Maria Jenmalm | Linköping University (original) (raw)

Papers by Maria Jenmalm

Research paper thumbnail of Combined prenatal Lactobacillus reuteri and ω-3 supplementation synergistically modulates DNA methylation in neonatal T helper cells

Clinical Epigenetics, 2021

Background Environmental exposures may alter DNA methylation patterns of T helper cells. As T hel... more Background Environmental exposures may alter DNA methylation patterns of T helper cells. As T helper cells are instrumental for allergy development, changes in methylation patterns may constitute a mechanism of action for allergy preventive interventions. While epigenetic effects of separate perinatal probiotic or ω-3 fatty acid supplementation have been studied previously, the combined treatment has not been assessed. We aimed to investigate epigenome-wide DNA methylation patterns from a sub-group of children in an on-going randomised double-blind placebo-controlled allergy prevention trial using pre- and postnatal combined Lactobacillus reuteri and ω-3 fatty acid treatment. To this end, > 866000 CpG sites (MethylationEPIC 850K array) in cord blood CD4+ T cells were examined in samples from all four study arms (double-treatment: n = 18, single treatments: probiotics n = 16, ω-3 n = 15, and double placebo: n = 14). Statistical and bioinformatic analyses identified treatment-assoc...

Research paper thumbnail of Changes in peripheral immune populations during pregnancy and modulation by probiotics and ω-3 fatty acids

Scientific Reports, 2020

Allergic diseases have become a major health problem, partly due to reduced microbial stimulation... more Allergic diseases have become a major health problem, partly due to reduced microbial stimulation and a decreased dietary ω-3/ω-6 long-chain polyunsaturated fatty acid ratio. Prenatal exposures have been reported to influence allergy development, possibly induced via changes in maternal immune regulation. In a randomized double-blind placebo-controlled multicenter allergy prevention trial (PROOM-3), pregnant women were recruited at gestational week 20, and randomized to four study groups, one receiving bothL. reuterioil drops and ω-3 PUFA capsules (n = 22), the second receiving ω-3 PUFA supplementation and placebo regardingL. reuteri(n = 21), the third receivingL. reuteriand placebo regarding ω-3 PUFA (n = 22) and the fourth group receiving placebo capsules and placebo oil drops (n = 23). In this substudy, supplemental and pregnancy-related effects on maternal peripheral immune cell populations during pregnancy were assessed by flow cytometry immune phenotyping at gestational week 2...

Research paper thumbnail of Intralymphatic immunotherapy: a 3-year randomized, double-blind study in 72 patients with allergic rhinitis due to birch and grass

Background: There is need for a fast, e cient, and safe way to induce tolerance in patients with ... more Background: There is need for a fast, e cient, and safe way to induce tolerance in patients with severe allergic rhinitis. Methods: Patients with severe birch and timothy allergy were randomized and received three doses of 0.1 ml of birch and 5-grass allergen extracts (10,000 SQ units/ml, ALK-Abelló), or birch and placebo or 5grass and placebo by ultrasound-guided injections into inguinal lymph nodes at monthly intervals. We have no clean placebo group but the pollen seasons are mostly divided by time. Rhinoconjunctivitis Total Symptom Score, Medication Score and Rhinoconjunctivitis Quality of Life Questionnaire were evaluated before treatment and after each birch and grass pollen season during three subsequent years. Circulating proportions of T helper subsets and allergen-induced cytokine and chemokine production were analyzed by ow cytometry and Luminex. Results: The three groups reported fewer symptoms, lower use of medication and improved quality of life during the birch and grass pollen seasons each year after treatment at an almost similar rate independently of treatment. Mild local pain was the most common adverse event. IgE levels to birch decreased, whereas birch-induced IL-10 secretion increased in all three groups. IgG4 levels to birch and timothy and skin prick test reactivity remained mainly unchanged. Conjunctival challenge tests with timothy extract showed a higher threshold for allergen. In all three groups, regulatory T cell frequencies were increased three years after treatment. Conclusion: Intralymphatic immunotherapy against grass and birch pollen allergy was safe, seemed to be effective, and to be associated with bystander immune modulatory responses.

Research paper thumbnail of Childhood allergy is preceded by an absence of gut lactobacilli species and higher levels of atopy-related plasma chemokines

Clinical and Experimental Immunology, 2020

SummaryAlterations in the composition and reduced diversity of the infant microbiome are associat... more SummaryAlterations in the composition and reduced diversity of the infant microbiome are associated with allergic disease in children. Further, an altered microbiota is linked to immune dysregulation, including skewing of different T helper (Th) subsets, which is also seen in atopic individuals. The aim of this study was, therefore, to investigate the associations between gut lactobacilli and Th-related plasma factors in allergy development during childhood. A total of 194 children with known allergy status at 1 year of age were followed to 10 years of age. We used real-time polymerase chain reaction (PCR) to investigate the presence of three lactobacilli species (Lactobacillus casei, L. paracasei, L. rhamnosus) in infant fecal samples (collected between 1 week and 2 months of age) from a subgroup of children. Plasma chemokines and cytokines were quantified at 6 months and at 1, 2, 5 and 10 years of age with Luminex or enzyme-linked immunosorbent assay (ELISA). Fractional exhaled ni...

Research paper thumbnail of Pre‐ and postnatal Lactobacillus reuteri treatment alters DNA methylation of infant T helper cells

Pediatric Allergy and Immunology, 2020

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial ... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Research paper thumbnail of Maintained thymic output of conventional and regulatory T cells during human pregnancy

Journal of Allergy and Clinical Immunology, 2018

We thank the midwives at the maternity care unit at Vrinnevi Hospital, Norrk€ oping, Sweden, for ... more We thank the midwives at the maternity care unit at Vrinnevi Hospital, Norrk€ oping, Sweden, for their invaluable help with recruiting and taking samples from the pregnant women included in the study and the nurses at Clinical Immunology, Link€ oping University Hospital, for taking blood samples from all the healthy controls. We also thank J. Raffetseder for help with the Foxp3 RT-PCR.

