RESUMEN
Intestinal helminth infection triggers a type 2 immune response that promotes a 'weep-and sweep' response characterised by increased mucus secretion and intestinal hypermotility, which function to dislodge the worm from its intestinal habitat. Recent studies have discovered that several other pathogens cause intestinal dysmotility through major alterations to the immune and enteric nervous systems (ENS), and their interactions, within the gastrointestinal tract. However, the involvement of these systems has not been investigated for helminth infections. Eosinophils represent a key cell type recruited by the type 2 immune response and alter intestinal motility under steady-state conditions. Our study aimed to investigate whether altered intestinal motility driven by the murine hookworm, Nippostrongylus brasiliensis, infection involves eosinophils and how the ENS and smooth muscles of the gut are impacted. Eosinophil deficiency did not influence helminth-induced intestinal hypermotility and hypermotility did not involve gross structural or functional changes to the ENS. Hypermotility was instead associated with a dramatic increase in smooth muscle thickness and contractility, an observation that extended to another rodent nematode, Heligmosomoides polygyrus. In summary our data indicate that, in contrast to other pathogens, helminth-induced intestinal hypermotility is driven by largely by myogenic, rather than neurogenic, alterations with such changes occurring independently of eosinophils. (<300 words).
Asunto(s)
Sistema Nervioso Entérico , Eosinófilos , Motilidad Gastrointestinal , Músculo Liso , Nippostrongylus , Animales , Ratones , Eosinófilos/inmunología , Músculo Liso/parasitología , Sistema Nervioso Entérico/parasitología , Sistema Nervioso Entérico/inmunología , Motilidad Gastrointestinal/fisiología , Nematospiroides dubius/fisiología , Nematospiroides dubius/inmunología , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/parasitología , Parasitosis Intestinales/inmunología , Parasitosis Intestinales/parasitología , Helmintiasis/inmunología , Helmintiasis/parasitología , Neuronas/parasitología , Neuronas/metabolismo , Ratones Endogámicos C57BLRESUMEN
Eosinophils play divergent roles in health and disease, contributing to both immunoregulatory and proinflammatory responses. Helminth infection is strongly associated with eosinophilia and the induction of the type 2 cytokines interleukin (IL)-5, IL-4 and IL-13. This study aimed to elucidate the heterogeneity of pulmonary eosinophils in response to helminth infection and the roles of IL-5, IL-4 and IL-13 in driving pulmonary eosinophil responses. Using the murine helminth model Nippostrongylus brasiliensis (Nb), we characterize a subtype of eosinophils, defined by high expression of CD101, that is induced in the lungs of Nb-infected mice and are phenotypically distinct from lung eosinophils that express low levels of CD101. Strikingly, we show that the two eosinophil subtypes have distinct anatomical localization within the lung: CD101low eosinophils are predominantly localized in the lung vasculature, whereas Nb-induced CD101hi eosinophils are predominantly localized in the extravascular lung niche. We show that CD101hi eosinophils are also induced across other models of pulmonary infection and inflammation, including a nonlung-migrating helminth infection, house dust mite-induced allergic inflammation and influenza infection. Furthermore, we demonstrate that the induction of CD101hi tissue eosinophils is independent of IL-5 and IL-4 signaling, but is dependent on intact IL-13 signaling. These results suggest that IL-13 produced during helminth infection and other disease states promotes a pulmonary tissue-infiltrating program in eosinophils defined by high expression of CD101.
