Randall M. Goldblum

Anti‐inflammatory Properties of Human Milk

ABSTRACT. An hypothesis was developed which predicts that human milk protects against infections of the alimentary tract of the breast‐fed infant by non‐inflammatory mechanisms. Human milk is poor in the initiators and mediators of inflammation and rich in anti‐inflammatory agents. Furthermore, many of the anti‐inflammatory agents are comparatively resistant to digestive enzymes and therefore might be expected to remain active in the gastrointestinal tract of the recipient. Further studies of these factors in in vivo models will be required to validate the hypothesis.

Environmental estrogens induce mast cell degranulation and enhance IgE-mediated release of allergic mediators

Background Prevalence and morbidity of allergic diseases have increased over the last decades. Based on the recently recognized differences in asthma prevalence between the sexes, we have examined the effect of endogenous estrogens on a key element of the allergic response. Some lipophilic pollutants have estrogen-like activities and are termed environmental estrogens. These pollutants tend to degrade slowly in the environment and to bioaccumulate and bioconcentrate in the food chain; they also have long biological half-lives. Objectives Our goal in this study was to identify possible pathogenic roles for environmental estrogens in the development of allergic diseases. Methods We screened a number of environmental estrogens for their ability to modulate the release of allergic mediators from mast cells. We incubated a human mast cell line and primary mast cell cultures derived from bone marrow of wild type and estrogen receptor α (ER-α )–deficient mice with environmental estrogens with and without estradiol or IgE and allergens. We assessed degranulation of mast cells by quantifying the release of β -hexosaminidase. Results All of the environmental estrogens tested caused rapid, dose-related release of β -hexosaminidase from mast cells and enhanced IgE-mediated release. The combination of physiologic concentrations of 17β -estradiol and several concentrations of environmental estrogens had additive effects on mast cell degranulation. Comparison of bone marrow mast cells from ER-α –sufficient and ER-α –deficient mice indicated that much of the effect of environmental estrogens was mediated by ER-α . Conclusions Our findings suggest that estrogenic environmental pollutants might promote allergic diseases by inducing and enhancing mast cell degranulation by physiologic estrogens and exposure to allergens.

Milk- and soy protein-induced enterocolitis: Evidence for lymphocyte sensitization to specific food proteins

Stimulation ( [3H]thymidine incorporation) of blood lymphocytes cultured with food proteins was evaluated in infants with food protein-induced enterocolitis and correlated with the results of oral diagnostic challenges with the same foods (soy, cows milk, and egg white). The geometric mean stimulation index for lymphocytes from patients with positive oral soy protein challenge that were cultured with soy protein was 8.5, and for patients with positive cows milk challenge the stimulation index was 6.0 when casein was used in the cultures. Both values are significantly different from the values obtained from patients with negative oral challenges (p less than 0.01). The enhanced lymphocyte responses were specific for the food proteins responsible for clinical symptoms. It is not clear whether these lymphocyte responses are due to systemic immunization secondary to macromolecular absorption, or to an abnormality in immune regulation such as a delay in the development of oral tolerance mechanisms. They suggest, however, that circulating lymphocytes sensitive to the food antigens that produce the clinical symptoms are frequent in infants with this discrete form of food protein hypersensitivity.

Maternal bisphenol a exposure promotes the development of experimental asthma in mouse pups

Background We recently reported that various environmental estrogens induce mast cell degranulation and enhance IgE-mediated release of allergic mediators in vitro. Objectives We hypothesized that environmental estrogens would enhance allergic sensitization as well as bronchial inflammation and responsiveness. To test this hypothesis, we exposed fetal and neonatal mice to the common environmental estrogen bisphenol A (BPA) via maternal loading and assessed the pups’ response to allergic sensitization and bronchial challenge. Methods Female BALB/c mice received 10 μg/mL BPA in their drinking water from 1 week before impregnation to the end of the study. Neonatal mice were given a single 5 μg intraperitoneal dose of ovalbumin (OVA) with aluminum hydroxide on postnatal day 4 and 3% OVA by nebulization for 10 min on days 13, 14, and 15. Forty-eight hours after the last nebulization, we assessed serum IgE antibodies to OVA by enzyme-linked immunosorbent assay (ELISA) and airway inflammation and hyperresponsiveness by enumerating eosinophils in bronchoalveolar lavage fluid, whole-body barometric plethysmography, and a forced oscillation technique. Results Neonates from BPA-exposed mothers responded to this “suboptimal” sensitization with higher serum IgE anti-OVA concentrations compared with those from unexposed mothers (p < 0.05), and eosinophilic inflammation in their airways was significantly greater. Airway responsiveness of the OVA-sensitized neonates from BPA-treated mothers was enhanced compared with those from unexposed mothers (p < 0.05). Conclusions Perinatal exposure to BPA enhances allergic sensitization and bronchial inflammation and responsiveness in a susceptible animal model of asthma.