Research paper thumbnail of Bugging allergy; role of pre-, pro- and synbiotics in allergy prevention

Allergology International, 2017

Large-scale biodiversity loss and complex changes in social behaviors are altering human microbia... more Large-scale biodiversity loss and complex changes in social behaviors are altering human microbial ecology. This is increasingly implicated in the global rise in inflammatory diseases, most notably the "allergy epidemic" in very early life. Colonization of human ecological niches, particularly the gastrointestinal tract, is critical for normal local and systemic immune development and regulation. Disturbances in composition, diversity and timing of microbial colonization have been associated with increased allergy risk, indicating the importance of strategies to restore a dysbiotic gut microbiota in the primary prevention of allergic diseases, including the administration of probiotics, prebiotics and synbiotics. Here, we summarize and discuss findings of randomized clinical trials that have examined the effects of these microbiome-related strategies on short and long-term allergy preventative effects e including new guidelines from the World Allergy Organization which now recommend probiotics and prebiotics for allergy prevention under certain conditions. The relatively low quality evidence, limited comparative studies and large heterogeneity between studies, have collectively hampered recommendations on specific probiotic strains, specific timing and specific conditions for the most effective preventive management. At the same time the risk of using available products is low. While further research is needed before specific practice guidelines on supplement probiotics and prebiotics, it is equally important that the underlying dietary and lifestyle factors of dysbiosis are addressed at both the individual and societal levels.

Research paper thumbnail of The mother-offspring dyad: microbial transmission, immune interactions and allergy development

Journal of Internal Medicine, 2017

The increasing prevalence of allergy in affluent countries may be caused by reduced intensity and... more The increasing prevalence of allergy in affluent countries may be caused by reduced intensity and diversity of microbial stimulation, resulting in abnormal postnatal immune maturation. Most studies investigating the underlying immunomodulatory mechanisms have focused on postnatal microbial exposure, for example demonstrating that the gut microbiota differs in composition and diversity during the first months of life in children who later do or do not develop allergic disease. However, it is also becoming increasingly evident that the maternal microbial environment during pregnancy is important in childhood immune programming, and the first microbial encounters may occur already in utero. During pregnancy, there is a close immunological interaction between the mother and her offspring, which provides important opportunities for the maternal microbial environment to influence the immune development of the child. In support of this theory, combined pre-and postnatal supplementation seems to be crucial for the preventive effect of probiotics on infant eczema. Here, the influence of microbial and immune interactions within the mother-offspring dyad on childhood allergy development will be discussed. In addition, how perinatal transmission of microbes and immunomodulatory factors from mother to offspring may shape appropriate immune maturation during infancy and beyond, potentially via epigenetic mechanisms, will be examined. Deeper understanding of these interactions between the maternal and offspring microbiome and immunity is needed to identify efficacious preventive measures to combat the allergy epidemic.

Research paper thumbnail of Vaccination and allergy: EAACI position paper, practical aspects

Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, Jan 4, 2017

Immunization is highly effective in preventing infectious diseases and therefore an indispensable... more Immunization is highly effective in preventing infectious diseases and therefore an indispensable public health measure. Allergic patients deserve access to the same publicly recommended immunizations as nonallergic patients unless risks associated with vaccination outweigh the gains. Whereas the number of reported possible allergic reactions to vaccines is high, confirmed vaccine-triggered allergic reactions are rare. Anaphylaxis following vaccination is rare, affecting less than 1/100,000, but can occur in any patient. Some patient groups, notably those with a previous allergic reaction to a vaccine or its components, are at heightened risk of allergic reaction and require special precautions. Allergic reactions, however, may occur in patients without known risk factors and cannot be predicted by currently available tools. Unwarranted fear and uncertainty can result in incomplete vaccination coverage for children and adults with or without allergy. In addition to concerns about an...

Research paper thumbnail of Pre- and probiotics for allergy prevention: time to revisit recommendations?

Clinical & Experimental Allergy, 2016

Reduced intensity and diversity of microbial exposure is considered a major factor driving abnorm... more Reduced intensity and diversity of microbial exposure is considered a major factor driving abnormal postnatal immune maturation and increasing allergy prevalence, particularly in more affluent regions. Quantitatively the largest important source of early immune-microbial interaction, the gut microbiota is of particular interest in this context, with variations in composition and diversity in the first months of life associated with subsequent allergy development. Attempting to restore the health consequences of the 'dysbiotic drift' in modern society, interventions modulating gut microbiota for allergy prevention have been evaluated in several randomized placebo controlled trials. In this review, we provide an Accepted Article This article is protected by copyright. All rights reserved. overview of these trials and discuss recommendations from international expert bodies regarding prebiotic, probiotic and synbiotic interventions. Recent guidelines from the World Allergy Organization recommend the use of probiotics for the primary prevention of eczema in pregnant and breastfeeding mothers of infants at high risk for developing allergy and in high risk infants. It is however stressed that these recommendations are conditional, based on very low quality evidence and great heterogeneity between studies, which also impedes specific and practical advice to consumers on the most effective regimens. We discuss how the choice of probiotic strains, timing and duration of administration can critically influence the outcome due to different effects on immune modulation and gut microbiota composition. Furthermore, we propose strategies to potentially improve allergy preventive effects and enable future evidence-based implementation.

Research paper thumbnail of Aberrant IgA responses to the gut microbiota during infancy precede asthma and allergy development

Journal of Allergy and Clinical Immunology, 2017

Background: Although a reduced gut microbiota diversity and low mucosal total IgA levels in infan... more Background: Although a reduced gut microbiota diversity and low mucosal total IgA levels in infancy have been associated with allergy development, IgA responses to the gut microbiota have not yet been studied. Objective: We sought to determine the proportions of IgA coating together with the characterization of the dominant bacteria, bound to IgA or not, in infant stool samples in relation to allergy development. Methods: A combination of flow cytometric cell sorting and deep sequencing of the 16S rDNA gene was used to characterize the bacterial recognition patterns by IgA in stool samples collected at 1 and 12 months of age from children staying healthy or having allergic symptoms up to 7 years of age. Results: The children with allergic manifestations, particularly asthma, during childhood had a lower proportion of IgA bound to fecal bacteria at 12 months of age compared with healthy children. These alterations cannot be attributed to differences in IgA levels or bacterial load between the 2 groups. Moreover, the bacterial targets of early IgA responses (including coating of the Bacteroides genus), as well as IgA recognition patterns, differed between healthy children and children with allergic manifestations. Altered IgA recognition patterns in children with allergy were observed already at 1 month of age, when the IgA antibodies are predominantly maternally derived in breast-fed children. Conclusion: An aberrant IgA responsiveness to the gut microbiota during infancy precedes asthma and allergy development, possibly indicating an impaired mucosal barrier function in allergic children.

