| 1. |
- Spreckels, Johanne, et al.
(author)
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Lactobacillus reuteri Colonisation of Extremely Preterm Infants in a Randomised Placebo-Controlled Trial
- 2021
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In: Microorganisms. - : MDPI AG. - 2076-2607. ; 9:5
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Journal article (peer-reviewed)abstract
- Lactobacillus reuteri DSM 17938 supplementation reduces morbidities in very low birth weight infants (<1500 g), while the effect on extremely low birth weight infants (ELBW, <1000 g) is still questioned. In a randomised placebo-controlled trial (ClinicalTrials.gov ID NCT01603368), head growth, but not feeding tolerance or morbidities, improved in L. reuteri-supplemented preterm ELBW infants. Here, we investigate colonisation with the probiotic strain in preterm ELBW infants who received L. reuteri DSM 17938 or a placebo from birth to postmenstrual week (PMW) 36. Quantitative PCR was used on 582 faecal DNA samples collected from 132 ELBW infants at one, two, three, and four weeks, at PMW 36, and at two years of age. Human milk oligosaccharides were measured in 31 milk samples at two weeks postpartum. At least 86% of the ELBW infants in the L. reuteri group were colonised with the probiotic strain during the neonatal period, despite low gestational age, high antibiotic pressure, and independent of infant feeding mode. Higher concentrations of lacto-N-tetraose, sialyl-lacto-N-neotetraose c, and 6 '-sialyllactose in mother's milk weakly correlated with lower L. reuteri abundance. Within the L. reuteri group, higher L. reuteri abundance weakly correlated with a shorter time to reach full enteral feeding. Female sex and L. reuteri colonisation improved head growth from birth to four weeks of age. In conclusion, L. reuteri DSM 17938 supplementation leads to successful colonisation in ELBW infants.
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| 2. |
- Badolati, Isabella, et al.
(author)
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Staphylococcus aureus-derived factors promote human Th9 cell polarization and enhance a transcriptional program associated with allergic inflammation
- 2023
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In: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 53:3
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Journal article (peer-reviewed)abstract
- T helper (Th) 9 cells, characterized by robust secretion of IL-9, have been increasingly associated with allergic diseases. However, whether and how Th9 cells are modulated by environmental stimuli remains poorly understood. In this study, we show that in vitro exposure of human PBMCs or isolated CD4 T-cells to Staphylococcus (S.) aureus-derived factors, including its toxins, potently enhances Th9 cell frequency and IL-9 secretion. Furthermore, as revealed by RNA sequencing analysis, S. aureus increases the expression of Th9-promoting factors at the transcriptional level, such as FOXO1, miR-155, and TNFRSF4. The addition of retinoic acid (RA) dampens the Th9 responses promoted by S. aureus and substantially changes the transcriptional program induced by this bacterium, while also altering the expression of genes associated with allergic inflammation. Together, our results demonstrate a strong influence of microbial and dietary factors on Th9 cell polarization, which may be important in the context of allergy development and treatment.
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| 3. |
- Badolati, Isabella, et al.
(author)
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Th9 cells in allergic diseases : A role for the microbiota?
- 2020
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In: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 91:4
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Journal article (peer-reviewed)abstract
- Since their discovery about 10 years ago, Th9 cells have been increasingly linked to allergic pathologies. Within this review, we summarize the current knowledge on associations between Th9 cells and allergic diseases and acknowledge Th9 cells as important targets in future treatment of allergic diseases. However, until today, it is not fully understood how these Th9 cell responses are modulated. We describe current literature suggesting that these Th9 cell responses might be stimulated by microbial species such as Staphylococcus aureus and Candida albicans, while on the other hand, microbial and dietary compounds such as retinoic acid (RA), butyrate and vitamin D show suppressive capacity on allergy-related Th9 responses. By reviewing this recent research, we provide new insights into the modulating capacity of the microbiota on Th9 cell responses. Consequently, microbial and dietary factors may be used as innovative tools to target Th9 cells in the treatment of allergic diseases. However, further research is needed to elucidate the mechanisms behind these interactions in order to translate this knowledge into clinical allergy settings.
