Association between prenatal immune phenotyping and cord blood leukocyte telomere length in the PRISM pregnancy cohort.

BACKGROUND: Environmental exposures including air pollutants, toxic metals, and psychosocial stress have been associated with shorter telomere length (TL) in newborns. These exposures have in turn been linked to an enhanced inflammatory immune response. Increased inflammation during pregnancy may be a central biological pathway linking environmental factors with reduced TL at birth. Approaches that more comprehensively characterize the prenatal inflammatory milieu rather than targeting specific individual cytokines in relation to newborn TL may better elucidate inflammatory mechanisms. METHODS: Analyses included 129 mother-child dyads enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort. We measured 92 inflammation related proteins during pregnancy in maternal serum using the Olink protein array and quantified cord blood relative leukocyte TL (rLTL) via qPCR. We leveraged a tree-based machine learning algorithm to select the most important inflammatory related proteins jointly associated with rLTL. We then evaluated the combined association between the selected proteins with rLTL using Bayesian Weighted Quantile Sum (BWQS) Regression. Analyses were adjusted for gestational week of serum collection, maternal race/ethnicity, age, and education, and fetal sex. We evaluated major biological function of the identified proteins by using the UniProtKB, a centralized repository of curated functional information. RESULTS: Three proteins were negatively and linearly associated with rLTL (CASP8 ß: -0.22 p = 0.008, BNGF ß: -0.43 p = 0.033, TRANCE ß: 0.38 p = 0.004). Results from BWQS regression showed a significant overall decrease in rLTL (ß: -0.26 95%CrI: -0.43, -0.07) per quartile increase of the mixture, with CASP8 contributing the greatest weight (CASP8 50%; BNGF 27%, and TRANCE 23%). The identified proteins were involved in the regulation of apoptotic processes and cell proliferation. CONCLUSIONS: This proteomics approach identifies novel maternal prenatal inflammatory protein biomarkers associated with shortened rLTL in newborns.

Immune Basis of Allergic Reactions to Food.

Food allergies are diseases where the normal tolerance response to oral antigens is altered. Recent advances have begun to uncover mechanisms that mediate sensitization to food allergens and maintenance of the disease. Production of alarmins by epithelial cells triggers a cascade that leads to allergen-specific IgE synthesis. IL-9 has also been shown to play a role in mast cell recruitment and amplification of the allergic response. In recent years, increasing evidence suggests that sensitization to food allergens can be developed via nonoral routes, in particular the skin, thus leading to the "dual exposure hypothesis". Environmental factors such as diet or microbiota can shape the immune system to promote tolerance or sensitization to food antigens. While the mechanism of primary tolerance to food antigens is quite clear, that leading to permanent tolerance in food-allergic individuals through immunotherapy is still under study. Understanding the mechanisms by which oral tolerance is suppressed and sensitization develops will help to identify new targets to develop combined therapies for the treatment of food allergies.

Immune basis of allergic reactions to food

Food allergies are diseases where the normal tolerance response to oral antigens is altered. Recent advances have begun to uncover mechanisms that mediate sensitization to food allergens and maintenance of the disease. Production of alarmins by epithelial cells triggers a cascade that leads to allergen-specific IgE synthesis. IL-9 has also been shown to play a role in mast cell recruitment and amplification of the allergic response. In recent years, increasing evidence suggests that sensitization to food allergens can be developed via nonoral routes, in particular the skin, thus leading to the "dual exposure hypothesis". Environmental factors such as diet or microbiota can shape the immune system to promote tolerance or sensitization to food antigens. While the mechanism of primary tolerance to food antigens is quite clear, that leading to permanent tolerance in food-allergic individuals through immunotherapy is still under study. Understanding the mechanisms by which oral tolerance is suppressed and sensitization develops will help to identify new targets to develop combined therapies for the treatment of food allergies

La alergia alimentaria es una enfermedad en la que la respuesta fisiológica normal de tolerancia a los antígenos orales se encuentra alterada. Los nuevos avances en la investigación han comenzado a desvelar los mecanismos que median tanto en la sensibilización a los alérgenos alimentarios como en la persistencia de la enfermedad. La producción de alarminas por parte de las células epiteliales desencadena una cascada que conduce a la síntesis de IgE específica frente a los alérgenos alimentarios. También se ha identificado el papel de la IL-9 en el reclutamiento de mastocitos y la amplificación de la respuesta alérgica. Además en estos últimos años se han completado diversas investigaciones que sugieren que la sensibilización a los alérgenos alimentarios puede desarrollarse por vías no orales, en particular a través de la piel, lo cual ha llevado a la propuesta de la denominada "hipótesis de la doble exposición". Por último, factores ambientales como la dieta o la microbiota pueden moldear el sistema inmunológico para promover la tolerancia o la sensibilización a los antígenos alimentarios. Si bien el mecanismo de tolerancia primaria a los antígenos alimentarios es bastante claro, el que conduce a la tolerancia permanente en individuos que ya tienen alergia a los alimentos a través de la inmunoterapia aún está en estudio. Comprender los mecanismos mediante los cuales se suprime la tolerancia oral y se desarrolla la sensibilización ayudará a identificar nuevos objetivos para desarrollar terapias combinadas para el tratamiento de alergias alimentarias

Mechanisms underlying induction of allergic sensitization by Pru p 3.