Research paper thumbnail of Probiotics for treatment and primary prevention of allergic diseases and asthma: looking back and moving forward

Expert review of clinical immunology, Jan 28, 2016

Microbial ecosystems cover the surface of the human body and it is becoming increasingly clear th... more Microbial ecosystems cover the surface of the human body and it is becoming increasingly clear that our modern environment has profound effects on microbial composition and diversity. A dysbiotic gut microbiota has been associated with allergic diseases and asthma in cross-sectional and observational studies. In an attempt to restore this dysbiosis, probiotics have been evaluated in randomized controlled trials. Here, we review treatment and primary prevention studies, recent meta-analyses, and discuss the current understanding of the role of probiotics in this context. Many meta-analyses have shown a moderate benefit of probiotics for eczema prevention, whereas there is less evidence of a benefit for other allergic manifestations. Because of very low quality evidence and heterogeneity between studies, specific advice on the most effective regimens cannot yet be given - not even for eczema prevention. To be able to adopt results into specific recommendations, international expert or...

Research paper thumbnail of The Placental Immune Milieu is Characterized by a Th2- and Anti-Inflammatory Transcription Profile, Regardless of Maternal Allergy, and Associates with Neonatal Immunity

American journal of reproductive immunology (New York, N.Y. : 1989), Jan 10, 2014

How maternal allergy affects the systemic and local immunological environment during pregnancy an... more How maternal allergy affects the systemic and local immunological environment during pregnancy and the immune development of the offspring is unclear. Expression of 40 genes was quantified by PCR arrays in placenta, peripheral blood mononuclear cells (PBMC), and cord blood mononuclear cells (CBMC) from 7 allergic and 12 non-allergic women and their offspring. Placental gene expression was dominated by a Th2-/anti-inflammatory profile, irrespectively of maternal allergy, as compared to gene expression in PBMC. p35 expression in placenta correlated with fetal Tbx21 (ρ = -0.88, P < 0.001) and IL-5 expression in PBMC with fetal galectin1 (ρ = 0.91, P < 0.001). Increased expression of Th2-associated CCL22 in CBMC preceded allergy development. Gene expression locally and systemically during pregnancy was partly associated with the offspring's gene expression, possibly indicating that the immunological milieu is important for fetal immune development. Maternal allergy was not ass...

Research paper thumbnail of Th2-like chemokine levels are increased in allergic children and influenced by maternal immunity during pregnancy

Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, 2014

The influence of the intra-uterine environment on the immunity and allergy development in the off... more The influence of the intra-uterine environment on the immunity and allergy development in the offspring is unclear. We aimed to investigate (i) whether the pregnancy magnifies the Th2 immunity in allergic and non-allergic women, (ii) whether the maternal chemokine levels during pregnancy influenced the offspring's chemokine levels during childhood and (iii) the relationship between circulating Th1/Th2-associated chemokines and allergy in mothers and children. The Th1-associated chemokines CXCL9, CXCL10, CXCL11, and the Th2-associated chemokines CCL17, CCL18 and CCL22 were quantified by Luminex and ELISA in 20 women with and 36 women without allergic symptoms at gestational week (gw) 10-12, 15-16, 25, 35, 39 and 2 and 12 months post-partum and in their children at birth, 6, 12, 24 months and 6 years of age. Total IgE levels were measured using ImmunoCAP Technology. The levels of the Th2-like chemokines were not magnified by pregnancy. Instead decreased levels were shown during pr...

Research paper thumbnail of The gut microbiota and its role in the development of allergic disease: a wider perspective

Clinical & Experimental Allergy, 2014

The gut microbiota are critical in the homeostasis of multiple interconnected host metabolic and ... more The gut microbiota are critical in the homeostasis of multiple interconnected host metabolic and immune networks. If early microbial colonisation is delayed, the gut associated lymphoid tissues (GALT) fail to develop, leading to persistent immune dysregulation in mice. Microbial colonisation has also been proposed as a major driver for the normal age-related maturation of both Th1 and T regulatory (Treg) pathways that appear important in suppressing early propensity for Th2 allergic responses. There is emerging evidence that resident symbionts induce tolerogenic gut-associated Treg cells and dendritic cells that ensure the preferential growth of symbionts; keeping pathogenic strains in check and constraining proinflammatory Th1, Th2 and Th17 clones. Some effects of symbionts are mediated by short-chain fatty acids, which play a critical role in mucosal integrity, local and systemic metabolic function and stimulate the regulatory immune responses. The homeostatic IL-10/TGF-β dominated tolerogenic response within the GALT also signals the production of secretory IgA, which have a regulating role in mucosal integrity. Contrary to the "sterile womb" paradigm, recent studies suggest that maternal microbial transfer to the offspring begins during pregnancy, providing a pioneer microbiome. It is likely that appropriate microbial stimulation both pre-and postnatally are required for optimal Th1 and Treg development to avoid the pathophysiological processes leading to allergy. Disturbed gut colonisation patterns have been associated with allergic disease, but whether microbial variation is the cause or effect of these diseases is still under investigation. We are far from understanding what constitutes a "healthy gut microbiome" that promotes tolerance. This remains a major limitation and might explain some of the inconsistency in human intervention studies with prebiotics and probiotics. Multidisciplinary integrative approaches with researchers working in networks, using harmonised outcomes and methodologies are needed to advance our understanding in this field.