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| 4. |
- Björkander, Sofia, et al.
(author)
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Childhood allergy is preceded by an absence of gut lactobacilli species and higher levels of atopy-related plasma chemokines
- 2020
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In: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 202:3, s. 288-299
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Journal article (peer-reviewed)abstract
- Alterations 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 nitrogen oxide (FeNO) was measured and spirometry performed at 10 years of age. The data were analysed by non‐parametric testing and a logistic regression model adjusted for parental allergy. An absence of these lactobacilli and higher levels of the chemokines BCA‐1/CXCL13, CCL17/TARC, MIP‐3α/CCL20 and MDC/CCL22 in plasma at 6 months of age preceded allergy development. The presence of lactobacilli associated with lower levels of atopy‐related chemokines during infancy, together with higher levels of interferon (IFN)‐γ and lower FeNO during later childhood. The results indicate that the presence of certain lactobacilli species in the infant gut may influence allergy‐related parameters in the peripheral immune system, and thereby contribute to allergy protection.
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| 5. |
- Lasaviciute, Gintare, et al.
(author)
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Deficits in the IgG+ memory B‐cell recovery after anthracycline treatment is confined to the spleen of rhesus macaques
- 2020
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In: Clinical & Translational Immunology (CTI). - : Wiley. - 2050-0068. ; 9:7
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Journal article (peer-reviewed)abstract
- Objectives. Loss of vaccine-induced antibodies (Abs) after chemotherapy against paediatric acute lymphoblastic leukaemia (ALL) is common and often necessitates re-immunisation after cessation of treatment. Even so, some ALL survivors fail to mount or to maintain protective Abs. Germinal centres (GCs) are clusters of proliferating B cells in follicles of secondary lymphoid tissues (SLTs) formed during adaptive immune responses and the origins of long-lived memory B and plasma cells that are the source of Abs. Furthermore, productive GC reactions depend on T follicular helper (TFH) cells. To understand why chemotherapy induces deficits in Ab responses, we examined how SLTs were affected by chemotherapy. Methods. Rhesus macaques were infused with either three cycles of the anthracycline doxorubicin or saline, followed by immunisation with a de novo and booster antigen. Spleen and lymph nodes were removed, and memory B, bulk T and TFH cells were examined. Results. Despite adequate GC morphology, a diminished memory and IgG+ B-cell population along with diminished total and booster vaccine-specific IgGproducing memory B cells were noted in the spleens of macaques with past doxorubicin exposure compared to the saline-treated controls (P < 0.05). Intact bulk T and TFH cells were found in the SLTs of treated macaques, which displayed higher CD40L upregulation capacity by their splenic CXCR5+ helper T cells (P < 0.01). In contrast to the spleen, the immune cell populations studied were comparable between the lymph nodes of both saline- and doxorubicin-treated macaques. Conclusion. Our findings suggest that the splenic memory B-cell subset, compared to its lymph node counterpart, is more severely altered by anthracycline treatment.
