Human Milk Blocks DC-SIGN-Pathogen Interaction via MUC1.

Nathalie Koning,Sabine F M Kessen,Prescilla V Jeurink,Leon M J Knippels,Johan Garssen,Yvette Van Kooyk,Ben J Appelmelk,J Patrick Van Der Voorn

doi:10.3389/fimmu.2015.00112

Abstract

Beneficial effects of breastfeeding are well-recognized and include both immediate neonatal protection against pathogens and long-term protection against allergies and autoimmune diseases. Although several proteins have been identified to have anti-viral or anti-bacterial effects like secretory IgA or lactoferrin, the mechanisms of immune modulation are not fully understood. Recent studies identified important beneficial effects of glycans in human milk, such as those expressed in oligosaccharides or on glycoproteins. Glycans are recognized by the carbohydrate receptors C-type lectins on dendritic cell (DC) and specific tissue macrophages, which exert important functions in immune modulation and immune homeostasis. A well-characterized C-type lectin is dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), which binds terminal fucose. The present study shows that in human milk, MUC1 is the major milk glycoprotein that binds to the lectin domain of DC-SIGN and prevents pathogen interaction through the presence of Lewis x-type oligosaccharides. Surprisingly, this was specific for human milk, as formula, bovine or camel milk did not show any presence of proteins that interacted with DC-SIGN. The expression of DC-SIGN is found in young infants along the entire gastrointestinal tract. Our data thus suggest the importance of human milk glycoproteins for blocking pathogen interaction to DC in young children. Moreover, a potential benefit of human milk later in life in shaping the infants immune system through DC-SIGN cannot be ruled out.

Highlights

Inflammatory diseases like allergies and autoimmune diseases are increasing in the Western world
HUMAN MILK BINDS dendritic cell (DC)-SIGN ON DCs To establish the presence of dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) binding glycoproteins in human milk, interaction of human milk with DCs was tested in a cell adhesion assay
We show how the heavily glycosylated protein mucin 1 (MUC1) in human milk prevents pathogen interaction via Lewis x interaction with DC-SIGN, which is expressed on DCs throughout the gastrointestinal tract of young infants

Summary

Introduction

Inflammatory diseases like allergies and autoimmune diseases are increasing in the Western world. These disorders are associated with a disturbed immune balance, feeding the necessity to unravel mechanisms of immune tolerance induction, early in life. It is known that breastfeeding has beneficial effects for infants at young age, for example, by strongly reducing the mortality rate from infections by common pathogens. Milk components were identified as possible immune modulators. The major milk protein lactoferrin is well known for its anti-viral and anti-bactericidal activity [5], and similar effects have been described for lysozyme [6]. Other immunologically interesting components of human milk include growth hormones, cytokines, and glycans

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