The gut microbiota of preterm infants develops predictably
, with pioneer species colonizing the gut after birth, followed by an ordered succession of microorganisms. The gut microbiota is vital to ...the health of preterm infants
, but the forces that shape these predictable dynamics of microbiome assembly are unknown. The environment, the host and interactions between microorganisms all potentially shape the dynamics of the microbiota, but in such a complex ecosystem, identifying the specific role of any individual factor is challenging
. Here we use multi-kingdom absolute abundance quantification, ecological modelling and experimental validation to address this challenge. We quantify the absolute dynamics of bacteria, fungi and archaea in a longitudinal cohort of 178 preterm infants. We uncover microbial blooms and extinctions, and show that there is an inverse correlation between bacterial and fungal loads in the infant gut. We infer computationally and demonstrate experimentally in vitro and in vivo that predictable assembly dynamics may be driven by directed, context-dependent interactions between specific microorganisms. Mirroring the dynamics of macroscopic ecosystems
, a late-arriving member of the microbiome, Klebsiella, exploits the pioneer microorganism, Staphylococcus, to gain a foothold within the gut. Notably, we find that interactions between different kingdoms can influence assembly, with a single fungal species-Candida albicans-inhibiting multiple dominant genera of gut bacteria. Our work reveals the centrality of simple microbe-microbe interactions in shaping host-associated microbiota, which is critical both for our understanding of microbiota ecology and for targeted microbiota interventions.
Wiskott-Aldrich syndrome: a comprehensive review Massaad, Michel J.; Ramesh, Narayanaswamy; Geha, Raif S.
Annals of the New York Academy of Sciences,
20/May , Letnik:
1285, Številka:
1
Journal Article
Recenzirano
Wiskott‐Aldrich syndrome (WAS) is a rare X‐linked primary immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and an increased incidence of autoimmunity and ...malignancies. The disease is caused by mutations in the WAS gene expressed exclusively in hematopoietic cells. WAS protein (WASp) is a multidomain protein that exists in complex with several partners that play important roles in its function. WASp belongs to a family of proteins that relay signals from the surface of the cell to the actin cytoskeleton. Mutations in the WAS gene have various effects on the level of WASp, which, in turn, correlates with the severity of the disease. In addition to WAS, mutations in the WAS gene can result in the mild variant X‐linked thrombocytopenia, or in X‐linked neutropenia, characterized by neutropenia with myelodysplasia. The absence of functional WASp leads to a severe clinical phenotype that can result in death if not diagnosed and treated early in life. The treatment of choice with the best outcome is hematopoietic stem cell transplantation, preferably from a matched related donor.
Thymic stromal lymphopoietin He, Rui; Geha, Raif S.
Annals of the New York Academy of Sciences,
January 2010, Letnik:
1183, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Thymic stromal lymphopoietin (TSLP) is an epithelial cell‐derived cytokine expressed in skin, gut, lungs, and thymus. TSLP signals via a TSLP receptor (TSLPR), a heterodimer of the IL‐7 receptor α ...chain and the TSLPR chain. The TSLPR chain is closely related to the common receptor γ chain that is expressed on a wide range of cell types in the adaptive and innate immune system. TSLP exerts a profound influence on the polarization of dendritic cells to drive T helper (Th) 2 cytokine production. TSLP also directly promotes T‐cell proliferation in response to T‐cell receptor activation and Th2 cytokine production and supports B‐cell expansion and differentiation. TSLP further amplifies Th2 cytokine production by mast cells and natural killer T cells. These properties confer on TSLP a critical role in driving Th2‐mediated inflammation. This role is supported by the finding that TSLP expression is upregulated in keratinocytes of atopic dermatitis skin lesions and in bronchial epithelial cells in asthma.