Research paper thumbnail of No effect of probiotics on respiratory allergies: a seven‐year follow‐up of a randomized controlled trial in infancy

Pediatric Allergy and Immunology, 2013

BackgroundSupplementation with the probiotic Lactobacillus reuteri reduced the incidence of IgE‐a... more BackgroundSupplementation with the probiotic Lactobacillus reuteri reduced the incidence of IgE‐associated allergic disease in infancy. This treatment might therefore also reduce the risk of asthma and allergic rhinoconjunctivitis in school age.ObjectiveTo evaluate whether perinatal and infant supplementation with L. reuteri reduced the prevalence of respiratory allergic disease in school age and to explore whether this supplementation was associated with any long‐term side effects.MethodsA randomized, placebo‐controlled trial with oral supplementation with L. reuteri ATCC 55730 (1 × 108 CFU) during the last month of gestation and through the first year of life comprising 232 families with allergic disease, of whom 184 completed a 7‐yr follow‐up. The primary outcomes at 7 yr of age were allergic disease and skin prick test reactivity (ClinicalTrials.gov ID NCT01285830).ResultsThe prevalence of asthma (15% in the probiotic vs. 16% in placebo group), allergic rhinoconjunctivitis (27% ...

Research paper thumbnail of Reduced IFN-γ and IL-10 responses to paternal antigens during and after pregnancy in allergic women

Journal of Reproductive Immunology, 2012

Normal pregnancy and allergy are both characterized by a T helper (Th) 2 deviation. In the curren... more Normal pregnancy and allergy are both characterized by a T helper (Th) 2 deviation. In the current study, we hypothesized that paternal antigen-induced cytokine responses during pregnancy would be deviated towards Th2 and an anti-inflammatory profile, and that the Th2 deviation would be more pronounced in allergic pregnant women. Blood samples were collected longitudinally on three occasions during pregnancy and two occasions post partum (pp). Of the 86 women initially included, 54 women had a normal pregnancy and completed the sampling procedures. Twelve women fulfilled the criteria for allergy (allergic symptoms and circulating immunoglobulin (Ig) E antibodies to inhalant allergens) and 20 were nonallergic (nonsensitized without symptoms). The levels of Th1 and Th2 associated cytokines and chemokines, the Th17 cytokine IL-17 and the anti-inflammatory cytokine IL-10 were compared between the groups. Paternal antigen induced IL-4 and IL-10 responses increased from the first to the third trimester. Allergy was associated with a decreased paternal antigeninduced IFN-γ and CXCL10 secretion in the non-pregnant state (one year post partum) and also decreased IFN-γ/IL-4 and IFN-γ/IL-13 ratios during pregnancy. We also observed a decreased paternal antigen induced IL-10 response in allergic compared with non-allergic women during pregnancy, along with a decreased IL-10/IL-13 ratio. In conclusion, our findings support the hypothesis of lower Th1 responses towards paternal antigens in allergic than in non-allergic women but also indicate that allergy is associated with a lower capacity to induce anti-inflammatory IL-10 responses after paternal antigen stimulation during pregnancy.

Research paper thumbnail of Immunological status in patients undergoing in vitro fertilisation: responses to hormone treatment and relationship to outcome

Journal of Reproductive Immunology, 2012

We aimed to prospectively investigate the paternal antigen-induced cytokine secretion by peripher... more We aimed to prospectively investigate the paternal antigen-induced cytokine secretion by peripheral blood mononuclear cells (PBMC) in response to hormone treatment in women undergoing in vitro fertilization (IVF) and to examine the predictive value of the cytokine secretion in the outcome of IVF treatment in a pilot study. Twenty-five women were included and IVF treatment was successful for six and unsuccessful for 19 women. Blood samples were collected before IVF treatment, on four occasions during IVF and 4 weeks after embryo transfer. The numbers of Th1-, Th2-and Th17-associated cytokine secreting cells and cytokine levels in cell supernatants were analyzed by enzyme linked immunospot-forming (ELISpot), enzyme-linked immune-sorbent (ELISA) or Luminex assay. None of the cytokines (IFN-γ, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17, TNF and GM-CSF) had any predictive value regarding IVF outcome. The majority of the cytokines reached their peak levels at ovum pickup, suggesting an enhancing influence of the hormonal stimulation. Pregnancy was associated with a high number of IL-4-, IL-5-and IL-13-secreting cells four weeks after ET. In conclusion, the results do not support our hypothesis of a more pronounced peripheral Th1 and Th17 deviation towards paternal antigens in infertile women with an unsuccessful IVF outcome, although this is based on a small number of observations. Thus, a larger study should be conducted to confirm this conclusion. Higher numbers of Th2-associated cytokinesecreting cells in pregnant women four weeks after ET do corroborate the hypothesis of a Th2 deviation during pregnancy.

Research paper thumbnail of Cord blood Th2-related chemokine CCL22 levels associate with elevated total-IgE during preschool age

Clinical & Experimental Allergy, 2012

Research paper thumbnail of Cytokine responses to allergens during the first 2 years of life in Estonian and Swedish children

Clinical <html_ent glyph="@amp;" ascii="&amp;"/> Experimental Allergy, 2006

Background: The prevalence of atopic disease among children in the formerly socialist countries i... more Background: The prevalence of atopic disease among children in the formerly socialist countries in Europe, with a life style similar to that prevailing in Western Europe 30-40 years ago, is low, whereas there has been a pronounced increase in industrialised countries over the last decades. The environment during infancy influences the risk of developing allergy for many years, perhaps even for life. Objective: To investigate the development of allergen specific cytokine responses during the first two years of life in two geographically adjacent countries with marked differences in living conditions and incidence of atopic diseases, i e Estonia and Sweden. Methods: The development of immune responses to the food (β-lactoglobulin (BLG) and ovalbumin) and inhalant (cat and birch) allergens were studied from birth up to the age of two years in 30 Estonian and 76 Swedish infants. Clinical investigation and skin prick tests were performed and blood samples obtained at birth and at 3, 6, 12 and 24 months. Results: The levels of IL-5, IL-10 and IL-13 secreted by PBMC stimulated with BLG, ovalbumin and cat allergen in the Estonian and Swedish infants declined during the first 3 months of life. All cytokines then progressively increased in the Swedish infants, indicating the replacement of non specifically responding immature cord blood T-cells with specific T-memory cells, which are primed postnatally. The resurgence of allergenspecific responses in the Estonian infants was less marked. These differences were particularly notable for birch-specific T-cell responses, which correlated with development of atopic disease in the Swedish children. Malin F Böttcher 3 Conclusions: The development of specific T-cell memory to food and inhalant allergens during the first two years of life differs between infants living in Sweden and Estonia, and mirrors the disparate patterns of expression of allergic disease which subsequently develops in the respective populations.

