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1.
Nature ; 564(7734): E5, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30377311

RESUMEN

The spelling of author Qianting Yang was corrected; the affiliation of author Stephanus T. Malherbe was corrected; and graphs in Fig. 4b and c were corrected owing to reanalysis of the data into the correct timed intervals.

2.
Nature ; 560(7720): 644-648, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30135583

RESUMEN

Most infections with Mycobacterium tuberculosis (Mtb) manifest as a clinically asymptomatic, contained state, known as latent tuberculosis infection, that affects approximately one-quarter of the global population1. Although fewer than one in ten individuals eventually progress to active disease2, tuberculosis is a leading cause of death from infectious disease worldwide3. Despite intense efforts, immune factors that influence the infection outcomes remain poorly defined. Here we used integrated analyses of multiple cohorts to identify stage-specific host responses to Mtb infection. First, using high-dimensional mass cytometry analyses and functional assays of a cohort of South African adolescents, we show that latent tuberculosis is associated with enhanced cytotoxic responses, which are mostly mediated by CD16 (also known as FcγRIIIa) and natural killer cells, and continuous inflammation coupled with immune deviations in both T and B cell compartments. Next, using cell-type deconvolution of transcriptomic data from several cohorts of different ages, genetic backgrounds, geographical locations and infection stages, we show that although deviations in peripheral B and T cell compartments generally start at latency, they are heterogeneous across cohorts. However, an increase in the abundance of circulating natural killer cells in tuberculosis latency, with a corresponding decrease during active disease and a return to baseline levels upon clinical cure are features that are common to all cohorts. Furthermore, by analysing three longitudinal cohorts, we find that changes in peripheral levels of natural killer cells can inform disease progression and treatment responses, and inversely correlate with the inflammatory state of the lungs of patients with active tuberculosis. Together, our findings offer crucial insights into the underlying pathophysiology of tuberculosis latency, and identify factors that may influence infection outcomes.


Asunto(s)
Progresión de la Enfermedad , Células Asesinas Naturales/inmunología , Linfocitos/inmunología , Tuberculosis/inmunología , Adolescente , China , Proteínas Ligadas a GPI/inmunología , Humanos , Internacionalidad , Células Asesinas Naturales/citología , Tuberculosis Latente/genética , Tuberculosis Latente/inmunología , Estudios Longitudinales , Linfocitos/citología , Neumonía/inmunología , Neumonía/patología , Receptores de IgG/inmunología , Sudáfrica , Transcriptoma , Resultado del Tratamiento , Tuberculosis/genética , Tuberculosis/patología , Tuberculosis/terapia
3.
Allergy ; 76(9): 2809-2826, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33782956

RESUMEN

BACKGROUND: Multifood oral immunotherapy (mOIT) with adjunctive anti-IgE (omalizumab, XOLAIR® ) treatment affords safe, effective, and rapid desensitization to multiple foods, although the specific immune mechanisms mediating this desensitization remain to be fully elucidated. METHODS: Participants in our phase 2 mOIT trial (NCT02643862) received omalizumab from baseline to week 16 and mOIT from week 8 to week 36. We compared the immune profile of PBMCs and plasma taken at baseline, week 8, and week 36 using high-dimensional mass cytometry, component-resolved diagnostics, the indirect basophil activation test, and Luminex. RESULTS: We found (i) decreased frequency of IL-4+ peanut-reactive CD4+ T cells and a marked downregulation of GPR15 expression and CXCR3 frequency among γδ and CD8+ T-cell subsets at week 8 during the initial, omalizumab-alone induction phase; (ii) significant upregulation of the skin-homing receptor CCR4 in peanut-reactive CD4+ T and Th2 effector memory (EM) cells and of cutaneous lymphocyte-associated antigen (CLA) in peanut-reactive CD8+ T and CD8+ EM cells; (iii) downregulation of CD86 expression among antigen-presenting cell subsets; and (iv) reduction in pro-inflammatory cytokines, notably IL-17, at week 36 post-OIT. We also observed significant attenuation of the Th2 phenotype post-OIT, defined by downregulation of IL-4 peanut-reactive T cells and OX40 in Th2EM cells, increased allergen component-specific IgG4/IgE ratio, and decreased allergen-driven activation of indirectly sensitized basophils. CONCLUSIONS: This exploratory study provides novel comprehensive insight into the immune underpinnings of desensitization through omalizumab-facilitated mOIT. Moreover, this study provides encouraging results to support the complex immune changes that can be induced by OIT.


Asunto(s)
Omalizumab , Hipersensibilidad al Cacahuete , Administración Oral , Alérgenos , Desensibilización Inmunológica , Humanos , Inmunoglobulina E , Omalizumab/uso terapéutico
4.
Sci Immunol ; 8(81): eade3525, 2023 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-37000856

RESUMEN

The response of gamma delta (γδ) T cells in the acute versus chronic phases of the same infection is unclear. How γδ T cells function in acute Mycobacterium tuberculosis (Mtb) infection is well characterized, but their response during persistent Mtb infection is not well understood, even though most infections with Mtb manifest as a chronic, clinically asymptomatic state. Here, we analyze peripheral blood γδ T cells from a South African adolescent cohort and show that a unique CD8+ γδ T cell subset with features of "memory inflation" expands in chronic Mtb infection. These cells are hyporesponsive to T cell receptor (TCR)-mediated signaling but, like NK cells, can mount robust CD16-mediated cytotoxic responses. These CD8+ γδ T cells comprise a highly focused TCR repertoire, with clonotypes that are Mycobacterium specific but not phosphoantigen reactive. Using multiparametric single-cell pseudo-time trajectory analysis, we identified the differentiation paths that these CD8+ γδ T cells follow to develop into effectors in this infection state. Last, we found that circulating CD8+ γδ T cells also expand in other chronic inflammatory conditions, including cardiovascular disease and cancer, suggesting that persistent antigenic exposure may drive similar γδ T cell effector programs and differentiation fates.