RESUMEN
Increased permeability of the intestinal epithelial layer is linked to the pathogenesis and perpetuation of a wide range of intestinal and extra-intestinal diseases. Infecting humans with controlled doses of helminths, such as human hookworm (termed hookworm therapy), is proposed as a treatment for many of the same diseases. Helminths induce immunoregulatory changes in their host which could decrease epithelial permeability, which is highlighted as a potential mechanism through which helminths treat disease. Despite this, the influence of a chronic helminth infection on epithelial permeability remains unclear. This study uses the chronically infecting intestinal helminth Heligmosomoides polygyrus to reveal alterations in the expression of intestinal tight junction proteins and epithelial permeability during the infection course. In the acute infection phase (1 week postinfection), an increase in intestinal epithelial permeability is observed. Consistent with this finding, jejunal claudin-2 is upregulated and tricellulin is downregulated. By contrast, in the chronic infection phase (6 weeks postinfection), colonic claudin-1 is upregulated and epithelial permeability decreases. Importantly, this study also investigates changes in epithelial permeability in a small human cohort experimentally challenged with the human hookworm, Necator americanus. It demonstrates a trend toward small intestinal permeability increasing in the acute infection phase (8 weeks postinfection), and colonic and whole gut permeability decreasing in the chronic infection phase (24 weeks postinfection), suggesting a conserved epithelial response between humans and mice. In summary, our findings demonstrate dynamic changes in epithelial permeability during a chronic helminth infection and provide another plausible mechanism by which chronic helminth infections could be utilized to treat disease.
Asunto(s)
Mucosa Intestinal , Permeabilidad , Animales , Humanos , Mucosa Intestinal/parasitología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunología , Enfermedad Crónica , Nematospiroides dubius/inmunología , Ratones , Necator americanus , Parasitosis Intestinales/inmunología , Uniones Estrechas/metabolismo , Proteínas de Uniones Estrechas/metabolismo , Intestino Delgado/parasitología , Intestino Delgado/inmunología , Femenino , Ratones Endogámicos C57BL , Masculino , Helmintiasis/inmunología , Helmintiasis/parasitología , Necatoriasis/inmunología , Proteína 2 con Dominio MARVEL/metabolismoRESUMEN
Visceral adipose tissue (VAT) is an energy store and endocrine organ critical for metabolic homeostasis. Regulatory T (Treg) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct Treg cell populations: prototypical serum stimulation 2-positive (ST2+) Treg cells that are enriched in males and a previously uncharacterized population of C-X-C motif chemokine receptor 3-positive (CXCR3+) Treg cells that are enriched in females. We show that the transcription factors GATA-binding protein 3 and peroxisome proliferator-activated receptor-γ, together with the cytokine interleukin-33, promote the differentiation of ST2+ VAT Treg cells but repress CXCR3+ Treg cells. Conversely, the differentiation of CXCR3+ Treg cells is mediated by the cytokine interferon-γ and the transcription factor T-bet, which also antagonize ST2+ Treg cells. Finally, we demonstrate that ST2+ Treg cells preserve glucose homeostasis, whereas CXCR3+ Treg cells restrain inflammation in lean VAT and prevent glucose intolerance under high-fat diet conditions. Overall, this study defines two molecularly and developmentally distinct VAT Treg cell types with unique context- and sex-specific functions.
Asunto(s)
Proteína 1 Similar al Receptor de Interleucina-1 , Linfocitos T Reguladores , Femenino , Masculino , Humanos , Grasa Intraabdominal , Citocinas , Inflamación , GlucosaRESUMEN
T helper 2 (Th2) cells stochastically express from the Il4 locus but it has not been determined whether allelic expression is linked or independent. Here, we provide evidence that alleles are independently activated and inactivated. We compared Il4 locus expression in T cells from hemizygous IL-4 reporter mice in culture and in vivo following exposure to type 2 immunogens. In culture, Il4 alleles had independent, heritable expression probabilities. Modeling showed that in co-expressors, dual allele transcription occurs for only short periods, limiting per-cell mRNA variation in individual cells within a population of Th2 cells. In vivo profiles suggested that early in the immune response, IL-4 output was derived predominantly from single alleles, but co-expression became more frequent over time and were tuned by STAT6, supporting the probabilistic regulation of Il4 alleles in vivo among committed IL-4 producers. We suggest an imprinted probability of expression from individual alleles with a short transcriptional shutoff time controls the magnitude of T cell IL-4 output, but the amount produced per allele is amplified by STAT6 signaling. This form of regulation may be a relevant general mechanism governing cytokine expression.
