56 research outputs found

    Partnering with the Old Order Mennonites in the Finger Lakes Region of New York State to Identify the Mechanisms of Protective Immunity Against Atopic Disease Development

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    Old Order Mennonites (OOM) follow a traditional agrarian lifestyle; key aspects include home births, large families, limited antibiotic usage, consumption of whole foods and unpasteurized milk, and early exposure to soil, stables, and farm animals. There is evidence that a farming lifestyle protects against asthma and allergies, yet the biological mechanisms behind this protective effect remain unknown. The “Zooming into Old Order Mennonites” (ZOOM) cohort study was established to further explore protective factors and mechanisms. This study compares immune development among OOM children from the Finger Lakes Region of New York to those residing 65 miles northwest in Rochester, NY. Participants completed prenatal and post-natal questionnaires and biomarker sampling throughout the infant’s first two years. Questionnaires on lifestyle, diet, and environmental exposures continued through year five. The success of this study depended on a partnership between the University of Rochester study team and the OOM community, which began in 2009 with a pilot study on prenatal lifestyle behaviors and environmental exposures. Since then, the study team and the OOM community have collaborated to investigate the prevalence and mechanisms underlying atopic disease. The study team has remained mindful of OOM cultural practices by carefully engaging community members and potential participants through key informant interviews, focus groups, and “town hall” data-sharing meetings. To truly respect this community, they must be involved at every step of the research process. Through these efforts, the ZOOM study team recruited 90 OOM mother-infant pairs. Ultimately, this study marks a step closer to preventing allergic disease. [Abstract by authors.

    Novel multiplex assay for profiling influenza antibodies in breast milk and serum of mother-infant pairs [version 2; referees: 2 approved]

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    Background: During early life, systemic protection to influenza is passively provided by transplacental transfer of IgG antibodies and oral and gastrointestinal mucosal protection via breast milk (BM) containing predominantly IgA. Immune imprinting, influenced by initial exposure of the infant immune system to influenza, has recently been recognized as an important determinant of future influenza immune responses. Methods: We utilized stored frozen BM from a prospective birth cohort to assess immune factors in human milk. The earliest available BM and a paired, timed serum sample was assessed from each of  7 mothers. Paired infant serum samples were assayed at up to three time points during the first 12 months of life, one prior to assumed disappearance of transplacentally transferred IgG, and one after. We utilized a novel multiplex assay to assess mothers’ and infants’ IgG and IgA antibodies in serum to a panel of  30 individual recombinant hemagglutinin (rHA) proteins of influenza virus strains and chimeric rHAs. We also characterized IgA and IgG antibody levels in breast milk which provide mucosal protection. Results: Our pilot results, analyzing a small number of samples demonstrate the feasibility of this method for studying paired maternal-infant IgG and IgA anti-influenza immunity patterns. Unlike IgG antibodies, breast milk influenza virus HA-specific IgA antibody levels and patterns were mostly discordant compared to serum.  As expected, there was a steady decay of infant influenza specific IgG levels by 6 to 8 months of age, which was not, however, comparable in all infants. In contrast, most of the infants showed an increase in IgA responses throughout the first year of life Conclusions:  This new analytical method can be applied in a larger study to understand the impact of maternal imprinting on influenza immunity