Research paper thumbnail of Combined prenatal Lactobacillus reuteri and ω-3 supplementation synergistically modulates DNA methylation in neonatal T helper cells

Clinical Epigenetics, 2021

Background Environmental exposures may alter DNA methylation patterns of T helper cells. As T hel... more Background Environmental exposures may alter DNA methylation patterns of T helper cells. As T helper cells are instrumental for allergy development, changes in methylation patterns may constitute a mechanism of action for allergy preventive interventions. While epigenetic effects of separate perinatal probiotic or ω-3 fatty acid supplementation have been studied previously, the combined treatment has not been assessed. We aimed to investigate epigenome-wide DNA methylation patterns from a sub-group of children in an on-going randomised double-blind placebo-controlled allergy prevention trial using pre- and postnatal combined Lactobacillus reuteri and ω-3 fatty acid treatment. To this end, > 866000 CpG sites (MethylationEPIC 850K array) in cord blood CD4+ T cells were examined in samples from all four study arms (double-treatment: n = 18, single treatments: probiotics n = 16, ω-3 n = 15, and double placebo: n = 14). Statistical and bioinformatic analyses identified treatment-assoc...

Research paper thumbnail of Changes in peripheral immune populations during pregnancy and modulation by probiotics and ω-3 fatty acids

Scientific Reports, 2020

Allergic diseases have become a major health problem, partly due to reduced microbial stimulation... more Allergic diseases have become a major health problem, partly due to reduced microbial stimulation and a decreased dietary ω-3/ω-6 long-chain polyunsaturated fatty acid ratio. Prenatal exposures have been reported to influence allergy development, possibly induced via changes in maternal immune regulation. In a randomized double-blind placebo-controlled multicenter allergy prevention trial (PROOM-3), pregnant women were recruited at gestational week 20, and randomized to four study groups, one receiving bothL. reuterioil drops and ω-3 PUFA capsules (n = 22), the second receiving ω-3 PUFA supplementation and placebo regardingL. reuteri(n = 21), the third receivingL. reuteriand placebo regarding ω-3 PUFA (n = 22) and the fourth group receiving placebo capsules and placebo oil drops (n = 23). In this substudy, supplemental and pregnancy-related effects on maternal peripheral immune cell populations during pregnancy were assessed by flow cytometry immune phenotyping at gestational week 2...

Research paper thumbnail of Intralymphatic immunotherapy: a 3-year randomized, double-blind study in 72 patients with allergic rhinitis due to birch and grass

Background: There is need for a fast, e cient, and safe way to induce tolerance in patients with ... more Background: There is need for a fast, e cient, and safe way to induce tolerance in patients with severe allergic rhinitis. Methods: Patients with severe birch and timothy allergy were randomized and received three doses of 0.1 ml of birch and 5-grass allergen extracts (10,000 SQ units/ml, ALK-Abelló), or birch and placebo or 5grass and placebo by ultrasound-guided injections into inguinal lymph nodes at monthly intervals. We have no clean placebo group but the pollen seasons are mostly divided by time. Rhinoconjunctivitis Total Symptom Score, Medication Score and Rhinoconjunctivitis Quality of Life Questionnaire were evaluated before treatment and after each birch and grass pollen season during three subsequent years. Circulating proportions of T helper subsets and allergen-induced cytokine and chemokine production were analyzed by ow cytometry and Luminex. Results: The three groups reported fewer symptoms, lower use of medication and improved quality of life during the birch and grass pollen seasons each year after treatment at an almost similar rate independently of treatment. Mild local pain was the most common adverse event. IgE levels to birch decreased, whereas birch-induced IL-10 secretion increased in all three groups. IgG4 levels to birch and timothy and skin prick test reactivity remained mainly unchanged. Conjunctival challenge tests with timothy extract showed a higher threshold for allergen. In all three groups, regulatory T cell frequencies were increased three years after treatment. Conclusion: Intralymphatic immunotherapy against grass and birch pollen allergy was safe, seemed to be effective, and to be associated with bystander immune modulatory responses.

Research paper thumbnail of Childhood allergy is preceded by an absence of gut lactobacilli species and higher levels of atopy-related plasma chemokines

Clinical and Experimental Immunology, 2020

SummaryAlterations in the composition and reduced diversity of the infant microbiome are associat... more SummaryAlterations in the composition and reduced diversity of the infant microbiome are associated with allergic disease in children. Further, an altered microbiota is linked to immune dysregulation, including skewing of different T helper (Th) subsets, which is also seen in atopic individuals. The aim of this study was, therefore, to investigate the associations between gut lactobacilli and Th-related plasma factors in allergy development during childhood. A total of 194 children with known allergy status at 1 year of age were followed to 10 years of age. We used real-time polymerase chain reaction (PCR) to investigate the presence of three lactobacilli species (Lactobacillus casei, L. paracasei, L. rhamnosus) in infant fecal samples (collected between 1 week and 2 months of age) from a subgroup of children. Plasma chemokines and cytokines were quantified at 6 months and at 1, 2, 5 and 10 years of age with Luminex or enzyme-linked immunosorbent assay (ELISA). Fractional exhaled ni...

Research paper thumbnail of Pre‐ and postnatal Lactobacillus reuteri treatment alters DNA methylation of infant T helper cells

Pediatric Allergy and Immunology, 2020

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial ... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Research paper thumbnail of Maintained thymic output of conventional and regulatory T cells during human pregnancy

Journal of Allergy and Clinical Immunology, 2018

We thank the midwives at the maternity care unit at Vrinnevi Hospital, Norrk€ oping, Sweden, for ... more We thank the midwives at the maternity care unit at Vrinnevi Hospital, Norrk€ oping, Sweden, for their invaluable help with recruiting and taking samples from the pregnant women included in the study and the nurses at Clinical Immunology, Link€ oping University Hospital, for taking blood samples from all the healthy controls. We also thank J. Raffetseder for help with the Foxp3 RT-PCR.