Asunto(s)
Interleucina-4 , Células Th2 , Animales , Ratones , Alelos , Citocinas , ARN Mensajero/genéticaRESUMEN
The intestinal barrier is a dynamic multi-layered structure which can adapt to environmental changes within the intestinal lumen. It has the complex task of allowing nutrient absorption while limiting entry of harmful microbes and microbial antigens present in the intestinal lumen. Excessive entry of microbial antigens via microbial translocation due to 'intestinal barrier dysfunction' is hypothesised to contribute to the increasing incidence of allergic, autoimmune and metabolic diseases, a concept referred to as the 'epithelial barrier theory'. Helminths reside in the intestinal tract are in intimate contact with the mucosal surfaces and induce a range of local immunological changes which affect the layers of the intestinal barrier. Helminths are proposed to prevent, or even treat, many of the diseases implicated in the epithelial barrier theory. This review will focus on the effect of helminths on intestinal barrier function and explore whether this could explain the proposed health benefits delivered by helminths.
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Enfermedades Gastrointestinales , Helmintos , Enfermedades Intestinales , Humanos , Animales , Mucosa Intestinal , Intestinos , Enfermedades Intestinales/metabolismo , AntígenosRESUMEN
The ability of a third dose of the Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine to stimulate immune responses against subvariants, including Omicron BA.1, has not been assessed in New Zealand populations. Unlike many overseas populations, New Zealanders were largely infection naïve at the time they were boosted. This adult cohort of 298 participants, oversampled for at-risk populations, was composed of 29% Maori and 28% Pacific peoples, with 40% of the population aged 55+. A significant proportion of the cohort was obese and presented with at least one comorbidity. Sera were collected 28 days and 6 months post second vaccination and 28 days post third vaccination. SARS-CoV-2 anti-S IgG titres and neutralising capacity using surrogate viral neutralisation assays against variants of concern, including Omicron BA.1, were investigated. The incidence of SARS-CoV-2 infection, within our cohort, prior to third vaccination was very low (<6%). This study found a third vaccine significantly increased the mean SARS-CoV-2 anti-S IgG titres, for every demographic subgroup, by a minimum of 1.5-fold compared to titres after two doses. Diabetic participants experienced a greater increase (â¼4-fold) in antibody titres after their third vaccination, compared to non-diabetics (increase of â¼ 2-fold). This corrected for the deficiency in antibody titres within diabetic participants which was observed following two doses. A third dose also induced a neutralising response against Omicron variant BA.1, which was absent after two doses. This neutralising response improved regardless of age, BMI, ethnicity, or diabetes status. Participants aged ≥75 years consistently had the lowest SARS-CoV-2 anti-S IgG titres at each timepoint, however experienced the greatest improvement after three doses compared to younger participants. This study shows that in the absence of prior SARS-CoV-2 infection, a third Pfizer-BioNTech BNT162b2 vaccine enhances immunogenicity, including against Omicron BA.1, in a cohort representative of at-risk groups in the adult New Zealand population.
