RESUMEN

Multiple sclerosis (MS) has been considered as a T cell-mediated autoimmune disease. However, the signaling pathways regulating effector T cells in MS have yet to be elucidated. Janus kinase 2 (JAK2) plays a crucial role in hematopoietic/immune cytokine receptor signal transduction. Here, we tested the mechanistic regulation of JAK2 and the therapeutic potential of pharmacological JAK2 inhibition in MS. Both inducible whole-body JAK2 knockout and T cell-specific JAK2 knockout completely prevented the onset of experimental autoimmune encephalomyelitis (EAE), a widely used MS animal model. Mice with JAK2 deficiency in T cells exhibited minimal demyelination and minimal CD45+ leukocyte infiltration in the spinal cord, accompanied by a remarkable reduction of T helper cell type 1 (TH1) and type 17 (TH17) in the draining lymph nodes and spinal cord. In vitro experiments showed that disruption of JAK2 markedly suppressed TH1 differentiation and IFNγ production. The phosphorylation of signal transducer and activator of transcription 5 (STAT5) was reduced in JAK2 deficient T cells, while STAT5 overexpression significantly increased TH1 and IFNγ production in STAT5 transgenic mice. Consistent with these results, JAK1/2 inhibitor baricitinib or selective JAK2 inhibitor fedratinib attenuated the frequencies of TH1 as well as TH17 in the draining lymph nodes and alleviated the EAE disease activity in mice. Our findings suggest that overactive JAK2 signaling in T lymphocytes is the culprit in EAE, which may serve as a potent therapeutic target for autoimmune disease.

Asunto(s)

Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Ratones , Animales , Factor de Transcripción STAT5/metabolismo , Janus Quinasa 2/metabolismo , Médula Espinal/patología , Esclerosis Múltiple/patología , Ratones Transgénicos , Ratones Endogámicos C57BL , Células Th17 , Células TH1

RESUMEN

Cancer testis antigen PRAME is over-expressed in a variety of malignant cells but is not or minimally expressed in normal non-germ line cells. Adoptive transfer of PRAME-specific T cells is thus under investigation in clinical trials as an innovative therapeutic option for acute myeloid leukemia (AML). However, their senescence-inducing activity has not been studied. This study therefore examines senescence induction in AML cells by PRAME-specific TH1 cells. Analysis of cell cycle and marker expression demonstrate that the supernatants of antigen-stimulated PRAME-specific TH1 cells induce senescence in AML cell lines Kasumi and Nomo-1 through combinative IFN-γ and TNF-α. Additionally IFN-γ and TNF-α secreted by TCR-activated Vδ2+ or CMV-specific T cells can also drive these AML cell lines into terminal growth arrest. G1/0 arrest is also suggested in patient-derived AML by TH1 cytokines or supernatants from Zoledronate-stimulated or aCD3/aCD28-stimulated PBMCs. Thus, we show for the first time that senescence is induced in AML cells by combined IFN-γ and TNF-α, and that these cytokines can be derived either from TCR-engineered CD4+ T cells, or intriguingly from Virus-specific as well as innate Vδ2+ T cells responding to their cognate antigens, namely T-cell responses targeting an antigen that is NOT expressed by the leukemic cells.

Asunto(s)

Citocinas , Leucemia Mieloide Aguda , Humanos , Interferón gamma/metabolismo , Leucemia Mieloide Aguda/terapia , Masculino , Receptores de Antígenos de Linfocitos T , Factor de Necrosis Tumoral alfa

RESUMEN

Schisandrin B (Sch B) is the major active ingredient of the traditional Chinese medicine Schisandra chinensis and has antitumor activity, anti-inflammatory activity. CD4+ Th subsets orchestrate immune responses to plenty of pathogen infections and participate in the pathogenesis of many immune-related diseases. However, little is known about the relationship between Sch B and T cell differentiation. Here, we showed that Sch B might participate in T cell receptor signaling pathway by using the TCMIO database. Importantly, Sch B promoted TH1 cell differentiation. Furthermore, Sch B did not affect TH2 cell and Treg differentiation. Mechanismly, Sch B increased the level of IFN-γ of CD4+ T cells by upregulating the phosphorylation of STAT1 protein. Then, STAT1 promoted T-bet expression in CD4+ T cells. In conclusion, Sch B modulates the differentiation of naïve CD4+ T cells into TH1 subset by STAT1/T-bet signaling, which may have the potential for the treatment of T cell-mediated-immune diseases.

