nutrients Review The Breast Milk Immunoglobulinome Karla Rio-Aige 1,2 , Ignasi Azagra-Boronat 1,2 , Margarida Castell 1,2 , Marta Selma-Royo 3 , María Carmen Collado 3 , María J. Rodríguez-Lagunas 1,2 and Francisco J. Pérez-Cano 1,2, *   Citation: Rio-Aige, K.; Azagra- Boronat, I.; Castell, M.; Selma-Royo, M.; Collado, M.C.; Rodríguez- Lagunas, M.J.; Pérez-Cano, F.J. The Breast Milk Immunoglobulinome. Nutrients 2021, 13, 1810. https:// doi.org/10.3390/nu13061810 Academic Editor: Paola Roggero Received: 2 May 2021 Accepted: 23 May 2021 Published: 26 May 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Physiology Section, Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Science, University of Barcelona (UB), 08028 Barcelona, Spain; rioaigekarla@ub.edu (K.R.-A.); ignasiazagra@ub.edu (I.A.-B.); margaridacastell@ub.edu (M.C.); mjrodriguez@ub.edu (M.J.R.-L.) 2 Nutrition and Food Safety Research Institute (INSA-UB), 08921 Santa Coloma de Gramenet, Spain 3 Institute of Agrochemistry and Food Technology-National Research Council (IATA-CSIC), 46890 Paterna, Valencia, Spain; mselma@iata.csic.es (M.S.-R.); mcolam@iata.csic.es (M.C.C.) * Correspondence: franciscoperez@ub.edu; Tel.: +34-934-024-505 Abstract: Breast milk components contribute to the infant’s immune development and protection, and among other immune factors, immunoglobulins (Igs) are the most studied. The presence of IgA in milk has been known for a long time; however, less information is available about the presence of other Igs such as IgM, IgG, and their subtypes (IgG1, IgG2, IgG3, and IgG4) or even IgE or IgD. The total Ig concentration and profile will change during the course of lactation; however, there is a great variability among studies due to several variables that limit establishing a clear pattern. In this context, the aim of this review was firstly to shed light on the Ig concentration in breast milk based on scientific evidence and secondly to study the main factors contributing to such variability. A search strategy provided only 75 studies with the prespecified eligibility criteria. The concentrations and proportions found have been established based on the intrinsic factors of the study—such as the sampling time and quantification technique—as well as participant-dependent factors, such as lifestyle and environment. All these factors contribute to the variability of the immunoglobulinome described in the literature and should be carefully addressed for further well-designed studies and data interpretation. Keywords: immunoglobulin; IgA; breast milk; immunoglobulinome 1. Introduction 1.1. Breast Milk: A Source of Immunomodulatory Components Breast milk is the biological fluid produced by the mother’s breasts of mammalians in order to nourish infants and also to confer on them protection from disease until their own immune system matures [1]. Accordingly, the World Health Organization (WHO) recommends exclusive breastfeeding for the first 6 months of life, followed by continued breastfeeding with adequate complementary foods for up to 2 years or beyond, as mutually desired by mother and infant [2]. Breast milk has been tailored during human evolution to meet the demands of the infant. Its composition varies within feeds, during the day, and between mothers [3]. Interindividual variability has been attributed to genetic variation, maternal adiposity, and nutrition, among other factors [4–6]. The composition of human milk is dynamic and changes throughout lactation. The first form of milk produced by the mammary glands during the first 2–4 days after delivery is colostrum, which is produced in low volumes (300–400 mL/day) and has higher levels of protein and lower levels of carbohydrates and fat content than mature breast milk. Moreover, colostrum is richer in immunological components, such as immunoglobulins (Igs), lactoferrin, leucocytes, and oligosaccharides, suggesting that its primary functions are immunological rather than nutritional [3,7]. From days 4–5 after delivery, colostrum changes to transition milk, which is characterized by a higher yield (500–800 mL/day) and by lower protein and Ig Nutrients 2021, 13, 1810. https://doi.org/10.3390/nu13061810 https://www.mdpi.com/journal/nutrients