For breast-fed infants, human milk is a source of various nutrients (e.g., proteins, peptides, antibodies) and bioactive components that promote neonatal growth and protect infants from viral and bacterial infection. Moreover, in terms of infant nutrition and protection the functions of many human milk components are very different from those of blood and other biological fluids of healthy adults. For example, catalytic antibodies ("abzymes") with synthetic activities (protein, oligosaccharide, and lipid kinase activities) have been found in human breast milk that are absent in the blood of healthy people. Abzymes with hydrolyzing functions have been detected not only in milk, but also in the blood of patients with autoimmune diseases. Obviously, feeding newborns human milk has a very specific role and it is a unique aspect of mammalian nutrition. Ribonuclease and DNase autoantibodies or abzymes are found in milk and blood of lactating women, but not in blood sera of healthy men and nonpregnant woman. Here, we present the first evidence that human milk secretory IgA molecules (sIgA) can effectively hydrolyze ribooligonucleotides containing 23 different bases [(pN) 23 ribooligonucleotides] and 4 microRNAs: miR-9-5p, miR-219-2-3p, miR-137, and miR-219a-5p. Ribonuclease activity is an inherent property of sIgAs. We showed that 7 individual sIgAs hydrolyzed the ribooligonucleotides (pA) 23 , (pU) 23 , and (pC) 23 nonspecifically and with comparable efficiency, whereas hydrolysis of the 4 microRNAs by sIgAs was site-specific. Sites of hydrolysis of 4 microRNAs by IgG from blood of patients with schizophrenia have been previously identified. The sites of hydrolysis of 4 microRNAs by sIgA-abzymes were very different from the previously identified sites of hydrolysis by IgG in patients with schizophrenia. In addition, in contrast to IgG, milk sIgAs efficiently hydrolyzed microRNAs in their loop and duplex regions.
Human milk provides neonates with various components that ensure newborns’ growth, including protection from bacterial and viral infections. In neonates, the biological functions of many breast milk components can be very different compared with their functions in the body fluids of healthy adults. Catalytic antibodies-abzymes hydrolyzing peptides, proteins, DNAs, RNAs, and oligosaccharides were detected not only in the blood sera of autoimmune patients but also in human milk. Non-coding microRNAs (18–25 nucleotides) are intra- and extra-cellular molecules of different human fluids. MiRNAs possess many different biological functions, including regulating several hundred genes. Five of them: miR-148a-3p, miR-200c-3p, miR-378a-3p, miR-146b-5p and let-7f-5p were previously found in milk in increased concentrations. Here, we determined number of copies of these miRNAs in 1 mg of analyzed cells, lipid fractions, and plasmas of human milk samples. The relative amount of microRNA decreases in the following order: cells » lipid fraction > plasma. IgGs and sIgAs were isolated from milk plasma, and their activity in the hydrolysis of five microRNAs was compared. In general, sIgAs demonstrated higher miRNA-hydrolyzing activity than IgGs antibodies. The hydrolysis of five microRNAs by sIgAs and IgGs was site-specific. The relative activity of each microRNA hydrolysis was very dependent on the milk preparation. The correlation coefficients between the content of five RNAs in milk plasma and the relative activity of sIgAs than IgGs in their hydrolysis strongly depended on individual microRNA and changed from −0.01 to 0.80. Thus, it was shown that milk contains specific antibodies-abzymes hydrolyzing microRNAs specific for human milk.
Mother’s milk provides breast-fed infants with various nutrients, including peptides, proteins, DNA, RNA, antibodies, and other bioactive components promoting neonatal growth and protecting infants from viral and bacterial infection. The functions of many human milk components regarding the nutrition and protection of newborns may be very different compared to those of various biological fluids of healthy adults. For example, human milk contains catalytic antibodies (abzymes) with protein, lipid, and oligosaccharide kinase activities, which are absent in the biological fluids of healthy people and autoimmune patients. Obviously, the nutrition of infants with fresh breast milk is a special phenomenon having a very specific and important role. Here, we have shown that mother’s milk IgGs effectively split homo-(pN)23, and four miRNAs: miR-137, miR-219a-5p, miR-219-2-3p, and miR-9-5p. It was shown that ribonuclease activity is a unique property of milk IgGs. On average, individual IgGs hydrolyze (pA)23, (pU)23, and (pC)23 nonspecifically and with comparable efficiency, whereas the hydrolysis of four miRNAs is predominately site-specific. The specific sites of the hydrolysis of four miRNAs by IgGs from the blood of schizophrenic (SCZ) patients and secretory immunoglobulins A (sIgAs) from human milk were found earlier. The sites of the hydrolysis of four miRNAs by milk IgGs and sIgA-abzymes are almost the same, but are significantly different in comparison with those for SCZ IgGs. In addition, in contrast to the SCZ IgGs, milk IgGs and sIgAs efficiently hydrolyzed miRNAs in the duplex regions formed by their terminal sequences.
In the milk of healthy women, antibodies were found with different catalytic activities (abzymes), which are absent in the sera of other healthy people. Moreover, it was previously shown that DNase antibodies-abzymes of patients with autoimmune diseases are cytotoxic to cancer cells. In this work, it was first shown that IgG and secretory IgA (sIgA) do not possess embryotoxicity; they practically do not affect the development of fertilized eggs of sea urchins but demonstrate sperm toxicity. After addition to the eggs of sperm preincubated with IgG and sIgA, the number of unfertilized eggs was increased, in the case of sIgA 1.6-fold higher than that for IgG. The suppression of the growth of MCF-7 breast cancer cells by sIgA was 2.2 times more effective than with IgG antibodies. The relative enzymatic activity of milk sIgA was higher than IgG (-fold): 1.9 (DNase), 4.6 (amylase), 1.7 (peroxidase), 1.3 (protease), 3.7 [hydrolysis of poly(C)], 3.3 [hydrolysis of poly(U)], and 1.7 (oxidation of 3,3′-diaminobenzidine). One of the possible reasons for the observed difference between sIgA and IgG could be that all 6 catalytic activities of sIgA were, on average, 2.6 times higher than that for IgG. Correlation coefficients between all the relative 6 enzymatic activities of IgG and sIgA and their toxicity to sea urchin sperm and to cancer cells were calculated. Maximum correlation coefficients were observed for DNase (+0.71), protease (+0.64) activities for sIgA, as well as protease (+0.59) and RNase (+0.77) of IgG with their toxicity toward sperm. The correlation coefficients were also high between peroxidase activity (+0.85) of sIgA and poly(U) hydrolysis by IgG (+0.58) with their suppression of tumor cell growth. It has been suggested that the catalytic activities of abzymes may be important in the manifestation of their sperm toxicity and inhibition of cancer cell growth.
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