Asunto(s)

Diferenciación Celular/efectos de los fármacos , Lignanos/farmacología , Compuestos Policíclicos/farmacología , Factor de Transcripción STAT1/metabolismo , Células TH1/efectos de los fármacos , Animales , Linfocitos B/efectos de los fármacos , Ciclooctanos/farmacología , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente , Immunoblotting , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena en Tiempo Real de la Polimerasa , Factor de Transcripción STAT1/efectos de los fármacos

Asunto(s)

Dermatitis Atópica , Mastocitos , Células Dendríticas , Humanos , Interleucina-12 , Interleucina-13

Asunto(s)

Síndrome de Job , Factores de Intercambio de Guanina Nucleótido/genética , Humanos

RESUMEN

BACKGROUND: Our current understanding of atopic dermatitis (AD) and psoriasis pathophysiology is largely derived from skin biopsy studies that cause scarring and may be impractical in large-scale clinical trials. Although tape strips show promise as a minimally invasive technique in these common diseases, a comprehensive molecular profiling characterizing and differentiating the 2 diseases in tape strips is unavailable. OBJECTIVE: Our aim was to construct a global transcriptome of tape strips from lesional and nonlesional skin of adults with moderate-to-severe AD and psoriasis. METHODS: A total of 20 tape strips were obtained from lesional and nonlesional skin of patients with AD and psoriasis and skin from controls (n = 20 each); the strips were subjected to RNA sequencing (RNA-seq), with quantitative RT-PCR validation of immune and barrier biomarkers. RESULTS: We detected RNA-seq profiles in 96 of 100 of samples (96%), with 4123 and 5390 genes differentially expressed in AD and psoriasis lesions versus in controls, respectively (fold change ≥ 2; false discovery rate [FDR] < 0.05). Nonlesional tape-stripped skin from patients with AD was more similar to lesional skin than to nonlesional skin of patients with psoriasis, which showed larger differentiation from lesions. AD and psoriasis tissues shared increases in levels of dendritic cell and T-cell markers (CD3, ITGAX/CD11c, and CD83), but AD tissues showed preferential TH2 skewing (IL-13, CCL17/TARC, and CCL18), whereas psoriasis was characterized by higher levels of expression of TH17-related (IL-17A/F and IL-36A/IL-36G), TH1-related (IFN-γ and CXCL9/CXCL10), and innate immunity-related (nitric oxide synthase 2/inducible nitric oxide synthase and IL-17C) products (FDR < 0.05). Terminal differentiation (FLG2 and LCE5A), tight junction (CLDN8), and lipid biosynthesis and metabolism (FA2H and ALOXE3) products were significantly downregulated in both AD and psoriasis (FDR < 0.05). Nitric oxide synthase 2/inducible nitric oxide synthase expression (determined by quantitative PCR) differentiated AD and psoriasis with 100% accuracy. CONCLUSION: RNA-seq tape strip profiling detected distinct immune and barrier signatures in lesional and nonlesional AD and psoriasis skin, suggesting their utility as a minimally invasive alternative to biopsies for detecting disease biomarkers.

Asunto(s)

Citocinas , Dermatitis Atópica , Psoriasis , RNA-Seq , Linfocitos T Colaboradores-Inductores/inmunología , Adolescente , Adulto , Citocinas/genética , Citocinas/inmunología , Dermatitis Atópica/genética , Dermatitis Atópica/inmunología , Femenino , Proteínas Filagrina , Humanos , Masculino , Persona de Mediana Edad , Psoriasis/genética , Psoriasis/inmunología

