Immune Cells Produce a Distinct Subset of Antibodies in Human Milk

Written by: Jyoti Madhusoodanan, Ph.D. | Issue # 117 | 2023

In response to antigens, immune cells known as B cells produce large amounts of antibodies that bind to foreign molecules either to neutralize them or to mark them for destruction by other cells. Circulating antibodies comprise 15 to 25 percent of all proteins in human serum and are also present in maternal milk where they confer immune protection early in life [1]. But precisely which antibodies enter human milk, and how they do so, has been a mystery. 

Different B cells synthesize a wide range of immunoglobulin, and—in theory—cells throughout the human body could produce 1016 to 1018 distinct kinds of antibodies. In reality, however, only a few hundred kinds of antibodies dominate the population, forming about 50 to 90 percent of circulating immunoglobulins both in serum and in human milk, according to a study by researchers at Utrecht University in the Netherlands [2].  

Antibodies that enter human milk must undergo additional processing so they can cross epithelial cell layers. To accomplish this, two or more immunoglobulin molecules are linked to each other via a joining (J-) chain. This linked up polymer binds to a receptor to be transported across layers of epithelial cells and is then cleaved to form the secretory form of the immunoglobulin. The researchers, led by analytic chemist Albert Heck, set out to learn whether one kind of immunoglobulin in serum and milk, known as IgA1, originated from the same cells. “IgAs play a very critical role in the early immune development of the infant,” said Kelly Dingess, a senior scientist at Danone Nutritional Research who co-authored the study [2]. 

In 2021, the team characterized the IgA1 antibodies present in the serum and milk of two healthy human donors at multiple time points over the first four months of lactation [2]. There was little variation in the immunoglobulins present in human milk over that time period. About 80 percent of secretory IgA1 molecules (sIgA1) present at 16 weeks of lactation were the same as those present in the first week. Although many of these immunoglobulins were similar across the serum and milk of a single donor, there were almost no antibodies common between the two donors. “Nobody produces the exact same antibodies as another person. This is really highly individual, specific, and unique,” Dingess said in an interview. “Also, all of the antibodies that we find in our blood are not necessarily the antibodies we find in milk either.”

In a subsequent study, the authors examined serum and human milk IgA1 to understand the similarities and differences between antibodies in these two fluids [3]. The team compared paired milk and serum samples from three healthy donors between the ages of 27 and 35 years. The samples were collected approximately once a month over a period of three months.  As before, the researchers found that there was little variation in the antibody profile of samples from a single donor over time, and almost no commonality amongst the IgA1 clones present in samples from different donors. 

The team identified approximately 370–400 IgA1 clones in serum, and approximately 600 sIgA1 clones in human milk. Overall, about 45 percent of the IgA1 molecules in serum were also detected in milk. 

Because the classical theory is that an antibody-producing B cell produces only one antibody, molecules common in milk and serum should both have the J-chain, which is necessary for antibodies to be transported into milk. The authors looked for dimers and other polymers of IgA antibodies both in serum and milk. They found that 83 percent of IgA in serum is present as monomers, and only 17 percent occurs in the dimeric J-chain linked form. But nearly half of IgA in milk was present in the dimer form. The team also reported that 33 percent was present as trimers and 17 percent in a tetramer form, with four IgA molecules linked to each other. Although these same IgA1 molecules bearing the J-chain were present in serum, they often existed in the monomeric or dimeric form, not the polymers detected in milk. “Typically, when people think of antibodies found in blood, they think of this very simple Y-like structure, whereas the antibodies found in milk can be highly complex,” Dingess said in the interview. 

Secretory IgAs in milk are important for training the infant immune system to protect against infections and in helping to establish the infant gut microbiome, Dingess added, and the secretory J-chain protects the antibody from being digested in the infant gut. “This becomes really important because we need those antibodies to survive the stomach and the gastrointestinal tract,” she said.

Identifying differences in the structures of immunoglobulins present in milk and serum is a crucial step toward understanding whether they also play different roles in protection against infections and in the development of a healthy gut microbiome. Although other components of milk, such as human milk oligosaccharides (HMOs), are typically thought to regulate the gut microbiome, IgA plays an important role as well, Dingess said. “Milk is a complex system,” she said. “It’s not any one thing that does something. All of these things that are really working together.” 

References

1. Gonzalez-Quintela A, Alende R, Gude FA, Campos J, Rey J, Meijide LM, Fernandez-Merino C, Vidal C. Serum levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with alcohol consumption, smoking and common metabolic abnormalities. Clinical & Experimental Immunology. 2008 Jan;151(1):42-50.
2. Bondt A, Dingess KA, Hoek M, van Rijswijck DM, Heck AJ. A direct MS-Based approach to profile human milk secretory immunoglobulin A (IgA1) reveals donor-specific clonal repertoires with high longitudinal stability. Frontiers in Immunology. 2021 Dec 6;12:789748.
3. Dingess KA, Hoek M, van Rijswijk DM, Tamara S, den Boer MA, Veth T, Damen MJ, Barendregt A, Romijn M, Juncker HG, van Keulen BJ. Identification of common and distinct origins of human serum and breastmilk IgA1 by mass spectrometry-based clonal profiling. Cellular & Molecular Immunology. 2023 Jan;20(1):26-37.

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