Maternal determinants of neonatal immune response to ovalbumin: effect of breast feeding on development of anti-ovalbumin antibody in the neonate

Inbred Brown-Norway female rats were immunized intraperitoneally with ovalbumin (OVA) or sham-immunized 14 days before and 10 days after mating. In subsequent studies with OVA, babies fed by immunized mothers, regardless of whether they were born from immunized or sham-immunized mothers, showed suppression of IgG, IgM and IgE anti-OVA responses. In additional studies, these babies developed OX-8-positive but W3/25-negative phenotypic suppressor T-cells specific for anti-OVA antibody production. However, these regulatory cells did not react with OVA itself when tested for in vitro proliferative response to OVA. Subsequent immunization of the neonates with OVA appeared to abrogate suppression of IgG and IgM antibody responses. However, maternally induced suppression of IgE persisted and was not influenced by subsequent immunization.     

Maternal aggression persists following lipopolysaccharide-induced activation of the immune system

Lactating females direct aggressive behaviors towards intruders presumably to reduce the likelihood of infanticide of their pups. Infected animals display a constellation of responses that include lethargy, anorexia, and decreased social interactions. This suite of responses is referred to as sickness behavior, and is putatively part of an adaptive strategy to aid the organism in recovery from infection. Previous work has suggested that animals can suppress the behavioral symptoms of sickness in order to engage in adaptive behaviors. To test whether adaptive nest defense is affected by illness, dams received a peripheral injection of either saline or lipopolysaccharide (LPS [50, 400, or 1000 microg/kg]), a non-replicating component of bacterial cell walls that activates the immune system. Simulated infection with LPS reduced body mass and food intake in dams and interfered with litter growth in a dose-dependent manner. Generally, nest defense was unaffected by LPS; the proportion of dams displaying maternal aggression against a male intruder, as well as the latency and duration of aggressive encounters were only suppressed at the highest LPS dose tested. Further, LPS treatment also altered non-agonistic behavior during the aggression test as indicated by reduced social investigation of the intruder and an increased time spent immobile during the session. LPS administration also significantly increased serum corticosterone concentrations in lactating females. These findings suggest that maternal aggression is not suppressed by LPS-evoked immune activation at doses that attenuate other aspects of maternal and social behavior.     

Maternal and neonatal drug resistance

The debatable article gives new evidence for the possibility, conditions, and resistance rate of the resistance to nevirapine, which results from its single use during labor for the prevention of vertical HIV transmission. The author analyzes the results of the 2009-2010 studies dealing with the use of high-sensitive methods for mutation detection, the impact of minor mutations on therapeutic effectiveness, and the evaluation of the effect of therapeutic support. She expressed the idea that it is expedient to test HIV for nevirapine resistance mutations in different periods after single administration of the drug as a prophylactic agent, the possible effects and algorithm of treatment if the above mutations are detected.     

Maternal stress and T-cell differentiation of the developing immune system: possible implications for the development of asthma and atopy

The constant increase in asthma and atopy prevalences--despite improved treatment and knowledge of many aspects of the diseases--has raised growing concern. Accumulating evidence suggests that these increases in atopic diseases are largely attributable to environmental and lifestyle factors, and the lack of systemic childhood infections has in many studies emerged as a major factor. In addition to current high standards of hygiene and the lack or scarcity of such infections, another factor characteristic of our present-day lives could be involved. This review briefly outlines the possibility that prolonged maternal stress associated with sustained excessive cortisol secretion could affect the developing immune system--especially T(H)1/T(H)2 cell differentiation--and further increase the susceptibility to asthma and atopy in genetically predisposed individuals. This hypothesis is critically evaluated in the light of current knowledge.     

Maternal immune transfer in mollusc

Maternal immunity refers to the immunity transferred from mother to offspring via egg, playing an important role in protecting the offspring at early life stages and contributing a trans-generational effect on offspring’s phenotype. Because fertilization is external in most of the molluscs, oocytes and early embryos are directly exposed to pathogens in the seawater, and thus maternal immunity could provide a better protection before full maturation of their immunological systems. Several innate immune factors including pattern recognition receptors (PRRs) like lectins, and immune effectors like lysozyme, lipopolysaccharide binding protein/bacterial permeability-increasing proteins (LBP/BPI) and antioxidant enzymes have been identified as maternally derived immune factors in mollusc eggs. Among these immune factors, some maternally derived lectins and antibacterial factors have been proved to endue mollusc eggs with effective defense ability against pathogen infection, while the roles of other factors still remain untested. The physiological condition of mollusc broodstock has a profound effect on their offspring fitness. Many other factors such as nutrients, pathogens, environment conditions and pollutants could exert considerable influence on the maternal transfer of immunity. The parent molluscs which have encountered an immune stimulation endow their offspring with a trans-generational immune capability to protect them against infections effectively. The knowledge on maternal transfer of immunity and the trans-generational immune effect could provide us with an ideal management strategy of mollusc broodstock to improve the immunity of offspring and to establish a disease-resistant family for a long-term improvement of cultured stocks.     