RESUMEN

BACKGROUND: Atopic dermatitis (AD) is characterized by a skin barrier defect aggravated by mechanical injury inflicted by scratching, a TH2 cell-dominated immune response, and susceptibility to viral skin infections that are normally restrained by a TH1 cell response. The signals leading to a TH2 cell-dominated immune response in AD are not completely understood. OBJECTIVE: Our aim was to determine the role of IL-13 in initiation of the TH cell response to cutaneously encountered antigens. METHODS: Wild-type, Il13-/-, Il1rl1-/-, and Il4ra-/- mice, as well as mice with selective deficiency of IL-13 in mast cells (MCs) were studied; in addition, dendritic cells (DCs) purified from the draining lymph nodes of tape-stripped and ovalbumin (OVA)-sensitized skin were examined for their ability to polarize naive OVA-TCR transgenic CD4+ T cells. Cytokine expression was examined by reverse-transcriptase quantitative PCR, intracellular flow cytometry, and ELISA. Contact hypersensitivity to dinitrofluorobenzene was examined. RESULTS: Tape stripping caused IL-33-driven upregulation of Il13 expression by skin MCs. MC-derived IL-13 acted on DCs from draining lymph nodes of OVA-sensitized skin to selectively suppress their ability to polarize naive OVA-TCR transgenic CD4+ T cells into IFN-γ-secreting cells. MC-derived IL-13 inhibited the TH1 cell response in contact hypersensitivity to dinitrofluorobenzene. IL-13 suppressed IL-12 production by mouse skin-derived DCs in vitro and in vivo. Scratching upregulated IL13 expression in human skin, and IL-13 suppressed the capacity of LPS-stimulated human skin DCs to express IL-12 and promote IFN-γ secretion by CD4+ T cells. CONCLUSION: Release of IL-13 by cutaneous MCs in response to mechanical skin injury inhibits the TH1 cell response to cutaneous antigen exposure in AD.

Asunto(s)

Citocinas/biosíntesis , Dermatitis Atópica/inmunología , Dermatitis Atópica/metabolismo , Mastocitos/inmunología , Mastocitos/metabolismo , Células TH1/inmunología , Células TH1/metabolismo , Animales , Antígenos/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Humanos , Interleucina-12/metabolismo , Interleucina-13/biosíntesis , Ratones , Ratones Noqueados , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo

RESUMEN

Today, Coronavirus Disease 2019 (COVID-19) is a global public health emergency and vaccination measures to counter its diffusion are deemed necessary. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of the disease, unleashes a T-helper 2 immune response in those patients requiring intensive care. Here, we illustrate the immunological mechanism to train the immune system towards a more effective and less symptomatic T-helper 1 immune response, to be exploited against SARS-CoV-2.

Asunto(s)

Vacuna BCG/administración & dosificación , Vacunas Bacterianas/administración & dosificación , Betacoronavirus/inmunología , Infecciones por Coronavirus/prevención & control , Inmunidad Innata/efectos de los fármacos , Pandemias/prevención & control , Neumonía Viral/prevención & control , Propionibacteriaceae/inmunología , Betacoronavirus/efectos de los fármacos , Betacoronavirus/patogenicidad , COVID-19 , Vacunas contra la COVID-19 , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Corynebacterium , Humanos , Esquemas de Inmunización , Inmunogenicidad Vacunal , Interleucinas/genética , Interleucinas/inmunología , Seguridad del Paciente , Neumonía Viral/epidemiología , Neumonía Viral/inmunología , Neumonía Viral/virología , SARS-CoV-2 , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/virología , Balance Th1 - Th2/efectos de los fármacos , Células Th2/efectos de los fármacos , Células Th2/inmunología , Células Th2/virología , Vacunación , Vacunas Virales/administración & dosificación , Vacunas Virales/biosíntesis