Pathogenesis-related proteins of plants as allergens

OBJECTIVE Many pathogenesis-related (PR) proteins from plants are allergenic. We review the evidence that PR proteins represent an increasingly important group of plant-derived allergens. DATA SOURCES A detailed literature search was conducted through PubMed and GenBank databases. STUDY SELECTION All reports in PubMed and GenBank related to PR protein allergens for which at least partial amino acid sequence is known were included. RESULTS Production of PR proteins by plants is induced in plants by stress. Members of PR-protein groups 2, 3, 4, 5, 8, 10, and 14 have demonstrated allergenicity. PR2-, 3-, 4-, and 8-homologous allergens are represented by the latex allergens. Cross-reactivity of PR3 latex allergen, Hev b 6.02, with some fruit allergens may be a reflection of the representation of homologous PR proteins among varied plants. The expression of one of the representative PR5-homologous cedar pollen allergens, Jun a 3, is highly variable across years and geographic areas, possibly because of variable induction of this PR protein by environmental factors. PR10-homologous birch pollen allergen, Bet v 1, is structurally similar to and cross-reacts with PR10 proteins from fruits (eg, Mal d 1) which cause oral allergy syndrome. PR14 allergens (eg, Zea m 14) consist of lipid transfer proteins found in grains and fruits and are inducers of anaphylaxis. CONCLUSIONS PR-homologous allergens are pervasive in nature. Similarity in the amino acid sequences among members of PR proteins may be responsible for cross-reactivity among allergens from diverse plants. Induced expression of PR-homologous allergens by environmental factors may explain varying degrees of allergenicity. Man-made environmental pollutants may also alter the expression of some PR protein allergens.

Human milk feeding enhances the urinary excretion of immunologic factors in low birth weight infants

ABSTRACT: The effects of fortified human milk feedings on the urinary excretion of lactoferrin, lysozyme, secretory component, IgA, and secretory IgA antibodies to Escherichia coli O antigens were investigated in very low birth wt infants. Infants were maintained on either a human milk or a cows milk preparation. The amounts of each immune factor that were ingested and excreted were quantified during balance studies conducted at 2.5 and 5 wk of age. Serum levels of these immune factors were similar in both feeding groups. The urinary excretion of all factors except lysozyme was 7- to 150-fold greater in infants fed human milk than in those fed cows milk formula. IgA was the only factor for which the amount of the factor excreted correlated with the amount ingested. Fragments as well as whole molecules of lactoferrin were found in the urine of the infants fed human milk, but the molecular sizes of the excreted proteins exceeded those normally filtered by the kidneys. Therefore, the genesis of the enhanced levels of host defense factors in the urine of infants fed human milk is not clear. Gastrointestinal absorption and subsequent renal excretion as well as enhanced production of immune factors in the infants urinary tract are possible explanations.

Rapid high-temperature treatment of human milk*

Increasing interest in feeding human milk to low-birth-weight infants raises concern about microbial contamination of milk that is pooled or stored. We examined the effect of rapid high-temperature treatment on bacteria and viruses and on the nutritional and immunologic quality of pooled human milk. Growth of endogenous bacteria and infectivity of added cytomegalovirus were undetectable after heating at 72 degrees C for 15 and 5 seconds, respectively. Folic acid and vitamins B1, B2, B6, and C were not affected, whereas bile salt-stimulated lipase was inactivated by these conditions. The concentration of lactoferrin and secretory IgA, and SIgA antibody activity were not changed by heating at 72 degrees C. Lysozyme concentration and enzymatic activity were increased significantly by heat treatment, suggesting that this component may be largely sequestered in milk. Our findings suggest that rapid high-temperature treatment can reduce microbial contamination without destroying the unique nutritional and immunologic qualities of human milk.