Research paper thumbnail of Bugging allergy; role of pre-, pro- and synbiotics in allergy prevention

Allergology International, 2017

Large-scale biodiversity loss and complex changes in social behaviors are altering human microbia... more Large-scale biodiversity loss and complex changes in social behaviors are altering human microbial ecology. This is increasingly implicated in the global rise in inflammatory diseases, most notably the "allergy epidemic" in very early life. Colonization of human ecological niches, particularly the gastrointestinal tract, is critical for normal local and systemic immune development and regulation. Disturbances in composition, diversity and timing of microbial colonization have been associated with increased allergy risk, indicating the importance of strategies to restore a dysbiotic gut microbiota in the primary prevention of allergic diseases, including the administration of probiotics, prebiotics and synbiotics. Here, we summarize and discuss findings of randomized clinical trials that have examined the effects of these microbiome-related strategies on short and long-term allergy preventative effects e including new guidelines from the World Allergy Organization which now recommend probiotics and prebiotics for allergy prevention under certain conditions. The relatively low quality evidence, limited comparative studies and large heterogeneity between studies, have collectively hampered recommendations on specific probiotic strains, specific timing and specific conditions for the most effective preventive management. At the same time the risk of using available products is low. While further research is needed before specific practice guidelines on supplement probiotics and prebiotics, it is equally important that the underlying dietary and lifestyle factors of dysbiosis are addressed at both the individual and societal levels.

Research paper thumbnail of The mother-offspring dyad: microbial transmission, immune interactions and allergy development

Journal of Internal Medicine, 2017

The increasing prevalence of allergy in affluent countries may be caused by reduced intensity and... more The increasing prevalence of allergy in affluent countries may be caused by reduced intensity and diversity of microbial stimulation, resulting in abnormal postnatal immune maturation. Most studies investigating the underlying immunomodulatory mechanisms have focused on postnatal microbial exposure, for example demonstrating that the gut microbiota differs in composition and diversity during the first months of life in children who later do or do not develop allergic disease. However, it is also becoming increasingly evident that the maternal microbial environment during pregnancy is important in childhood immune programming, and the first microbial encounters may occur already in utero. During pregnancy, there is a close immunological interaction between the mother and her offspring, which provides important opportunities for the maternal microbial environment to influence the immune development of the child. In support of this theory, combined pre-and postnatal supplementation seems to be crucial for the preventive effect of probiotics on infant eczema. Here, the influence of microbial and immune interactions within the mother-offspring dyad on childhood allergy development will be discussed. In addition, how perinatal transmission of microbes and immunomodulatory factors from mother to offspring may shape appropriate immune maturation during infancy and beyond, potentially via epigenetic mechanisms, will be examined. Deeper understanding of these interactions between the maternal and offspring microbiome and immunity is needed to identify efficacious preventive measures to combat the allergy epidemic.

Research paper thumbnail of Vaccination and allergy: EAACI position paper, practical aspects

Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, Jan 4, 2017

Immunization is highly effective in preventing infectious diseases and therefore an indispensable... more Immunization is highly effective in preventing infectious diseases and therefore an indispensable public health measure. Allergic patients deserve access to the same publicly recommended immunizations as nonallergic patients unless risks associated with vaccination outweigh the gains. Whereas the number of reported possible allergic reactions to vaccines is high, confirmed vaccine-triggered allergic reactions are rare. Anaphylaxis following vaccination is rare, affecting less than 1/100,000, but can occur in any patient. Some patient groups, notably those with a previous allergic reaction to a vaccine or its components, are at heightened risk of allergic reaction and require special precautions. Allergic reactions, however, may occur in patients without known risk factors and cannot be predicted by currently available tools. Unwarranted fear and uncertainty can result in incomplete vaccination coverage for children and adults with or without allergy. In addition to concerns about an...

Research paper thumbnail of Pre- and probiotics for allergy prevention: time to revisit recommendations?

Clinical & Experimental Allergy, 2016

Reduced intensity and diversity of microbial exposure is considered a major factor driving abnorm... more Reduced intensity and diversity of microbial exposure is considered a major factor driving abnormal postnatal immune maturation and increasing allergy prevalence, particularly in more affluent regions. Quantitatively the largest important source of early immune-microbial interaction, the gut microbiota is of particular interest in this context, with variations in composition and diversity in the first months of life associated with subsequent allergy development. Attempting to restore the health consequences of the 'dysbiotic drift' in modern society, interventions modulating gut microbiota for allergy prevention have been evaluated in several randomized placebo controlled trials. In this review, we provide an Accepted Article This article is protected by copyright. All rights reserved. overview of these trials and discuss recommendations from international expert bodies regarding prebiotic, probiotic and synbiotic interventions. Recent guidelines from the World Allergy Organization recommend the use of probiotics for the primary prevention of eczema in pregnant and breastfeeding mothers of infants at high risk for developing allergy and in high risk infants. It is however stressed that these recommendations are conditional, based on very low quality evidence and great heterogeneity between studies, which also impedes specific and practical advice to consumers on the most effective regimens. We discuss how the choice of probiotic strains, timing and duration of administration can critically influence the outcome due to different effects on immune modulation and gut microbiota composition. Furthermore, we propose strategies to potentially improve allergy preventive effects and enable future evidence-based implementation.

Research paper thumbnail of Aberrant IgA responses to the gut microbiota during infancy precede asthma and allergy development

Journal of Allergy and Clinical Immunology, 2017

Background: Although a reduced gut microbiota diversity and low mucosal total IgA levels in infan... more Background: Although a reduced gut microbiota diversity and low mucosal total IgA levels in infancy have been associated with allergy development, IgA responses to the gut microbiota have not yet been studied. Objective: We sought to determine the proportions of IgA coating together with the characterization of the dominant bacteria, bound to IgA or not, in infant stool samples in relation to allergy development. Methods: A combination of flow cytometric cell sorting and deep sequencing of the 16S rDNA gene was used to characterize the bacterial recognition patterns by IgA in stool samples collected at 1 and 12 months of age from children staying healthy or having allergic symptoms up to 7 years of age. Results: The children with allergic manifestations, particularly asthma, during childhood had a lower proportion of IgA bound to fecal bacteria at 12 months of age compared with healthy children. These alterations cannot be attributed to differences in IgA levels or bacterial load between the 2 groups. Moreover, the bacterial targets of early IgA responses (including coating of the Bacteroides genus), as well as IgA recognition patterns, differed between healthy children and children with allergic manifestations. Altered IgA recognition patterns in children with allergy were observed already at 1 month of age, when the IgA antibodies are predominantly maternally derived in breast-fed children. Conclusion: An aberrant IgA responsiveness to the gut microbiota during infancy precedes asthma and allergy development, possibly indicating an impaired mucosal barrier function in allergic children.