Maternal antibodies in human neonatal sera

Three hundred and sixty-three pairs of neonatal and maternal sera collected at delivery just after an influenza A2/Hongkong virus epidemic, were tested by complement fixation for influenza A2 antibodies. The results confirm an earlier suggestion. In this study the neonatal serum level of IgG class antibodies exceeded that of the mother in 109 of 329 cases, when the maternal value was low or normal, but in the case of a high maternal titre, the newborn had a higher titre than that of the mother in only four of thirty-four cases.     

Depletion of MCP-1 increases development of herpetic stromal keratitis by innate immune modulation

Chemokines are important chemoattractant inflammatory molecules, but their interdependent network in disease pathogenesis remains unclear. Studies in mouse models have shown that herpetic stromal keratitis (SK) is produced by the consequence of a tissue-destructive immunoinflammatory reaction involving herpes simplex virus type 1 (HSV) infection. Here we found that ocular HSV infection leads to increased expression of monocyte chemoattractant protein-1 (MCP-1), one of the major chemoattractants for immune cells that express CCR2, in the SK cornea. However, MCP-1 is unlikely to be a chemoattractant for infiltrating Gr-1(+), CD11b(+) cells in SK, as these cells are found to be CCR2 negative. Nevertheless, infection of MCP-1(-/-) mice resulted in more severe SK lesion severity compared with WT mice (P<0.01). We demonstrated that the loss of MCP-1 in the SK cornea caused a significant overexpression of macrophage inflammatory protein-2 (MIP-2) (P<0.01) on days 2 and 4 postinfection and increased infiltration of inflammatory cells (Gr-1-high and CD11b(+)) expressing CXCR2, a receptor for MIP-2, into the cornea. Subsequently, increased infiltration of inflammatory cells accelerated by MIP-2 overexpression might result in the high production of inflammatory molecules, including vascular endothelial growth factor (VEGF) and IL-1beta in SK, as well as CpG oligodeoxynucleotide (ODN)-implanted eyes of MCP-1(-/-) mice. These results indicate that MCP-1 in the SK cornea might regulate the expression of other chemokines, as well as the infiltration of inflammatory cells and control development of SK.     

Recent advances in immune modulation

Successful gene therapy protocols rely on the hypo-responsiveness of the immune system to transgene products generated from gene transfer vectors. In order to prevent cytotoxic lymphocyte or antibody formation induced by transgene expression, various strategies derived from recent advances in immune tolerance induction protocols have been tested in gene therapy model systems. Current immunosuppressive drugs were used to nonspecifically target T-cell activation, clonal expansion, and differentiation into effector cells. Central tolerance can be induced from intrathymic deletion of T cells with thymically expressed antigens or generation of hematopoietic mixed chimerism. Peripheral tolerance to transgenes may be achieved by several different pathways including deletion of activated/effector T cells by depleting antibodies, generation of T cell apoptosis or anergy by costimulation blockade, and active suppression by T regulatory cells. This review outlines the development of these strategies using various immune modulation regimens and protocols to induce long-term immune tolerance specific to the transgene product.     

An enhanced role for the recirculating lymphocyte in the neonatal immune system

Lymphocytes continually recirculate between the blood and the tissues via the lymph independent of antigen. A great deal is known regarding both the physiology and the molecular mechanisms responsible for the process in adults. However, relatively little is known regarding the development of the recirculating lymphocyte pool in very young animals or fetuses. We have directly measured the recirculation of lymphocyte subsets in antigen-inexperienced newborn animals, and found extensive recirculation of T cells through both intestinal and subcutaneous lymph nodes. Apparent selective migration of recirculating lymphocytes could be attributed to subset-specific migration of gammadelta-T cells through subcutaneous lymph nodes. This clearly demonstrates that the preference for gammadelta-T cells to recirculate through SCLN is lineage specific, and independent of the presence of antigen. Most surprising was the observation that the recirculating lymphocyte pool was proportionately larger in neonatal animals than in adults, which correlated with the histological appearance of newborn lymph nodes. This data strongly suggests that development of the recirculating lymphocyte pool is inversely correlated with antigen exposure, and decreases in size with age and the acquisition of immunological memory.     