Summary
The identification of patients with monogenic gene defects have illuminated the function of different proteins in the immune system, including proteins that regulate the actin cytoskeleton. ...Many of these actin regulatory proteins are exclusively expressed in leukocytes and regulate the formation and branching of actin filaments. Their absence or abnormal function leads to defects in immune cell shape, cellular projections, migration, and signaling. Through the study of patients’ mutations and generation of mouse models that recapitulate the patients’ phenotypes, our laboratory and others have gained a better understanding of the role these proteins play in cell biology and the underlying pathogenesis of immunodeficiencies and immune dysregulatory syndromes.
Background Cutaneous exposure to food allergens predisposes to food allergy, which is commonly associated with atopic dermatitis (AD). Levels of the epithelial cytokine IL-33 are increased in skin ...lesions and serum of patients with AD. Mast cells (MCs) play a critical role in food-induced anaphylaxis and express the IL-33 receptor ST2. The role of IL-33 in patients with MC-dependent food anaphylaxis is unknown. Objective We sought to determine the role and mechanism of action of IL-33 in patients with food-induced anaphylaxis in a model of IgE-dependent food anaphylaxis elicited by oral challenge of epicutaneously sensitized mice. Methods Wild-type, ST2-deficient, and MC-deficient Kit W-sh/W-sh mice were epicutaneously sensitized with ovalbumin (OVA) and then challenged orally with OVA. Body temperature was measured by means of telemetry, Il33 mRNA by means of quantitative PCR, and IL-33, OVA-specific IgE, and mouse mast cell protease 1 by means of ELISA. Bone marrow–derived mast cell (BMMC) degranulation was assessed by using flow cytometry. Results Il33 mRNA expression was upregulated in tape-stripped mouse skin and scratched human skin. Tape stripping caused local and systemic IL-33 release in mice. ST2 deficiency, as well as ST2 blockade before oral challenge, significantly reduced the severity of oral anaphylaxis without affecting the systemic TH 2 response to the allergen. Oral anaphylaxis was abrogated in Kit W-sh/W-sh mice and restored by means of reconstitution with wild-type but not ST2-deficient BMMCs. IL-33 significantly enhanced IgE-mediated degranulation of BMMCs in vitro. Conclusion IL-33 is released after mechanical skin injury, enhances IgE-mediated MC degranulation, and promotes oral anaphylaxis after epicutaneous sensitization by targeting MCs. IL-33 neutralization might be useful in treating food-induced anaphylaxis in patients with AD.
Allergic skin inflammation elicited in mice by epicutaneous (EC) sensitization with antigen shares characteristics with human atopic dermatitis (AD).
We characterized gene expression by single cells ...in mouse skin undergoing antigen-driven allergic inflammation and compared the results with findings in AD skin lesions.
Mice were EC sensitized by application of ovalbumin (OVA) or saline to tape-stripped skin. Single-cell RNA sequencing was performed on skin cells 12 days later. Flow cytometry analysis was performed to validate results.
Sequencing identified 7 nonhematopoietic and 6 hematopoietic cell subsets in EC-sensitized mouse skin. OVA sensitization resulted in the expansion in the skin of T cells, dendritic cells, macrophages, mast cells/basophils, fibroblasts, and myocytes cell clusters, and in upregulation of TH2 cytokine gene expression in CD4+ T cells and mast cells/basophils. Genes differentially expressed in OVA-sensitized skin included genes important for inflammation in dendritic cells and macrophages, collagen deposition, and leukocyte migration in fibroblasts, chemotaxis in endothelial cells and skin barrier integrity, and differentiation in KCs—findings that recapitulate those in AD skin lesions. Unexpectedly, mast cells/basophils, rather than T cells, were the major source of Il4 and ll13 in OVA-sensitized mouse skin. In addition, our results suggest novel pathways in fibroblast and endothelial cells that may contribute to allergic skin inflammation.
The gene expression profile of single cells in mouse skin undergoing antigen-driven shares many features with that in AD skin lesions and unveils novel pathways that may be involved in allergic skin inflammation.
