UMCU/WKZ Jeanette Leusen Gerco den Hartog University Munich Erika von Mutius Georg Loss Marcus Ege WUR HMI Nico Taverne Jerry Wells