Ontogeny of the murine immune system: development of antigen recognition and immune responsiveness

The grafting of a single spleen colony obtained from irradiated mice protected with 12-day fetal liver will reconstitute the lymphopoietic and erythropoietic system of irradiation-deprived syngeneic recipients. Using this experimental model, the early events during the ontogenic development of the immune system were studied in CBA mice. Cells capable of binding radio-iodine labeled S. adelaide polymerized flagellin were first detectable after 18 to 20 days of lymphopoiesis starting from presumably a single stem cell. However, antibody-forming cell production after immunization against the same antigen was not demonstrable until days 19 to 26. The same sequential development of antigen recognition (by rosette formation) followed by immune reactivity was observed for sheep red cell antigens, both events occurring later than those for POL. Our observed requirement for the ontogeny of an antigen-recognition spectrum is compatible with Jerne's theory on the generation of antibody diversity.     

Regulation of IgA B-cell development in the mucosal immune system

The factors regulating the differentiation of IgA B cells have been of great interest to mucosal immunologists as well as those generally interested in B-cell differentiation. It is now clear that such differentiation involves two major steps: first, isotype switch differentiation of surface IgM-bearing B cells into surface IgA-bearing B cells and, second, terminal differentiation of IgA B cells into IgA-producing plasma cells. Both of these steps are regulated processes that are under the influence of various cytokines and lymphokines. This paper presents data that define the role of cytokines and lymphokines in the regulation of IgA B-cell differentiation. A model of IgA B-cell differentiation is described in which the first step involves activation of the C alpha gene, while the latter is in germline configuration and thus the induction of surface IgM-bearing B cells partially committed to IgA expression. This occurs in Peyer's patches as a result of as yet incompletely defined signals from patch “switch cells.” The second step consists of conversion of the partially committed B cells to fully IgA-committed B cells and thus the completion of isotype switch differentiation. This step may be under the control of interleukin-4 (IL-4). The last step of the model involves the activation of IgA B cells (by antigen or mitogen) followed by the appearance on the cell surface of receptors which allow the cell to interact with cytokines or lymphokines (particularly IL-5). Such interaction results in cells capable of secreting IgA. Evidence is presented that an important adjuvant for mucosal immune responses, cholera toxin, acts to augment IgA production by promoting IgA B-cell differentiation at the isotype switch step.     

Rearing environment affects development of the immune system in neonates

Early‐life exposure to appropriate microbial flora drives expansion and development of an efficient immune system. Aberrant development results in increased likelihood of allergic disease or increased susceptibility to infection. Thus, factors affecting microbial colonization may also affect the direction of immune responses in later life. There is a need for a manipulable animal model of environmental influences on the development of microbiota and the immune system during early life. We assessed the effects of rearing under low‐ (farm, sow) and high‐hygiene (isolator, milk formula) conditions on intestinal microbiota and immune development in neonatal piglets, because they can be removed from the mother in the first 24 h for rearing under controlled conditions and, due to placental structure, neither antibody nor antigen is transferred in utero. Microbiota in both groups was similar between 2 and 5 days. However, by 12–28 days, piglets reared on the mother had more diverse flora than siblings reared in isolators. Dendritic cells accumulated in the intestinal mucosa in both groups, but more rapidly in isolator piglets. Importantly, the minority of 2–5‐day‐old farm piglets whose microbiota resembled that of an older (12–28‐day‐old) pig also accumulated dendritic cells earlier than the other farm‐reared piglets. Consistent with dendritic cell control of T cell function, the effects on T cells occurred at later time‐points, and mucosal T cells from high‐hygiene, isolator pigs made less interleukin (IL)‐4 while systemic T cells made more IL‐2. Neonatal piglets may be a valuable model for studies of the effects of interaction between microbiota and immune development on allergy.     