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| 6. |
- Lasaviciute, Gintare, 1990-
(author)
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Functions and memory features of adaptive- and innate immune cells in physiological and inflammatory settings
- 2022
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Doctoral thesis (other academic/artistic)abstract
- The immune system is a complex but well-regulated network which cooperates with the microbiota to maintain optimal homeostasis under physiological settings. A number of factors display the capacity to alter the immune system and thus microbiota crosstalk including host genetics, diet, environmental influences and drugs such as antibiotics or chemotherapeutic agents.We and others have previously demonstrated immune regulatory capacities of the gut commensal Limosilactobacillus reuteri (L. reuteri) that seem to act via myeloid cells. In paper I, we have further shown that priming of blood dendritic cells (DCs) or monocytes with L. reuteri-derived cell free supernatant (CFS) modifies how these cells respond to future stimulus challenge, even after monocytes differentiation to DCs (mo-DCs). Notably, priming conditions in mo-DCs skewed subsequent T-helper cell responses. In paper II, we continued to elaborate on whether microbial and gut-associated metabolites modify chemotherapy-induced effects. Thus far, we could show that the CFS from probiotic bacteria might imprint immune cells to modulate inflammatory responses when intestinal epithelial cells are compromised by chemotherapy exposure. In paper III, we investigated how chemotherapy agent Doxorubicin (Doxo) affects bone marrow resident mesenchymal stromal cells (BM MSCs) which support antibody secreting cells (ASCs) responsible for serological memory. Our findings have shown that Doxo-induced alterations in BM MSCs are not sufficient to disrupt their support to ASCs, thus alternative or additional factors might be implicated in ASC preservation during chemotherapy. Lastly, in paper IV, we investigated how Doxo affects secondary lymphoid organs and we found that splenic compartment is more prominently affected by Doxo treatment compared to its lymph node counterpart in an animal model of rhesus macaques.Collectively, this thesis outlines novel perceptions on innate immune memory-like capacity and how gut-associated factors influence such recall responses in innate immune cells. Further, this thesis increases our knowledge on how adaptive immune cells, required for long-term serological memory, are preserved during toxic conditions such as those induced by chemotherapy treatment.
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| 7. |
- Lasaviciute, Gintare, et al.
(author)
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Gut commensal Limosilactobacillus reuteri induces atypical memory-like phenotype in human dendritic cells in vitro
- 2022
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In: Gut microbes. - : Informa UK Limited. - 1949-0976 .- 1949-0984. ; 14:1
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Journal article (peer-reviewed)abstract
- Memory-like responses in innate immune cells confer nonspecific protection against secondary exposures. A number of microbial agents have been found to induce enhanced or diminished recall responses in innate cells, however, studies investigating the ability of probiotic bacteria to trigger such effects are lacking. Here, we show that priming of human monocytes with a secretome from the gut probiotic bacterium Limosilactobacillus (L.) reuteri induces a mixed secondary response phenotype in monocyte-derived dendritic cells (mo-DCs), with a strong IL-6 and IL-1β response but low TNFα, IL-23 and IL-27 secretion. Instead, blood DC priming with L. reuteri-secretome resembles a tolerant state upon secondary exposure. A similar pattern was found in conventional and gut-like (retinoic acid exposed) DCs, although retinoic acid hampered TNFα and IL-6 production and enrichment of histone modifications in L. reuteri-secretome primed mo-DC cultures. Further, we show that the memory-like phenotype of mo-DCs, induced by priming stimuli, is important for subsequent T helper (Th) cell differentiation pathways and might determine the inflammatory nature of Th cells. We also show enhanced recall responses characterized by robust inflammatory cytokines and lactate production in the gut-like mo-DCs derived from β-glucan primed monocytes. Such responses were accompanied with enriched histone modifications at the promoter of genes associated with a trained phenotype in myeloid cells. Altogether, we demonstrate that a gut commensal-derived secretome prompts recall responses in human DCs which differ from that induced by classical training agents such as β-glucan. Our results could be beneficial for future therapeutic interventions where T cell responses are needed to be modulated.
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| 8. |
- Lasaviciute, Gintare, 1990-, et al.
(author)
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Human Bone Marrow Mesenchymal Stromal Cell-Derived CXCL12, IL-6 and GDF-15 and Their Capacity to Support IgG-Secreting Cells in Culture Are Divergently Affected by Doxorubicin
- 2021
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In: Hemato. - : MDPI AG. - 2673-6357. ; 2:1, s. 154-166
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Journal article (peer-reviewed)abstract
- Various subsets of bone marrow mesenchymal stromal cells (BM MSCs), including fibroblasts, endothelial, fat and reticular cells, are implicated in the regulation of the hematopoietic microenvironment and the survival of long-lived antibody-secreting cells (ASCs). Nowadays it is widely acknowledged that vaccine-induced protective antibody levels are diminished in adults and children that are treated for hematological cancers. A reason behind this could be damage to the BM MSC niche leading to a diminished pool of ASCs. To this end, we asked whether cell cytotoxic treatment alters the capacity of human BM MSCs to support the survival of ASCs. To investigate how chemotherapy affects soluble factors related to the ASC niche, we profiled a large number of cytokines and chemokines from in vitro-expanded MSCs from healthy donors or children who were undergoing therapy for acute lymphoblastic leukemia (ALL), following exposure to a widely used anthracycline called doxorubicin (Doxo). In addition, we asked if the observed changes in the measured soluble factors after Doxo exposure impacted the ability of the BM niche to support humoral immunity by co-culturing Doxo-exposed BM MSCs with in vitro-differentiated ASCs from healthy blood donors, and selective neutralization of cytokines. Our in vitro results imply that Doxo-induced alterations in BM MSC-derived interleukin 6 (IL-6), CXCL12 and growth and differentiation factor 15 (GDF-15) are not sufficient to disintegrate the support of IgG-producing ASCs by the BM MSC niche, and that serological memory loss may arise during later stages of ALL therapy.
