Pearay L. Ogra

In Vivo Effects of Bifidobacteria and Lactoferrin on Gut Endotoxin Concentration and Mucosal Immunity in Balb/c Mice

The aim of the present study was to examine the effects of oral supplementation of newborn Balb/c mice with bifidobacteria (B. infantis, B. bifidum) and iron-free apo-lactoferrin (bovine, human) on gut endotoxin concentration and mucosal immunity. Endotoxin concentration was measured in ileocecal filtrates at 7, 14, 21, and 28 days postdelivery by a quantitative limulus amebocyte lysate test. While endotoxin levels in bifidobacteria-fed mice showed a steady rise over time, they were consistently lower than that observed in control animals. Results of lactoferrin supplementation varied depending on the specific time point, but overall by day 28, all treatment groups showed lower intestinal endotoxin concentrations compared to saline fed animals. Neither bifidobacteria nor lactoferrin stimulated an increase in B or T cells, or in cytokine production (IL-6, TNF-α, INF-γ), in Peyers patches as measured by flow cytometry. Bifidobacteria and lactoferrin were well tolerated as dietary supplements and showed promising potential to reduce gut endotoxin levels.

Immunologic and epidemiologic aspects of varicella infection acquired during infancy and early childhood.

The development of varicella zoster infection was studied in a population of infants under one year of age during three outbreaks of varicella in a semi-closed domiciliary institution for infants in Japan. Over a period of four years, many residents ranging in age from 27 days to 32 months were tested for cutaneous reactivity to VZV antigen, and VZV-specific antibody activity before, during, and after each outbreak of varicella. Of these, 85 subjects developed clinical varicella, with an overall attack rate of 100% for all susceptible subjects. All the infants under 2 months of age were infected following such exposure, despite the presence of pre-existing maternal antibody. The degree of cutaneous involvement appeared to be milder (less than 20 vesicles) in infants less than 2 months of age, and severe cutaneous disease (with over 300 eruptions or confluent rash) occurred more frequently in subjects 2 to 11 months of age. Pre-existing antibody did not prevent development of illness, or alter the degree of antibody or cellular immune response to subsequent infection. However, the peak cutaneous reactivity to VZV antigen after infection was found to be significantly lower in infants under 2 months of age.

Mucosal immunity: Some historical perspective on host-pathogen interactions and implications for mucosal vaccines

Historical perspectives are defined as synthesis of determining forces as inferred from past events. However, in reality, any historical overview is often fraught with biases underlying the inferences of the historian. History continues to be rewritten on the basis of emerging new facts or biases, and what is often perceived as authentic recorded past may not always be factual. As a result, such perspectives are often criticized for either ignoring or highlighting major or minor events or contributions, respectively, in the recorded history. While recognizing the outstanding contributions of many recent or contemporary investigators, this report is a modest effort to pay tribute largely to our earlier scientific ancestors. This reviewer accepts full responsibility for any errors in facts of past history and any perceived bias in the inclusion or exclusion of some important investigators and their contributions in the recent history of this still evolving field of human biology.

Ageing and its possible impact on mucosal immune responses.

The development, structural diversification, and functional maturation of mammalian immunologic repertoire at mucosal surfaces and the systemic lymphoid tissue is a remarkably dynamic and continuous process, which begins in early fetal life and eventually culminates in variable degree of senescence or cellular death with advancing age. This brief overview will highlight the status of our current understanding of the ontogeny of mucosal immunologic response. The role of mucosal microflora and other environmental macromolecules in the regulation of mucosal immunity relative to the process of ageing will also be reviewed.

Effects of early environment on mucosal immunologic homeostasis, subsequent immune responses and disease outcome.

During the neonatal period, the mammalian host is exposed through mucosal surfaces for the first time to a plethora of environmental macromolecules and microbial agents. The neonatal mucosa is endowed with all major elements of innate and adaptive immunologic repertoire. Rudimentary Peyer’s patches and mucosal lymphoid follicles expressing HLA-DR+ and CD4+ cells can be observed as early as 10-11 weeks of gestation. CD5+ and IgA+ B cells can be detected in Peyer’s patches by 16-18 weeks. CD7+ CD3+ T lymphocytes have been observed in fetal Peyer’s patches, epithelial surfaces as well as in the lamina propria. Interestingly, however, the early neonatal period is also characterized by a relative deficiency in antigen-presenting cell functions, altered cell-mediated immune responses, and a relative increase in apoptosis and eosinophilic responses. After birth, each human being may be colonized by over 100 trillion bacteria, representing over 500 bacterial species. The ratio of bacterial to human cells in a normal adult may exceed 10:1. The nature and the species of microflora acquired in the first few months of life is determined by many factors including, external environmental microflora, introduction of cow’s milk, use of antibiotics and immunomodulatory agents, and use of breastfeeding. Recent Investigations have shown that the nature of mucosal microflora acquired in early infancy determines the outcome of mucosal inflammation and the subsequent development of mucosal disease, autoimmunity and allergic disorders later in life. It appears that altered mucosal microflora in early childhood alters signaling reactions which determine T cell differentiation and/or the induction of tolerance. Reduced Th1 and increased Th2 cytokine expression in the respiratory tract associated with increased allergic disease has been correlated with reduced exposure to microbial agents associated with Th1 responses. In contrast, reduced exposure to helminthes in the gut associated with reduced Th2 expression appears to correlate well with dominant Th1 cytokine expression and inflammatory bowel disease. These observations suggest that the nature of interaction between the external environment and the mucosal tissues in the early neonatal period and infancy may be critical in directing and controlling the expression of disease-specific responses in later life.