Research paper thumbnail of Probiotics for treatment and primary prevention of allergic diseases and asthma: looking back and moving forward

Expert review of clinical immunology, Jan 28, 2016

Microbial ecosystems cover the surface of the human body and it is becoming increasingly clear th... more Microbial ecosystems cover the surface of the human body and it is becoming increasingly clear that our modern environment has profound effects on microbial composition and diversity. A dysbiotic gut microbiota has been associated with allergic diseases and asthma in cross-sectional and observational studies. In an attempt to restore this dysbiosis, probiotics have been evaluated in randomized controlled trials. Here, we review treatment and primary prevention studies, recent meta-analyses, and discuss the current understanding of the role of probiotics in this context. Many meta-analyses have shown a moderate benefit of probiotics for eczema prevention, whereas there is less evidence of a benefit for other allergic manifestations. Because of very low quality evidence and heterogeneity between studies, specific advice on the most effective regimens cannot yet be given - not even for eczema prevention. To be able to adopt results into specific recommendations, international expert or...

Research paper thumbnail of The Placental Immune Milieu is Characterized by a Th2- and Anti-Inflammatory Transcription Profile, Regardless of Maternal Allergy, and Associates with Neonatal Immunity

American journal of reproductive immunology (New York, N.Y. : 1989), Jan 10, 2014

How maternal allergy affects the systemic and local immunological environment during pregnancy an... more How maternal allergy affects the systemic and local immunological environment during pregnancy and the immune development of the offspring is unclear. Expression of 40 genes was quantified by PCR arrays in placenta, peripheral blood mononuclear cells (PBMC), and cord blood mononuclear cells (CBMC) from 7 allergic and 12 non-allergic women and their offspring. Placental gene expression was dominated by a Th2-/anti-inflammatory profile, irrespectively of maternal allergy, as compared to gene expression in PBMC. p35 expression in placenta correlated with fetal Tbx21 (ρ = -0.88, P < 0.001) and IL-5 expression in PBMC with fetal galectin1 (ρ = 0.91, P < 0.001). Increased expression of Th2-associated CCL22 in CBMC preceded allergy development. Gene expression locally and systemically during pregnancy was partly associated with the offspring's gene expression, possibly indicating that the immunological milieu is important for fetal immune development. Maternal allergy was not ass...

Research paper thumbnail of Th2-like chemokine levels are increased in allergic children and influenced by maternal immunity during pregnancy

Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, 2014

The influence of the intra-uterine environment on the immunity and allergy development in the off... more The influence of the intra-uterine environment on the immunity and allergy development in the offspring is unclear. We aimed to investigate (i) whether the pregnancy magnifies the Th2 immunity in allergic and non-allergic women, (ii) whether the maternal chemokine levels during pregnancy influenced the offspring's chemokine levels during childhood and (iii) the relationship between circulating Th1/Th2-associated chemokines and allergy in mothers and children. The Th1-associated chemokines CXCL9, CXCL10, CXCL11, and the Th2-associated chemokines CCL17, CCL18 and CCL22 were quantified by Luminex and ELISA in 20 women with and 36 women without allergic symptoms at gestational week (gw) 10-12, 15-16, 25, 35, 39 and 2 and 12 months post-partum and in their children at birth, 6, 12, 24 months and 6 years of age. Total IgE levels were measured using ImmunoCAP Technology. The levels of the Th2-like chemokines were not magnified by pregnancy. Instead decreased levels were shown during pr...

Research paper thumbnail of The gut microbiota and its role in the development of allergic disease: a wider perspective

Clinical & Experimental Allergy, 2014

The gut microbiota are critical in the homeostasis of multiple interconnected host metabolic and ... more The gut microbiota are critical in the homeostasis of multiple interconnected host metabolic and immune networks. If early microbial colonisation is delayed, the gut associated lymphoid tissues (GALT) fail to develop, leading to persistent immune dysregulation in mice. Microbial colonisation has also been proposed as a major driver for the normal age-related maturation of both Th1 and T regulatory (Treg) pathways that appear important in suppressing early propensity for Th2 allergic responses. There is emerging evidence that resident symbionts induce tolerogenic gut-associated Treg cells and dendritic cells that ensure the preferential growth of symbionts; keeping pathogenic strains in check and constraining proinflammatory Th1, Th2 and Th17 clones. Some effects of symbionts are mediated by short-chain fatty acids, which play a critical role in mucosal integrity, local and systemic metabolic function and stimulate the regulatory immune responses. The homeostatic IL-10/TGF-β dominated tolerogenic response within the GALT also signals the production of secretory IgA, which have a regulating role in mucosal integrity. Contrary to the "sterile womb" paradigm, recent studies suggest that maternal microbial transfer to the offspring begins during pregnancy, providing a pioneer microbiome. It is likely that appropriate microbial stimulation both pre-and postnatally are required for optimal Th1 and Treg development to avoid the pathophysiological processes leading to allergy. Disturbed gut colonisation patterns have been associated with allergic disease, but whether microbial variation is the cause or effect of these diseases is still under investigation. We are far from understanding what constitutes a "healthy gut microbiome" that promotes tolerance. This remains a major limitation and might explain some of the inconsistency in human intervention studies with prebiotics and probiotics. Multidisciplinary integrative approaches with researchers working in networks, using harmonised outcomes and methodologies are needed to advance our understanding in this field.