Asunto(s)
Linfocitos Intraepiteliales , Mycobacterium tuberculosis , Tuberculosis , Humanos , Adolescente , Receptores de Antígenos de Linfocitos T gamma-delta , Linfocitos T CD8-positivos
5.
Vaccine ; 31(8): 1178-86, 2013 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-23313815

RESUMEN

The ubiquitous gram-positive bacterium Staphylococcus aureus occupies a unique niche in humans for its ability to survive both as a commensal and a life-threatening pathogen. Its complex relationship with the host and its ability to engender a throng of virulence factors, have hindered the development of a successful vaccine against it. The use of immunoadjuvants to enhance host immunity and prevent the shift from commensalism to pathogenicity is a rational approach for containing infection. The objective of this study was to understand the mechanisms by which alum and two phytol-derived immunoadjuvants, phytanol (PHIS-01)(1) and phytanyl chloride (PCl)(2) shape the interaction between S. aureus and its murine host. We studied the effects of the phytol derivatives, relative to alum, on the induction of inflammatory cytokines and chemokines, recruitment of CD11b(+) cells, generation of specific anti-S. aureus antibodies and in vitro clearance of S. aureus. Our results showed that both PHIS-01 and PCl were stronger inducers of protective cytokines IL-17 and IL-1ß than alum, and far exceeded alum in enhancing anti-S. aureus antibody response. However, both alum and the phytol derivatives (particularly PCl) promoted efficient recruitment of CD11b(+) cells. Furthermore, PHIS-01, alum and to a lesser extent, PCl were able to up-regulate the expression of key inflammation-related genes that were highly down-regulated by S. aureus alone. In vitro killing assays showed that both PHIS-01 and PCl were far more potent than alum in promoting S. aureus clearance; this indicated their efficiency in shaping an effective anti-S. aureus immune microenvironment. In summary, our study provides evidence for the better effectiveness of phytol-derived immunoadjuvants over alum in enhancing anti-S. aureus immunity.


Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Compuestos de Alumbre/administración & dosificación , Diterpenos/administración & dosificación , Fitol/administración & dosificación , Vacunas Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Animales , Anticuerpos Antibacterianos/sangre , Citocinas/metabolismo , Femenino , Ratones , Ratones Endogámicos BALB C , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/prevención & control , Vacunas Estafilocócicas/administración & dosificación , Linfocitos T/inmunología , Vacunas de Productos Inactivados/administración & dosificación , Vacunas de Productos Inactivados/inmunología
6.
PLoS One ; 7(11): e48724, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23189134

RESUMEN

The use of biological scaffold materials for wound healing and tissue remodeling has profoundly impacted regenerative medicine and tissue engineering. The porcine-derived small intestinal submucosa (SIS) is a licensed bioscaffold material regularly used in wound and tissue repair, often in contaminated surgical fields. Complications and failures due to infection of this biomaterial have therefore been a major concern and challenge. SIS can be colonized and infected by wound-associated bacteria, particularly Staphylococcus aureus. In order to address this concern and develop novel intervention strategies, the immune microenvironment orchestrated by the combined action of S. aureus and SIS should be critically evaluated. Since the outcome of tissue remodeling is largely controlled by the local immune microenvironment, we assessed the innate immune profile in terms of cytokine/chemokine microenvironment and inflammasome-responsive genes. BALB/c mice were injected intra-peritoneally with heat-killed S. aureus in the presence or absence of SIS. Analyses of cytokines, chemokines and microarray profiling of inflammasome-related genes were done using peritoneal lavages collected 24 hours after injection. Results showed that unlike SIS, the S. aureus-SIS interactome was characterized by a Th1-biased immune profile with increased expressions of IFN-γ, IL-12 and decreased expressions of IL-4, IL-13, IL-33 and IL-6. Such modulation of the Th1/Th2 axis can greatly facilitate graft rejections. The S. aureus-SIS exposure also augmented the expressions of pro-inflammatory cytokines like IL-1ß, Tnf-α, CD30L, Eotaxin and Fractalkine. This heightened inflammatory response caused by S. aureus contamination could enormously affect the biocompatibility of SIS. However, the mRNA expressions of many inflammasome-related genes like Nlrp3, Aim2, Card6 and Pycard were down-regulated by heat-killed S. aureus with or without SIS. In summary, our study explored the innate immune microenvironment induced by the combined exposure of SIS and S. aureus. These results have practical implications in developing strategies to contain infection and promote successful tissue repair.


Asunto(s)
Microambiente Celular/inmunología , Inmunidad Innata , Mucosa Intestinal/inmunología , Intestino Delgado/inmunología , Staphylococcus aureus/inmunología , Animales , Ligando CD30/metabolismo , Microambiente Celular/genética , Quimiocina CX3CL1/inmunología , Quimiocina CX3CL1/metabolismo , Quimiocinas CC/inmunología , Quimiocinas CC/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Regulación de la Expresión Génica , Regeneración Tisular Dirigida , Inmunidad Innata/genética , Inflamasomas/genética , Inflamasomas/inmunología , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Ratones , Modelos Biológicos , Células TH1/inmunología , Células TH1/metabolismo , Células Th2/inmunología , Células Th2/metabolismo , Cicatrización de Heridas/inmunología
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