Neonatal immune responses to TLR2 stimulation: Influence of maternal atopy on Foxp3 and IL-10 expression

BACKGROUND: Maternal atopic background and stimulation of the adaptive immune system with allergen interact in the development of allergic disease. Stimulation of the innate immune system through microbial exposure, such as activation of the innate Toll-like-receptor 2 (TLR2), may reduce the development of allergy in childhood. However, little is known about the immunological effects of microbial stimulation on early immune responses and in association with maternal atopy. METHODS: We analyzed immune responses of cord blood mononuclear cells (CBMC) from 50 healthy neonates (31 non-atopic and 19 atopic mothers). Cells were stimulated with the TLR2 agonist peptidoglycan (Ppg) or the allergen house dust mite Dermatophagoides farinae (Derf1), and results compared to unstimulated cells. We analyzed lymphocyte proliferation and cytokine secretion of CBMC. In addition, we assessed gene expression associated with T regulatory cells including the transcription factor Foxp3, the glucocorticoid-induced TNF receptor (GITR), and the cytotoxic lymphocyte antigen 4 (CTLA4). Lymphocyte proliferation was measured by (3)H-Thymidine uptake, cytokine concentrations determined by ELISA, mRNA expression of T cell markers by real-time RT-PCR. RESULTS: Ppg stimulation induced primarily IL-10 cytokine production, in addition to IFN-γ, IL-13 and TNF-α secretion. GITR was increased following Ppg stimulation (p = 0.07). Ppg-induced IL-10 production and induction of Foxp3 were higher in CBMC without, than with maternal atopy (p = 0.04, p = 0.049). IL-10 production was highly correlated with increased expression of Foxp3 (r = 0.53, p = 0.001), GITR (r = 0.47, p = 0.004) and CTLA4 (r = 0.49, p = 0.003), independent of maternal atopy. CONCLUSION: TLR2 stimulation with Ppg induces IL-10 and genes associated with T regulatory cells, influenced by maternal atopy. Increased IL-10 and Foxp3 induction in CBMC of non-atopic compared to atopic mothers, may indicate an increased capacity to respond to microbial stimuli

The Expression of VEGF-A Is Down Regulated in Peripheral Blood Mononuclear Cells of Patients with Secondary Progressive Multiple Sclerosis

BACKGROUND: Most patients with relapsing-remitting multiple sclerosis (RRMS) eventually enter a secondary progressive (SPMS) phase, characterized by increasing neurological disability. The mechanisms underlying transition to SPMS are unknown and effective treatments and biomarkers are lacking. Vascular endothelial growth factor-A (VEGF-A) is an angiogenic factor with neuroprotective effects that has been associated with neurodegenerative diseases. SPMS has a prominent neurodegenerative facet and we investigated a possible role for VEGF-A during transition from RRMS to SPMS. METHODOLOGY/PRINCIPAL FINDINGS: VEGF-A mRNA expression in peripheral blood mononuclear (PBMC) and cerebrospinal fluid (CSF) cells from RRMS (n = 128), SPMS (n = 55) and controls (n = 116) were analyzed using real time PCR. We demonstrate reduced expression of VEGF-A mRNA in MS CSF cells compared to controls (p<0.001) irrespective of disease course and expression levels are restored by natalizumab treatment(p<0.001). VEGF-A was primarily expressed in monocytes and our CSF findings in part may be explained by effects on relative monocyte proportions. However, VEGF-A mRNA expression was also down regulated in the peripheral compartment of SPMS (p<0.001), despite unchanged monocyte counts, demonstrating a particular phenotype differentiating SPMS from RRMS and controls. A possible association of allelic variability in the VEGF-A gene to risk of MS was also studied by genotyping for six single nucleotide polymorphisms (SNPs) in MS (n = 1114) and controls (n = 1234), which, however, did not demonstrate any significant association between VEGF-A alleles and risk of MS. CONCLUSIONS/SIGNIFICANCE: Expression of VEGF-A in CSF cells is reduced in MS patients compared to controls irrespective of disease course. In addition, SPMS patients display reduced VEGF-A mRNA expression in PBMC, which distinguish them from RRMS and controls. This indicates a possible role for VEGF-A in the mechanisms regulating transition to SPMS. Decreased levels of PBMC VEGF-A mRNA expression should be further evaluated as a biomarker for SPMS

Lower Expression of TLR2 and SOCS-3 Is Associated with Schistosoma haematobium Infection and with Lower Risk for Allergic Reactivity in Children Living in a Rural Area in Ghana