Research paper thumbnail of No effect of probiotics on respiratory allergies: a seven‐year follow‐up of a randomized controlled trial in infancy

Pediatric Allergy and Immunology, 2013

BackgroundSupplementation with the probiotic Lactobacillus reuteri reduced the incidence of IgE‐a... more BackgroundSupplementation with the probiotic Lactobacillus reuteri reduced the incidence of IgE‐associated allergic disease in infancy. This treatment might therefore also reduce the risk of asthma and allergic rhinoconjunctivitis in school age.ObjectiveTo evaluate whether perinatal and infant supplementation with L. reuteri reduced the prevalence of respiratory allergic disease in school age and to explore whether this supplementation was associated with any long‐term side effects.MethodsA randomized, placebo‐controlled trial with oral supplementation with L. reuteri ATCC 55730 (1 × 108 CFU) during the last month of gestation and through the first year of life comprising 232 families with allergic disease, of whom 184 completed a 7‐yr follow‐up. The primary outcomes at 7 yr of age were allergic disease and skin prick test reactivity (ClinicalTrials.gov ID NCT01285830).ResultsThe prevalence of asthma (15% in the probiotic vs. 16% in placebo group), allergic rhinoconjunctivitis (27% ...

Research paper thumbnail of Reduced IFN-γ and IL-10 responses to paternal antigens during and after pregnancy in allergic women

Journal of Reproductive Immunology, 2012

Normal pregnancy and allergy are both characterized by a T helper (Th) 2 deviation. In the curren... more Normal pregnancy and allergy are both characterized by a T helper (Th) 2 deviation. In the current study, we hypothesized that paternal antigen-induced cytokine responses during pregnancy would be deviated towards Th2 and an anti-inflammatory profile, and that the Th2 deviation would be more pronounced in allergic pregnant women. Blood samples were collected longitudinally on three occasions during pregnancy and two occasions post partum (pp). Of the 86 women initially included, 54 women had a normal pregnancy and completed the sampling procedures. Twelve women fulfilled the criteria for allergy (allergic symptoms and circulating immunoglobulin (Ig) E antibodies to inhalant allergens) and 20 were nonallergic (nonsensitized without symptoms). The levels of Th1 and Th2 associated cytokines and chemokines, the Th17 cytokine IL-17 and the anti-inflammatory cytokine IL-10 were compared between the groups. Paternal antigen induced IL-4 and IL-10 responses increased from the first to the third trimester. Allergy was associated with a decreased paternal antigeninduced IFN-γ and CXCL10 secretion in the non-pregnant state (one year post partum) and also decreased IFN-γ/IL-4 and IFN-γ/IL-13 ratios during pregnancy. We also observed a decreased paternal antigen induced IL-10 response in allergic compared with non-allergic women during pregnancy, along with a decreased IL-10/IL-13 ratio. In conclusion, our findings support the hypothesis of lower Th1 responses towards paternal antigens in allergic than in non-allergic women but also indicate that allergy is associated with a lower capacity to induce anti-inflammatory IL-10 responses after paternal antigen stimulation during pregnancy.

Research paper thumbnail of Immunological status in patients undergoing in vitro fertilisation: responses to hormone treatment and relationship to outcome

Journal of Reproductive Immunology, 2012

We aimed to prospectively investigate the paternal antigen-induced cytokine secretion by peripher... more We aimed to prospectively investigate the paternal antigen-induced cytokine secretion by peripheral blood mononuclear cells (PBMC) in response to hormone treatment in women undergoing in vitro fertilization (IVF) and to examine the predictive value of the cytokine secretion in the outcome of IVF treatment in a pilot study. Twenty-five women were included and IVF treatment was successful for six and unsuccessful for 19 women. Blood samples were collected before IVF treatment, on four occasions during IVF and 4 weeks after embryo transfer. The numbers of Th1-, Th2-and Th17-associated cytokine secreting cells and cytokine levels in cell supernatants were analyzed by enzyme linked immunospot-forming (ELISpot), enzyme-linked immune-sorbent (ELISA) or Luminex assay. None of the cytokines (IFN-γ, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17, TNF and GM-CSF) had any predictive value regarding IVF outcome. The majority of the cytokines reached their peak levels at ovum pickup, suggesting an enhancing influence of the hormonal stimulation. Pregnancy was associated with a high number of IL-4-, IL-5-and IL-13-secreting cells four weeks after ET. In conclusion, the results do not support our hypothesis of a more pronounced peripheral Th1 and Th17 deviation towards paternal antigens in infertile women with an unsuccessful IVF outcome, although this is based on a small number of observations. Thus, a larger study should be conducted to confirm this conclusion. Higher numbers of Th2-associated cytokinesecreting cells in pregnant women four weeks after ET do corroborate the hypothesis of a Th2 deviation during pregnancy.

Research paper thumbnail of Cord blood Th2-related chemokine CCL22 levels associate with elevated total-IgE during preschool age

Clinical & Experimental Allergy, 2012

Research paper thumbnail of Cytokine responses to allergens during the first 2 years of life in Estonian and Swedish children

Clinical <html_ent glyph="@amp;" ascii="&amp;"/> Experimental Allergy, 2006

Background: The prevalence of atopic disease among children in the formerly socialist countries i... more Background: The prevalence of atopic disease among children in the formerly socialist countries in Europe, with a life style similar to that prevailing in Western Europe 30-40 years ago, is low, whereas there has been a pronounced increase in industrialised countries over the last decades. The environment during infancy influences the risk of developing allergy for many years, perhaps even for life. Objective: To investigate the development of allergen specific cytokine responses during the first two years of life in two geographically adjacent countries with marked differences in living conditions and incidence of atopic diseases, i e Estonia and Sweden. Methods: The development of immune responses to the food (β-lactoglobulin (BLG) and ovalbumin) and inhalant (cat and birch) allergens were studied from birth up to the age of two years in 30 Estonian and 76 Swedish infants. Clinical investigation and skin prick tests were performed and blood samples obtained at birth and at 3, 6, 12 and 24 months. Results: The levels of IL-5, IL-10 and IL-13 secreted by PBMC stimulated with BLG, ovalbumin and cat allergen in the Estonian and Swedish infants declined during the first 3 months of life. All cytokines then progressively increased in the Swedish infants, indicating the replacement of non specifically responding immature cord blood T-cells with specific T-memory cells, which are primed postnatally. The resurgence of allergenspecific responses in the Estonian infants was less marked. These differences were particularly notable for birch-specific T-cell responses, which correlated with development of atopic disease in the Swedish children. Malin F Böttcher 3 Conclusions: The development of specific T-cell memory to food and inhalant allergens during the first two years of life differs between infants living in Sweden and Estonia, and mirrors the disparate patterns of expression of allergic disease which subsequently develops in the respective populations.