Asunto(s)
Vacuna BNT162 , COVID-19 , Adulto , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19 , Inmunoglobulina G , Pueblo Maorí , Nueva Zelanda/epidemiología , SARS-CoV-2 , Vacunación , Persona de Mediana Edad , Pueblos Isleños del Pacífico , Inmunogenicidad VacunalRESUMEN
BACKGROUND: Human hookworm has been proposed as a treatment for ulcerative colitis (UC). This pilot study assessed the feasibility of a full-scale randomized control trial examining hookworm to maintain clinical remission in patients with UC. METHODS: Twenty patients with UC in disease remission (Simple Clinical Colitis Activity Index [SCCAI] ≤4 and fecal calprotectin (fCal) <100 ug/g) and only on 5-aminosalicylate received 30 hookworm larvae or placebo. Participants stopped 5-aminosalicylate after 12 weeks. Participants were monitored for up to 52 weeks and exited the study if they had a UC flare (SCCAI ≥5 and fCal ≥200 µg/g). The primary outcome was difference in rates of clinical remission at week 52. Differences were assessed for quality of life (QoL) and feasibility aspects including recruitment, safety, effectiveness of blinding, and viability of the hookworm infection. RESULTS: At 52 weeks, 4 of 10 (40%) participants in the hookworm group and 5 of 10 (50%) participants in the placebo group had maintained clinical remission (odds ratio, 0.67; 95% CI, 0.11-3.92). Median time to flare in the hookworm group was 231 days (interquartile range [IQR], 98-365) and 259 days for placebo (IQR, 132-365). Blinding was quite successful in the placebo group (Bang's blinding index 0.22; 95% CI, -0.21 to 1) but less successful in the hookworm group (0.70; 95% CI, 0.37-1.0). Almost all participants in the hookworm group had detectable eggs in their faeces (90%; 95% CI, 0.60-0.98), and all participants in this group developed eosinophilia (peak eosinophilia 4.35â ×â 10^9/L; IQR, 2.80-6.68). Adverse events experienced were generally mild, and there was no significant difference in QoL. CONCLUSIONS: A full-scale randomized control trial examining hookworm therapy as a maintenance treatment in patients with UC appears feasible.
This pilot study has shown a full-scale RCT examining hookworm therapy as maintenance therapy in patients with ulcerative colitis is feasible, safe, and will be well-tolerated.
RESUMEN
Recent studies propose that T follicular helper (Tfh) cells possess a high degree of functional plasticity in addition to their well-defined roles in mediating interleukin-4-dependent switching of germinal center B cells to the production of immunoglobulin (Ig)G1 and IgE antibodies. In particular Tfh cells have been proposed to be an essential stage in Th2 effector cell development that are able to contribute to innate type 2 responses. We used CD4-cre targeted deletion of BCL6 to identify the contribution Tfh cells make to tissue Th2 effector responses in models of atopic skin disease and lung immunity to parasites. Ablation of Tfh cells did not impair the development or recruitment of Th2 effector subsets to the skin and did not alter the transcriptional expression profile or functional activities of the resulting tissue resident Th2 effector cells. However, the accumulation of Th2 effector cells in lung Th2 responses was partially affected by BCL6 deficiency. These data indicate that the development of Th2 effector cells does not require a BCL6 dependent step, implying Tfh and Th2 effector populations follow separate developmental trajectories and Tfh cells do not contribute to type 2 responses in the skin.
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Linfocitos T CD4-Positivos , Linfocitos T Colaboradores-Inductores , Diferenciación Celular , Centro Germinal , Linfocitos B , Proteínas Proto-Oncogénicas c-bcl-6/genéticaRESUMEN
BACKGROUND: There is very little known about SARS-CoV-2 vaccine immune responses in New Zealand populations at greatest risk for serious COVID-19 disease. METHODS: This prospective cohort study assessed immunogenicity in BNT162b2 mRNA vaccine recipients in New Zealand without previous COVID-19, with enrichment for Maori, Pacific peoples, older adults ≥ 65 years of age, and those with co-morbidities. Serum samples were analysed at baseline and 28 days after second dose for presence of quantitative anti-S IgG by chemiluminescent microparticle immunoassay and for neutralizing capacity against Wuhan, Beta, Delta, and Omicron BA.1 strains using a surrogate viral neutralisation assay. RESULTS: 285 adults with median age of 52 years were included. 55% were female, 30% were Maori, 28% were Pacific peoples, and 26% were ≥ 65 years of age. Obesity, cardiac and pulmonary disease and diabetes were more common than in the general population. All participants received 2 doses of BNT162b2 vaccine. At 28 days after second vaccination, 99.6% seroconverted to the vaccine, and anti-S IgG and neutralising antibody levels were high across gender and ethnic groups. IgG and neutralising responses declined with age. Lower responses were associated with age ≥ 75 and diabetes, but not BMI. The ability to neutralise the Omicron BA.1 variant in vitro was severely diminished but maintained against other variants of concern. CONCLUSIONS: Vaccine antibody responses to BNT162b2 were generally robust and consistent with international data in this COVID-19 naïve cohort with representation of key populations at risk for COVID-19 morbidity. Subsequent data on response to boosters, durability of responses and cellular immune responses should be assessed with attention to elderly adults and diabetics.