    Skin exposure promotes a Th2-dependent sensitization to peanut allergens

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    Sensitization to foods often occurs in infancy, without a known prior oral exposure, suggesting that alternative exposure routes contribute to food allergy. Here, we tested the hypothesis that peanut proteins activate innate immune pathways in the skin that promote sensitization. We exposed mice to peanut protein extract on undamaged areas of skin and observed that repeated topical exposure to peanut allergens led to sensitization and anaphylaxis upon rechallenge. In mice, this epicutaneous peanut exposure induced sensitization to the peanut components Ara h 1 and Ara h 2, which is also observed in human peanut allergy. Both crude peanut extract and Ara h 2 alone served as adjuvants, as both induced a bystander sensitization that was similar to that induced by the atopic dermatitisassociated staphylococcal enterotoxin B. In cultured human keratinocytes and in murine skin, peanut extract directly induced cytokine expression. Moreover, topical peanut extract application induced an alteration dependent on the IL-33 receptor ST2 in skin-draining DCs, resulting in Th2 cytokine production from T cells. Together, our data support the hypothesis that peanuts are allergenic due to inherent adjuvant activity and suggest that skin exposure to food allergens contributes to sensitization to foods in early life.The work was supported by NIH grants AI044236 (to H.A. Sampson and M.C. Berin), AI093577 (to M.C. Berin), and AI091655 (to K.M. Järvinen) and Environmental Protection Agency grant R834064 (to M.C. Berin). Clinical specimens were provided by the Jaffe Food Allergy Resource Initiative, funded by Food Allergy Research and Education.Peer Reviewe

    Skin exposure promotes a Th2-dependent sensitization to peanut allergens

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    Sensitization to foods often occurs in infancy, without a known prior oral exposure, suggesting that alternative exposure routes contribute to food allergy. Here, we tested the hypothesis that peanut proteins activate innate immune pathways in the skin that promote sensitization. We exposed mice to peanut protein extract on undamaged areas of skin and observed that repeated topical exposure to peanut allergens led to sensitization and anaphylaxis upon rechallenge. In mice, this epicutaneous peanut exposure induced sensitization to the peanut components Ara h 1 and Ara h 2, which is also observed in human peanut allergy. Both crude peanut extract and Ara h 2 alone served as adjuvants, as both induced a bystander sensitization that was similar to that induced by the a topic dermatitis associated staphylococcal enterotoxin B. In cultured human keratinocytes and in murine skin, peanut extract directly induced cytokine expression. Moreover, topical peanut extract application induced an alteration dependent on the IL-33 receptor ST2 in skin-draining DCs, resulting in Th2 cytokine production from T cells. Together, our data support the hypothesis that peanuts are allergenic due to inherent adjuvant activity and suggest that skin exposure to food allergens contributes to sensitization to foods in early life

    Quantitative glycoproteomics of human milk and association with atopic disease

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    The prevalence of allergic diseases and asthma is increasing rapidly worldwide, with environmental and lifestyle behaviors implicated as a reason. Epidemiological studies have shown that children who grow up on farms are at lower risk of developing childhood atopic disease, indicating the presence of a protective "farm effect". The Old Order Mennonite (OOM) community in Upstate New York have traditional, agrarian lifestyles, a low rate of atopic disease, and long periods of exclusive breastfeeding. Human milk proteins are heavily glycosylated, although there is a paucity of studies investigating the milk glycoproteome. In this study, we have used quantitative glycoproteomics to compare the N-glycoprotein profiles of 54 milk samples from Rochester urban/suburban and OOM mothers, two populations with different lifestyles, exposures, and risk of atopic disease. We also compared N-glycoprotein profiles according to the presence or absence of atopic disease in the mothers and, separately, the children. We identified 79 N-glycopeptides from 15 different proteins and found that proteins including immunoglobulin A1, polymeric immunoglobulin receptor, and lactotransferrin displayed significant glycan heterogeneity. We found that the abundances of 38 glycopeptides differed significantly between Rochester and OOM mothers and also identified four glycopeptides with significantly different abundances between all comparisons. These four glycopeptides may be associated with the development of atopic disease. The findings of this study suggest that the differential glycosylation of milk proteins could be linked to atopic disease.Peer reviewe

    Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: a prospective lynch syndrome database

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    Background: we have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy. Methods: the cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. Results: cumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05). Conclusions: the hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval

    Association of Lipidome Remodeling in the Adipocyte Membrane with Acquired Obesity in Humans

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    The authors describe a new approach to studying cellular lipid profiles and propose a compensatory mechanism that may help maintain the normal membrane function of adipocytes in the context of obesity
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