Acquisition of immune function during the development of the Langerhans cell network in neonatal mice

The immunological function of the Langerhans cell (LC) network in neonatal skin was examined by defining the development of cutaneous immunity relative to the structure, phenotype and function of the epidermal LC network in neonatal, juvenile and adult mice. Analysis of epidermal sheets showed the presence of major histocompatibility complex (MHC) II+, multilectin receptor DEC-205- cells within the epidermis of 3-day-old mice; both cell density and DEC-205 expression increased until day 14. When visualized with antibodies directed at MHC II, the network was poorly formed in 3- and 7-day-old mice, as there was a lower cell density and poor MHC II expression on dendritic processes, compared to mice at day14. Application of a fluorescent antigen to 3-day-old mice revealed that the LC were inefficient in transporting antigen to the draining lymph node. There was an improvement at day 7 and by day 14 comparable numbers of antigen carrying cells were detected in the lymph nodes of 6-week-old mice. The reduced antigen carriage in 3- and 7-day-old mice correlated with a poor contact sensitivity response. This was not simply due to failure to present antigen, but development of immunosuppression, as transfer of T cells from adult mice that were previously treated with antigen when they were 3 days old, to adult recipients resulted in antigen specific immunosuppression. Analysis of CD80 and CD86 expression showed that LC from day 3 skin expressed CD80, but not CD86 and application of antigen through this skin was inefficient in upregulating CD86. These findings indicate that when the neonatal LC network is poorly developed it is functionally immature and antigen applied through this 'functionally immature network' results in antigen specific immunosuppression.     

Maternal smoking in pregnancy alters neonatal cytokine responses

BACKGROUND: Maternal cigarette smoking in pregnancy is an important, common and avoidable exposure that has been linked with elevated cord blood (CB) immunoglobulin E levels and subsequent asthma and allergic disease in childhood. Despite this, there is still very little information about the immunological effects of maternal smoking on the fetus. METHODS: This aim of this study was to compare cord blood mononuclear cell (CBMC) cytokine responses to allergens [ovalbumin (OVA) or house dust mite (HDM)] and mitogens [concanavalin A (ConA) or phytohemaglutinen (PHA)] in neonates whose mothers smoked throughout pregnancy (n = 17) with responses of neonates whose mothers never smoked (n = 40). Cell cultures were stimulated for 24 h and supernatants collected for cytokine detection by enzyme-linked immunosorbent assay [interleukin (IL)-13, IL-6, interferon (IFN)gamma and IL-10]. Cell pellets were also collected for cytokine mRNA detection (IL-5, IL-9, IFNgamma). RESULTS: Maternal smoking in pregnancy was associated with significantly higher neonatal T helper type 2 (IL-13 protein) responses to both HDM (P = 0.01) and OVA (P = 0.035). These effects remained statistically significant after allowing for confounding factors, including the effects of maternal atopy. Similar trends were also seen for IL-9mRNA, IL-5mRNA and IL-6 responses, although these were not statistically significant. Although IFNgamma mRNA responses to PHA (P = 0.015) and ConA (P = 0.025) were lower if mothers smoked in pregnancy, there were no differences in neonatal (Th1) IFNgamma protein responses to allergens or mitogens. CONCLUSIONS: These findings indicate that maternal cigarette smoking can modify aspects of fetal immune function and highlight the need for further studies in this area.     

Stress and immune modulation in fish

Stress is an event that most animals experience and that induces a number of responses involving all three regulatory systems, neural, endocrine and immune. When the stressor is acute and short-term, the response pattern is stimulatory and the fish immune response shows an activating phase that specially enhances innate responses. If the stressor is chronic the immune response shows suppressive effects and therefore the chances of an infection may be enhanced. In addition, coping with the stressor imposes an allostatic cost that may interfere with the needs of the immune response. In this paper the mechanisms behind these immunoregulatory changes are reviewed and the role of the main neuroendocrine mechanisms directly affecting the building of the immune response and their consequences are considered.     

Stress and immune modulation in fish

Stress is an event that most animals experience and that induces a number of responses involving all three regulatory systems, neural, endocrine and immune. When the stressor is acute and short-term, the response pattern is stimulatory and the fish immune response shows an activating phase that specially enhances innate responses. If the stressor is chronic the immune response shows suppressive effects and therefore the chances of an infection may be enhanced. In addition, coping with the stressor imposes an allostatic cost that may interfere with the needs of the immune response. In this paper the mechanisms behind these immunoregulatory changes are reviewed and the role of the main neuroendocrine mechanisms directly affecting the building of the immune response and their consequences are considered.