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Vacunas contra la COVID-19 , COVID-19 , Anciano , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacuna BNT162 , COVID-19/prevención & control , Femenino , Humanos , Inmunogenicidad Vacunal , Inmunoglobulina G , Masculino , Persona de Mediana Edad , Nueva Zelanda/epidemiología , Estudios Prospectivos , SARS-CoV-2 , Vacunas Sintéticas , Vacunas de ARNmRESUMEN
A characteristic feature of host responses to helminth infections is the development of profound systemic and tissue-localised Type 2 immune responses that play critical roles in immunity, tissue repair and tolerance of the parasite at tissue sites. These same Type 2 responses are also seen in the tissue-associated immune-pathologies seen in asthma, atopic dermatitis and many forms of allergies. The recent identification of new subtypes of immune cells and cytokine pathways that influence both immune and non-immune cells and tissues creates the opportunity for reviewing helminth parasite-host responses in the context of tissue specific immunity. This review focuses on the new discoveries of the cells and cytokines involved in tissue specific immune responses to helminths and how these contribute to host immunity against helminth infection and allow the host to accommodate the presence of parasites when they cannot be eliminated.
Asunto(s)
Helmintiasis , Helmintos , Parásitos , Animales , Inmunidad , Citocinas , Interacciones Huésped-ParásitosRESUMEN
Recent advances in the field of host immunity against parasitic nematodes have revealed the importance of macrophages in trapping tissue migratory larvae. Protective immune mechanisms against the rodent hookworm Nippostrongylus brasiliensis (Nb) are mediated, at least in part, by IL-4-activated macrophages that bind and trap larvae in the lung. However, it is still not clear how host macrophages recognize the parasite. An in vitro co-culture system of bone marrow-derived macrophages and Nb infective larvae was utilized to screen for the possible ligand-receptor pair involved in macrophage attack of larvae. Competitive binding assays revealed an important role for ß-glucan recognition in the process. We further identified a role for CD11b and the non-classical pattern recognition receptor ephrin-A2 (EphA2), but not the highly expressed ß-glucan dectin-1 receptor, in this process of recognition. This work raises the possibility that parasitic nematodes synthesize ß-glucans and it identifies CD11b and ephrin-A2 as important pattern recognition receptors involved in the host recognition of these evolutionary old pathogens. To our knowledge, this is the first time that EphA2 has been implicated in immune responses to a helminth.
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Interleucina-4 , Lectinas Tipo C , Ancylostomatoidea , Animales , Interleucina-4/metabolismo , Larva , Lectinas Tipo C/metabolismo , Macrófagos/metabolismo , Receptores InmunológicosRESUMEN
The signals driving the adaptation of type 2 dendritic cells (DC2s) to diverse peripheral environments remain mostly undefined. We show that differentiation of CD11blo migratory DC2s-a DC2 population unique to the dermis-required IL-13 signaling dependent on the transcription factors STAT6 and KLF4, whereas DC2s in lung and small intestine were STAT6-independent. Similarly, human DC2s in skin expressed an IL-4 and IL-13 gene signature that was not found in blood, spleen and lung DCs. In mice, IL-13 was secreted homeostatically by dermal innate lymphoid cells and was independent of microbiota, TSLP or IL-33. In the absence of IL-13 signaling, dermal DC2s were stable in number but remained CD11bhi and showed defective activation in response to allergens, with diminished ability to support the development of IL-4+GATA3+ helper T cells (TH), whereas antifungal IL-17+RORγt+ TH cells were increased. Therefore, homeostatic IL-13 fosters a noninflammatory skin environment that supports allergic sensitization.