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| 9. |
- Martí Generó, Magalí Martí, et al.
(author)
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Effects of Lactobacillus reuteri supplementation on the gut microbiota in extremely preterm infants in a randomized placebo-controlled trial
- 2021
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In: Cell Reports Medicine. - : Cell Press. - 2666-3791. ; 2:3
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Journal article (peer-reviewed)abstract
- Extremely low birth weight (ELBW) infants often develop an altered gut microbiota composition, which is related to clinical complications, such as necrotizing enterocolitis and sepsis. Probiotic supplementation may reduce these complications, and modulation of the gut microbiome is a potential mechanism underlying the probiotic effectiveness. In a randomized, double-blind, placebo-controlled trial, we assessed the effect of Lactobacillus reuteri supplementation, from birth to post-menstrual week (PMW)36, on infant gut microbiota. We performed 16S amplicon sequencing in 558 stool samples from 132 ELBW preterm infants at 1 week, 2 weeks, 3 weeks, 4 weeks, PMW36, and 2 years. Probiotic supplementation results in increased bacterial diversity and increased L. reuteri abundance during the 1st month. At 1 week, probiotic supplementation also results in a lower abundance of Enterobacteriaceae and Staphylococcaceae. No effects were found at 2 years. In conclusion, probiotics may exert benefits by modulating the gut microbiota composition during the 1st month in ELBW infants.
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| 10. |
- Mata Forsberg, Manuel, et al.
(author)
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Activation of human γδ T cells and NK cells by Staphylococcal enterotoxins requires both monocytes and conventional T cells
- 2022
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In: Journal of Leukocyte Biology. - 0741-5400 .- 1938-3673. ; 111:3, s. 597-609
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Journal article (peer-reviewed)abstract
- Staphylococcal enterotoxins (SE) pose a great threat to human health due to their ability to bypass antigen presentation and activate large amounts of conventional T cells resulting in a cytokine storm potentially leading to toxic shock syndrome. Unconventional T- and NK cells are also activated by SE but the mechanisms remain poorly understood. In this study, the authors aimed to explore the underlying mechanism behind SE-mediated activation of MAIT-, γδ T-, and NK cells in vitro. CBMC or PBMC were stimulated with the toxins SEA, SEH, and TSST-1, and cytokine and cytotoxic responses were analyzed with ELISA and flow cytometry. All toxins induced a broad range of cytokines, perforin and granzyme B, although SEH was not as potent as SEA and TSST-1. SE-induced IFN-γ expression in MAIT-, γδ T-, and NK cells was clearly reduced by neutralization of IL-12, while cytotoxic compounds were not affected at all. Kinetic assays showed that unconventional T cell and NK cell-responses are secondary to the response in conventional T cells. Furthermore, co-cultures of isolated cell populations revealed that the ability of SEA to activate γδ T- and NK cells was fully dependent on the presence of both monocytes and αβ T cells. Lastly, it was found that SE provoked a reduced and delayed cytokine response in infants, particularly within the unconventional T and NK cell populations. This study provides novel insights regarding the activation of unconventional T- and NK cells by SE, which contribute to understanding the vulnerability of young children towards Staphylococcus aureus infections.
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