Dokument

Summary:
The role of Toll-like receptors in the development of immunological tolerance in neonates Epidemiological and clinical studies based on Hygiene hypothesis indicate that maternal exposure to bacterial environment may modulate allergic diseases later in life. Also, evidences suggest that priming of the immune responses against allergens happens already in utero. This is a natures lesson taught by pregnancy immunity: maternal innate immunity via placental TLR signaling and adaptive immunity via maternal IgG and IgA transfer to fetus. The antibodies provide not only a passive protection, but are actively involved in the immunity of the child. Toll-like receptors (TLR) expressed on gut lymphoid tissue and epithelial cells of gastrointestinal-/respiratory tract, placenta etc. interact with environmental bacterial molecular patterns (e.g. endotoxin - LPS, DNA, LTA, dsRNA, ssRNA,flagellin etc.) and modulate maternal innate-/adaptive immune responses. In parallel, it also seems the T-cell system of the mother influences the development of children immune responses. Thus, in mother an appropriate colonization with probiotics helps to produce a balanced T helper cell response(TH1/TH2). Nevertheless, the (maternal and infant) respiratory tract has an obvious relationship with the environment and continuous exposure to microbial environment. Regarding, an important aspect of the study was to investigate the impact of non-pathogenic Gram+ (LGG), Gram- bacteria (Ac.lwoffii) or bacterial gears, (LA/LPS/ E.coli) to allergic asthma, and hypothesised that the activation of Toll-like receptors in the placenta plays an important role in prenatal transmission of protective immunological effects from mother to fetus. Consequently, the full development of innate host defense responses in the offspring lung requires expression of the maternal TLR in placenta. The receptors enhance expression of IL-1beta, TNF-alfa, IL-4, IL-10 and IFN-gamma. A balance of TH1/TH2 cytokine regulates the intensity and nature of the response. Maternal anti-allergic mechanism via TLRs signaling is in general associated with the maturation and migration of the lung dendritic cells to the lymph nodes and production of TH1 cytokine (IL-12), increasing the IFN-gamma production either in the lung and in the early placenta. Thus, we associated suppression of allergen-mediated inflammatory responses in placenta with: a cross-talk between trophoblasts and activated lymphocytes, using TLR pathways by maintaining the TH1/TH2 cytokine balance in pregnancy; secretion of immuno-suppressive molecules such as steroid hormones (progesterone,estradiol), prostaglandins, TGF-beta by trophoblasts and decidual immune cells; a significant increase of placental mRNA TNF-alfa and mRNA IL-1beta cytokine, resulting in a down-regulation of mRNA IFN-gamma expression under control of steroid hormones; passive blocking of lymphocyte activation by essential cytokine required for cell division, like IL-10; an immunoregulatory effect caused by the placental local production of specific sets of cytokine or chemokine, such as IL-4 and MCP-1; a specific cytostatic action of placenta CD8+ Tc cells, where the trend appears dominant in supplemented group; decidual NK cells – high amount in the early pregnancy are reduced in the 3rd trimester being unable to produce IFN-gamma, supporting the TH2 pregnancy phenotype and avoiding abortion; a strong induction of placental mRNA TLR4 and variation in expression of mRNA TLR1, TLR2, TLR5, TLR7, TLR9 expression into Gram- bacteria/gears supplemented group; placental cytokine modulate the TLR gene expression, but the effect varied between different cell types; maternal antibodies transfer to the fetus (a mechanism via trophoblast’s and gut’s IgG-FcRn complex induced by TLR signaling cascade). Moreover, frequent perinatal bacterial exposure suppressed in susceptible offspring: the allergen-specific sensitization - IgE production; the numbers of inflammatory cells, such as eosinophils in BALF and TH2 cytokines (IL-4, IL-5, IL-13) expressed in BALF and serum; in vivo, airway reactivity in response to Methacholine; lung mucus production. There is no doubt that early programming contributes to a large extend to the development of a normal state of immunological responses in offspring. A diminished expression and function of maternal TLR may help explain the poor adaptive immune responses, increasing the susceptibility to infections and allergies in the offspring. However, once a pregnancy is well developed, the newborn has a weakly TH2-biased immune response, and there is required a rapid postnatal down-regulated immunity. Therefore, the development of TH1 anti-allergic immunity in neonates, could be associated with the IFN-gamma compensation induced through a stable and specific perinatal non-pathogenic bacterial antigen exposure.

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