Mucosal immunity and viral infections

The mucosal surfaces are the first portals of entry for most infectious agents, among which respiratory and intestinal viruses are of greatest epidemiological importance. To combat these infections, the immune system uses unspecific and specific mechanisms. Unspecific responses include the production of virus-induced cytokines, such as type 1 interferons and natural killer (NK) cell activity, while specific immune responses mainly depend on cytotoxic T cells, which are important especially in the early course of a viral infection, and on antibodies. At the mucosal sites, antiviral secretory IgA antibodies play a major role in clearing viral infections and preventing or modifying disease after re-exposure. Passive transfer of virus-specific antibodies has been used in experimental and clinical settings to prevent or treat viral mucosal infections. In the future, the development of new mucosal vaccines promises to have the strongest impact on the epidemiology of viral infections.

Chapter 5 – Human Milk*

Mother’s milk delivered naturally through breastfeeding has been the sole source of infant nutrition in mammalian species for millions of years. Since human beings learned to domesticate cattle about 10,000 years ago, nonhuman mammalian milk also has been used to supplement or replace maternal milk in the human infant. The development and widespread use of commercially prepared infant formula products have been phenomena of the 20th century and notably of the past 6 decades. Such products provide an alternative to breastfeeding that is useful in certain situations. Nonetheless, compelling evidence demonstrates that breastfeeding is an ideal source of infant nutrition whose use is associated with lower rates of postnatal infant mortality in the United States and in other parts of the world.1-3 Human milk helps to protect the infant against a wide variety of infections and to reduce the risk for allergic and autoimmune diseases, the risk of obesity and its complications, and the risk for certain types of neoplasms later in life, and it has been associated with slightly better performances on tests of cognitive development in some studies.3 For these reasons, the American Academy of Pediatrics (AAP) and the World Health Organization (WHO) recommend that in the absence of specific contraindications (see “Benefits and Risks of Human Milk”) healthy term infants should be exclusively breastfed or fed expressed breast milk beginning within the first hour after birth through 6 months of age and supported with breastfeeding until at least 1 year of age.1-3 This chapter reviews existing information on major aspects of the physiologic, nutritional, and bioactive components of human milk. Developmental Anatomy of the Mammary Gland

Beta-chemokines in nasal secretions of infants with respiratory syncytial virus-induced respiratory infections

Immune mechanisms are believed to contribute to the pathogenesis of bronchiolitis, but the nature of the critical pathways is unknown. The purpose of this study was to determine if quantities of the beta-chemokines macrophage inflammatory protein 1 alpha (MIP1α), eotaxin, and regulated on expression, normal T-cell expressed and secreted (RANTES) were different among infants with various forms of illness due to respiratory syncytial virus (RSV) infection. Samples of nasopharyngeal secretions (NPS) were obtained from 56 infants and children less than 13 months of age with either upper respiratory illness (URI) alone (n = 25) or lower respiratory tract illness (n = 31) due to RSV infection. Seventeen asymptomatic infants served as controls. Quantities of chemokines in secretions were compared between groups using the t-test after logarithmic transformation of data. Quantities of all three chemokines were increased at the time of RSV infection regardless of whether wheezing was present. However, concentration...

Chapter 83 – Clinical Aspects of Bronchial Reactivity and Cell–Virus Interaction

This chapter illustrates the clinical importance of virus-induced wheezing and airway hyperreactivity (referred to as infectious asthma ). It reviews the evidence that is in support of the role of the immune system in provoking these illnesses, and summarizes the experimental data on the inducible expression of epithelial cell cytokines by respiratory viruses. Respiratory syncytial virus (RSV), the most common etiologic agent worldwide to induce lower respiratory tract infections in infants and young children, is linked to the development of asthma, airway hyperresponsiveness, and sensitization to environmental allergens. Massive infiltration of mononuclear cells and activation of eosinophil and basophil leukocytes correlates with the severity of acute RSV disease in both human and animal models. Inflammatory cytokines and CC chemokines with discrete target-cell selectivity for eosinophils and Th2 cells are strongly induced to express in RSV-infected respiratory epithelium. The secretion of CC chemokines, including RANTES and eotaxin by respiratory epithelial cells, in combination with Th2-derived cytokines, is the central pathogenetic event in airway mucosa inflammation, sensitization to bystander antigens, and augmentation of allergen-induced Th2 cell recruitment.

Respiratory infections in infants on mechanical ventilation: The immune response as a diagnostic aid

A prospective study was undertaken in 41 newborn infants receiving artificial respiration for evaluation of the incidence of respiratory infections. Clinical and radiologic evidence of pneumonia was compared with the appearance of serum antibodies against antigens prepared from microorganisms isolated from bronchial aspirates, and with serum and bronchial immunoglobulin M values. A significant specific immune response was documented in 24% of the patients studied. The data indicate that by correlating the clinical and radiographic findings with specific antibodies and IgM antibody responses, it is possible to document a significant number of respiratory infections. One implication of this study is that subclinical infections may not be uncommon. The significance of the presence and changes in concentration of IgM in bronchial aspirate requires further study.