Variable expression of pathogenesis-related protein allergen in mountain cedar (Juniperus ashei) pollen

Allergic diseases have been increasing in industrialized countries. The environment is thought to have both direct and indirect modulatory effects on disease pathogenesis, including alterating on the allergenicity of pollens. Certain plant proteins known as pathogenesis-related proteins appear to be up-regulated by certain environmental conditions, including pollutants, and some have emerged as important allergens. Thus, the prospect of environmentally regulated expression of plant-derived allergens becomes yet another potential environmental influence on allergic disease. We have identified a novel pathogenesis-related protein allergen, Jun a 3, from mountain cedar (Juniperus ashei) pollen. The serum IgE from patients with hypersensitivity to either mountain cedar or Japanese cedar were shown to bind to native and recombinant Jun a 3 in Western blot analysis and ELISA. Jun a 3 is homologous to members of the thaumatin-like pathogenesis-related (PR-5) plant protein family. The amounts of Jun a 3 extracted from mountain cedar pollen varied up to 5-fold in lots of pollen collected from the same region in different years and between different regions during the same year. Thus, Jun a 3 may contribute not only to the overall allergenicity of mountain cedar pollen, but variable levels of Jun a 3 may alter the allergenic potency of pollens produced under different environmental conditions.

Molecular forms of lactoferrin in stool and urine from infants fed human milk

ABSTRACT: The molecular forms of lactoferrin (LF) were examined in stools and urine collected at 2.5 or 5 wk of age from very low birth wt infants fed either a cows milk formula or a fortified human milk preparation. LF was not found by Western blotting in excreta from infants fed cows milk. In contrast, intact and fragmented forms of IF were detected in stools and concentrated urine of each infant who received human milk. Only intact LF was detected in the fortified human milk preparation, whereas many types of LF fragments were present in the stools and urine. The approximate molecular wt of the most prominent fragments were 44, 38, 34, and 32 kD. However, the stools also displayed lower molecular wt fragments that were not found in urines of those infants. The LF fragments in those excreta were similar in size to those produced in vitro by limited digestion of apo-LF with trypsin. Furthermore, fragments produced by in vitro proteolysis were immunoreactive in an ELISA for LF. Thus, the fragments of LF in stools of very low birth wt infants fed human milk appeared to be produced by in vivo proteolysis, and the close resemblance between the LF fragments in the stools and urine suggests that the urinary LF fragments originated in the gastrointestinal tract. It remains unclear, however, whether the whole LF molecules that were fragmented were derived solely from ingested LF in human milk or in part from LF produced by the infant in response to human milk feedings.

Food Protein-induced Enterocolitis: Altered Antibody Response to Ingested Antigen

Summary: To evaluate the role of immunologic mechanisms in one specific syndrome of food intolerance in infants, food protein-induced enterocolitis, we measured class-specific serum antibodies to three food proteins, ovalbumin, soy, and cow milk, prior to diagnostic food challenges in 18 infants suspected to have this syndrome. Infants with positive challenge reactions to egg, soy, or cow milk had 5–10 times higher levels of IgA antibody directed against that food than did the infants with negative challenges. Levels of IgG antibody to soy and egg were also significantly higher (greater than 10-fold) in infants with positive challenge responses. There was no significant difference in levels of IgM food antibodies between the two groups. IgA anti-soy antibody levels rose in all 12 infants tested 2–10 weeks after a single soy feeding (challenge). However, IgM anti-soy antibody increased in the five infants who had a negative response to the challenge feeding and decreased in those seven with a positive response. The difference between the two groups was statistically significant (P > 0.01). Some correlation existed (r = −0.68) between the increase in IgA anti-soy antibody and the decrease in IgM anti-soy antibody for infants with positive soy challenges. Although a pathogenic role for these antibodies is not proven, the findings suggest an altered immunologic response to ingestion of food antigens in infants with food protein-induced enterocolitis.