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Comunicación Celular , Diferenciación Celular , Interleucina-13/metabolismo , Células de Langerhans/metabolismo , Piel/metabolismo , Células Th17/metabolismo , Células Th2/metabolismo , Alérgenos/farmacología , Animales , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Células Cultivadas , Bases de Datos Genéticas , Humanos , Interleucina-13/genética , Células de Langerhans/efectos de los fármacos , Células de Langerhans/inmunología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Factor de Transcripción STAT6/genética , Factor de Transcripción STAT6/metabolismo , Transducción de Señal , Piel/citología , Piel/efectos de los fármacos , Piel/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th2/efectos de los fármacos , Células Th2/inmunología , TranscriptomaRESUMEN
Mature basophils play critical inflammatory roles during helminthic, autoimmune, and allergic diseases through their secretion of histamine and the type 2 cytokines interleukin 4 (IL-4) and IL-13. Basophils are activated typically by allergen-mediated IgE cross-linking but also by endogenous "innate" factors. The aim of this study was to identify the innate stimuli (cytokines, chemokines, growth factors, hormones, neuropeptides, metabolites, and bacterial products) and signaling pathways inducing primary basophil activation. Basophils from naïve mice or helminth-infected mice were cultured with up to 96 distinct stimuli and their influence on basophil survival, activation, degranulation, and IL-4 or IL-13 expression were investigated. Activated basophils show a heterogeneous phenotype and segregate into distinct subsets expressing IL-4, IL-13, activation, or degranulation markers. We find that several innate stimuli including epithelial derived inflammatory cytokines (IL-33, IL-18, TSLP, and GM-CSF), growth factors (IL-3, IL-7, TGFß, and VEGF), eicosanoids, metabolites, TLR ligands, and type I IFN exert significant direct effects on basophils. Basophil activation mediated by distinct upstream signaling pathways is always sensitive to Syk and IκB kinases-specific inhibitors but not necessarily to NFAT, STAT5, adenylate cyclase, or c-fos/AP-1 inhibitors. Thus, basophils are activated by very diverse mediators, but their activation seem controlled by a core checkpoint involving Syk and IκB kinases.
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Basófilos/inmunología , Basófilos/metabolismo , Quinasa I-kappa B/metabolismo , Inmunidad Innata , Transducción de Señal , Quinasa Syk/metabolismo , Animales , Basófilos/efectos de los fármacos , Biomarcadores , Degranulación de la Célula , Citocinas/metabolismo , Expresión Génica , Hormonas , Inmunidad Innata/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Ratones , Inhibidores de Proteínas Quinasas , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: The type 2 cytokines IL-4 and IL-13 promote not only atopic dermatitis (AD) but also the resolution of inflammation. How type 2 cytokines participate in the resolution of AD is poorly known. OBJECTIVE: Our aim was to determine the mechanisms and cell types governing skin inflammation, barrier dysfunction, and resolution of inflammation in a model of AD. METHODS: Mice that exhibit expression of IL-4, IL-13, and MCPT8 or that could be depleted of basophils or eosinophils, be deficient in IL-4 or MHC class II molecules, or have basophils lacking macrophage colony-stimulating factor (M-CSF) were treated with calcipotriol (MC903) as an acute model of AD. Kinetics of the disease; keratinocyte differentiation; and leukocyte accumulation, phenotype, function, and cytokine production were measured by transepidermal water loss, histopathology, molecular biology, or unbiased analysis of spectral flow cytometry. RESULTS: In this model of AD, basophils were activated systemically and were the initial and main source of IL-4 in the skin. Basophils and IL-4 promoted epidermal hyperplasia and skin barrier dysfunction by acting on keratinocyte differentiation during inflammation. Basophils, IL-4, and basophil-derived M-CSF inhibited the accumulation of proinflammatory cells in the skin while promoting the expansion and function of proresolution M2-like macrophages and the expression of probarrier genes. Basophils kept their proresolution properties during AD resolution. CONCLUSION: Basophils can display both beneficial and detrimental type 2 functions simultaneously during atopic inflammation.