Inflammatory diseases such as atopic disorders are a major health problem in the Western world, but their prevalence is also increasing in developing countries, especially in urban centres. There is increasing evidence that exposure to a rural environment with high burden of compounds derived from parasites and microorganisms is associated with protection from atopic disorders. Since urbanisation is progressing at a rapid pace, particularly in less-developed nations, there is a need to understand the molecular processes that control the progress towards the development of allergic diseases in developing countries. In this study we have examined a population of school children living in a rural area of Ghana, where helminth (worm) infections are prevalent and associated with protection from skin reactivity to house dust mite. Blood samples were collected from these children and analysed for the expression levels of several genes involved in the development of a pro allergic immune system. The results point at a potential molecular link that might explain the negative association between schistosome infections and allergies

Vitamin D supplementation during pregnancy: Effect on the neonatal immune system in a randomized controlled trial

RO1 HL101390 from the National Heart, Lung, and Blood Instituteparent clinical study by R01 HL091528 (to S.T.W. and A.A.L.)Open access for this article was funded by King’s College London

Changes in T Cell and Dendritic Cell Phenotype from Mid to Late Pregnancy Are Indicative of a Shift from Immune Tolerance to Immune Activation.

During pregnancy, the mother allows the immunologically distinct fetoplacental unit to develop and grow. Opinions are divided as to whether this represents a state of fetal-specific tolerance or of a generalized suppression of the maternal immune system. We hypothesized that antigen-specific T cell responses are modulated by an inhibitory T cell phenotype and modified dendritic cell (DC) phenotype in a gestation-dependent manner. We analyzed changes in surface markers of peripheral blood T cells, ex vivo antigen-specific T cell responses, indoleamine 2,3-dioxygenase (IDO) activity (kynurenine/tryptophan ratio, KTR), plasma neopterin concentration, and the in vitro expression of progesterone-induced blocking factor (PIBF) in response to peripheral blood mononuclear cell culture with progesterone. We found that mid gestation is characterized by reduced antigen-specific T cell responses associated with (1) predominance of effector memory over other T cell subsets; (2) upregulation of inhibitory markers (programmed death ligand 1); (3) heightened response to progesterone (PIBF); and (4) reduced proportions of myeloid DC and concurrent IDO activity (KTR). Conversely, antigen-specific T cell responses normalized in late pregnancy and were associated with increased markers of T cell activation (CD38, neopterin). However, these changes occur with a simultaneous upregulation of immune suppressive mechanisms including apoptosis (CD95), coinhibition (TIM-3), and immune regulation (IL-10) through the course of pregnancy. Together, our data suggest that immune tolerance dominates in the second trimester and that it is gradually reversed in the third trimester in association with immune activation as the end of pregnancy approaches

Influences perçues des prestations du Service Educatif Itinérant (SEI) sur la vulnérabilité à l'isolement de familles avec un enfant à besoins éducatifs particuliers (BEP). Étude quantitative et qualitative auprès de familles bénéficiant des prestations du SEI dans l'Est vaudois

Ce travail de recherche s’intéresse à la double thématique de la vulnérabilité à l’isolement et de la perception du soutien auprès de familles ayant des enfants à besoins éducatifs particuliers (BEP), suivies par les pédagogues d’une région d’un Service Éducatif Itinérant (SEI) vaudois. Il a pour ambition d’analyser l’influence des prestations offertes par une équipe SEI sur l’impression d’isolement des familles, constatée par les pédagogues. L’analyse examine dans quelle mesure les deux types de prestations, individuelles (la visite à domicile), et collectives (les petits collectifs mensuels et/ou ateliers saisonniers proposés) influent sur la vulnérabilité à l’isolement des familles. Un éclairage théorique va mettre en lumière la multidimensionnalité des deux thématiques (vulnérabilité à l’isolement et perception du soutien). La récolte des données empiriques, quantitative au moyen de deux questionnaires et qualitative grâce à des entretiens semi-directifs, s’est effectuée en deux temps. Les résultats ont mis en évidence que les prestations du SEI influent sur la vulnérabilité à l’isolement des familles, avec un effet positif sur l’empowerment des parents, davantage par le biais des visites à domicile que par les collectifs ponctuels. Les résultats mettent aussi en exergue l’impact des BEP de l’enfant sur l’exercice des fonctions familiales des parents, la nécessité d’un « feeling » avec l’intervenante pour les parents et la place à part du conjoint dans l’aide apportée. Enfin, il ressort de cette recherche l’importance du soutien à l’entourage de l’enfant à BEP, comblé par la prestation à domicile, conjointement à celui de la stimulation à l’enfant, davantage porté par la proposition des collectifs. Une analyse thématique en continu a permis de dégager au final des pistes pour la pratique sous la forme de deux arbres thématiques regroupant l’ensemble des données issues de l’analyse. </p