BACKGROUND: Recently, the nature of the lipid-ligand of Pru p 3, one of the most common plant food allergens in southern Europe, has been identified as a derivative of the alkaloid camptothecin bound to phytosphingosine. However, the origin of its immunological activity is still unknown. OBJECTIVE: We sought to evaluate the role of the Pru p 3 lipid-ligand in the immunogenic activity of Pru p 3. METHODS: In vitro cultures of different cell types (monocyte-derived dendritic cells [moDCs], PBMCs [peripheral blood mononuclear cells] and epithelial and iNKT-hybridoma cell lines) have been used to determine the immunological capacity of the ligand, by measuring cell proliferation, maturation markers and cytokine production. To study the capacity of the lipid-ligand to promote sensitization to Pru p 3 in vivo, a mouse model of anaphylaxis to peach has been produced and changes in the humoral and basophil responses have been analysed. RESULTS: The lipid-ligand of Pru p 3 induced maturation of moDCsc and proliferation of PBMCs. Its immunological activity resided in the phytosphingosine tail of the ligand. The adjuvant activity of the ligand was also confirmed in vivo, where the complex of Pru p 3-ligand induced higher levels of IgE than Pru p 3 alone. The immunological capacity of the Pru p 3 ligand was mediated by CD1d, as maturation of moDCs was inhibited by anti-CD1d antibodies and Pru p 3-ligand co-localized with CD1d on epithelial cells. Finally, Pru p 3-ligand presented by CD1d was able to interact with iNKTs. CONCLUSIONS AND CLINICAL RELEVANCE: The Pru p 3 lipid-ligand could act as an adjuvant to promote sensitization to Pru p 3, through its recognition by CD1d receptors. This intrinsic adjuvant activity of the accompanying lipid cargo could be a general essential feature of the mechanism underlying the phenomenon of allergenicity.

Role of maternal elimination diets and human milk IgA in the development of cow's milk allergy in the infants.

BACKGROUND: The role of maternal avoidance diets in the prevention of food allergies is currently under debate. Little is known regarding the effects of such diets on human milk (HM) composition or induction of infant humoral responses. OBJECTIVE: To assess the association of maternal cow's milk (CM) avoidance during breastfeeding with specific IgA levels in HM and development of cow's milk allergy (CMA) in infants. METHODS: We utilized HM and infant serum samples from a prospective birth cohort of 145 dyads. Maternal serum and HM samples were assessed for casein and beta-lactoglobulin (BLG)-specific IgA and IgG by ELISA; 21 mothers prophylactically initiated a strict maternal CM avoidance diet due to a sibling's history of food allergy and 16 due to atopic eczema or regurgitation/vomiting seen in their infants within the first 3 months of life. Infants' sera were assessed for casein and BLG-specific IgG, IgA and IgE; CMA was confirmed by an oral food challenge. The impact of HM on BLG uptake was assessed in transcytosis assays utilizing Caco-2 intestinal epithelial cell line. RESULTS: Mothers avoiding CM had lower casein- and BLG-specific IgA in HM than mothers with no CM restriction (P = 0.019 and P = 0.047). Their infants had lower serum casein- and BLG-specific IgG(1) (P = 0.025 and P < 0.001) and BLG-specific IgG(4) levels (P = 0.037), and their casein- and BLG-specific IgA levels were less often detectable than those with no CM elimination diet (P = 0.003 and P = 0.007). Lower CM-specific IgG4 and IgA levels in turn were associated with infant CMA. Transcytosis of BLG was impaired by HM with high, but not low levels of specific IgA. CONCLUSIONS: Maternal CM avoidance was associated with lower levels of mucosal-specific IgA levels and the development of CMA in infants. CLINICAL RELEVANCE: HM IgA may play a role in preventing excessive, uncontrolled food antigen uptake in the gut lumen and thereby in the prevention of CMA.

Comparative in vitro activity of temocillin and other antimicrobial agents against Enterobacteriaceae isolated from patients admitted to five Belgian hospitals.

Temocillin, a methoxy-derivative of the broad-spectrum penicillin, ticarcillin, has been introduced into clinical practice in Belgium in 1988. Since then, not many surveys of its in vitro activity have been published. This study addresses this issue in a prospective collection of 300 consecutive Gram-negative isolates originating from in-patients in five general hospitals throughout Belgium. In addition to temocillin, seven common antibiotics were tested: amoxicillin-clavulanate, piperacillin-tazobactam, cefotaxime, aztreonam, meropenem, ciprofloxacin and amikacin. Meropenem appeared to exhibit the best activity overall, whereas amoxicillin-clavulanate scored the worst. Cumulative MIC plot for two subsets of organisms are given: temocillin, meropenem and cefotaxime are the most active on E. coli and Klebsiella spp., while a significant percentage is resistant to ciprofloxacin and amoxicillin-clavulanate. In the group of inducible Enterobacteriaceae, temocillin, meropenem and amikacin are the most active drugs, while the activity of amoxicillin-clavulanate, piperacillin-tazobactam, cefotaxime and ciprofloxacin is largely decreased. Taking this well preserved in vitro activity of temocillin into account, and looking at its convenient pharmacokinetics and low cost of acquisition, this drug may prove a useful alternative in the treatment of severe nosocomial infections.