Mast cell (MC) mediator release after crosslinking of surface-bound IgE antibody by ingested antigen underlies food allergy. However, IgE antibodies are not uniformly associated with food allergy, ...and intestinal MC load is an important determinant. Atopic dermatitis (AD), characterized by pruritis and cutaneous sensitization to allergens, including foods, is strongly associated with food allergy. Tape stripping mouse skin, a surrogate for scratching, caused expansion and activation of small intestinal MCs, increased intestinal permeability, and promoted food anaphylaxis in sensitized mice. Tape stripping caused keratinocytes to systemically release interleukin-33 (IL-33), which synergized with intestinal tuft-cell-derived IL-25 to drive the expansion and activation of intestinal type-2 innate lymphoid cells (ILC2s). These provided IL-4, which targeted MCs to expand in the intestine. Duodenal MCs were expanded in AD. In addition to promoting cutaneous sensitization to foods, scratching may promote food anaphylaxis in AD by expanding and activating intestinal MCs.
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•Mechanical skin injury promotes intestinal mast-cell expansion•Intestinal mast-cell expansion requires skin-derived IL-33 and gut-derived IL-25•Intestinal mast-cell expansion requires ILC2 activation by IL-33 and IL-25•ILC2-derived IL-4 and IL-13 directly cause intestinal mast-cell expansion
Atopic dermatitis is a pruritic inflammatory skin disease highly associated with food allergy. Leyva-Castillo and colleagues demonstrate that a skin-to-gut crosstalk initiated by mechanical skin injury promotes food anaphylaxis by increasing mast cells in the gut.
Serum IL-22 levels are increased in patients with atopic dermatitis, which commonly precedes asthma in the atopic march. Epicutaneous sensitization in mice results in TH2-dominated skin inflammation ...that mimics atopic dermatitis and sensitizes the airways for antigen challenge–induced allergic inflammation characterized by the presence of both eosinophils and neutrophils. Epicutaneous sensitization results in increased serum levels of IL-22.
We sought to determine the role of IL-22 in antigen-driven airway allergic inflammation after inhalation challenge in epicutaneously sensitized mice.
Wild-type (WT) and Il22−/− mice were sensitized epicutaneously or immunized intraperitoneally with ovalbumin (OVA) and challenged intranasally with antigen. OVA T-cell receptor–specific T cells were TH22 polarized in vitro. Airway inflammation, mRNA levels in the lungs, and airway hyperresponsiveness (AHR) were examined.
Epicutaneous sensitization preferentially elicited an IL-22 response compared with intraperitoneal immunization. Intranasal challenge of mice epicutaneously sensitized with OVA elicited in the lungs Il22 mRNA expression, IL-22 production, and accumulation of CD3+CD4+IL-22+ T cells that coexpressed IL-17A and TNF-α. Epicutaneously sensitized Il22−/− mice exhibited diminished eosinophil and neutrophil airway infiltration and decreased AHR after intranasal OVA challenge. Production of IL-13, IL-17A, and TNF-α was normal, but IFN-γ production was increased in lung cells from airway-challenged and epicutaneously sensitized Il22−/− mice. Intranasal instillation of IFN-γ–neutralizing antibody partially reversed the defect in eosinophil recruitment. WT recipients of TH22-polarized WT, but not IL-22–deficient, T-cell receptor OVA-specific T cells, which secrete both IL-17A and TNF-α, had neutrophil-dominated airway inflammation and AHR on intranasal OVA challenge. Intranasal instillation of IL-22 with TNF-α, but not IL-17A, elicited neutrophil-dominated airway inflammation and AHR in WT mice, suggesting that loss of IL-22 synergy with TNF-α contributed to defective recruitment of neutrophils into the airways of Il22−/− mice. TNF-α, but not IL-22, blockade at the time of antigen inhalation challenge inhibited airway inflammation in epicutaneously sensitized mice.
Epicutaneous sensitization promotes generation of antigen-specific IL-22–producing T cells that promote airway inflammation and AHR after antigen challenge, suggesting that IL-22 plays an important role in the atopic march.
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