RESUMEN

COVID-19 is a major public health issue around the world and new data about its etiological agent, SARS-CoV-2, are urgently necessary, also translating the scientific knowledge acquired on its more similar predecessors, SARS-CoV-1 and MERS-CoV, the coronaviruses responsible for SARS and MERS, respectively. Like SARS-CoV-1, SARS-CoV-2 exploits the ACE2 receptors to enter the host cells; nevertheless, recent bioinformatics insights suggest a potential interaction of SARS-CoV-2 with the «moonlighting protein¼ CD26/DPP4, exactly how MERS-CoV works. CD26/DPP4 is overexpressed on T-helper type 1 (Th1) cells and its expression increases with aging, all factors which could well explain the Th1 immune lockdown, especially in the elderly, during fatal SARS-CoV-2 infections. Facing with this scenario, it is possible that Th1 and T-cytotoxic lymphocytes are the immune cells most affected by SARS-CoV-2, and that the immune system is forced to mount a T-helper type 2 (Th2) response, the only one still mountable, in the attempt to counteract the viral load. However, in this way, the symptomatic patient experiences all the negative effects of the Th2 response, which can seriously aggravate the clinical picture.

Asunto(s)

Infecciones por Coronavirus/inmunología , Dipeptidil Peptidasa 4/inmunología , Neumonía Viral/inmunología , Células TH1/inmunología , Adulto , Anciano , Autopsia , Betacoronavirus , COVID-19 , Biología Computacional , Regulación de la Expresión Génica , Humanos , Sistema Inmunológico , Italia , Masculino , Persona de Mediana Edad , Pandemias , Unión Proteica , SARS-CoV-2 , Linfocitos T Citotóxicos/virología , Células TH1/virología

RESUMEN

BACKGROUND: Allergic asthmatic subjects are uniquely susceptible to acute wheezing episodes provoked by rhinovirus. However, the underlying immune mechanisms and interaction between rhinovirus and allergy remain enigmatic, and current paradigms are controversial. OBJECTIVE: We sought to perform a comprehensive analysis of type 1 and type 2 innate and adaptive responses in allergic asthmatic subjects infected with rhinovirus. METHODS: Circulating virus-specific TH1 cells and allergen-specific TH2 cells were precisely monitored before and after rhinovirus challenge in allergic asthmatic subjects (total IgE, 133-4692 IU/mL; n = 28) and healthy nonallergic controls (n = 12) using peptide/MHCII tetramers. T cells were sampled for up to 11 weeks to capture steady-state and postinfection phases. T-cell responses were analyzed in parallel with 18 cytokines in the nose, upper and lower airway symptoms, and lung function. The influence of in vivo IgE blockade was also examined. RESULTS: In uninfected asthmatic subjects, higher numbers of circulating virus-specific PD-1+ TH1 cells, but not allergen-specific TH2 cells, were linked to worse lung function. Rhinovirus infection induced an amplified antiviral TH1 response in asthmatic subjects versus controls, with synchronized allergen-specific TH2 expansion, and production of type 1 and 2 cytokines in the nose. In contrast, TH2 responses were absent in infected asthmatic subjects who had normal lung function, and in those receiving anti-IgE. Across all subjects, early induction of a minimal set of nasal cytokines that discriminated high responders (G-CSF, IFN-γ, TNF-α) correlated with both egress of circulating virus-specific TH1 cells and worse symptoms. CONCLUSIONS: Rhinovirus induces robust TH1 responses in allergic asthmatic subjects that may promote disease, even after the infection resolves.

Asunto(s)

Asma/inmunología , Hipersensibilidad/inmunología , Infecciones por Picornaviridae/inmunología , Rhinovirus/fisiología , Células TH1/inmunología , Células Th2/inmunología , Alérgenos/inmunología , Antígenos Virales/inmunología , Células Cultivadas , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Humanos , Activación de Linfocitos , Receptor de Muerte Celular Programada 1/metabolismo , Ruidos Respiratorios

RESUMEN

Immune checkpoint therapy (ICT) shows encouraging results in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) but still elicits a sub-optimal response among those with bone metastases. Analysis of patients' bone marrow samples revealed increased Th17 instead of Th1 subsets after ICT. To further evaluate the different tumor microenvironments, we injected mice with prostate tumor cells either subcutaneously or intraosseously. ICT in the subcutaneous CRPC model significantly increases intra-tumoral Th1 subsets and improves survival. However, ICT fails to elicit an anti-tumor response in the bone CRPC model despite an increase in the intra-tumoral CD4 T cells, which are polarized to Th17 rather than Th1 lineage. Mechanistically, tumors in the bone promote osteoclast-mediated bone resorption that releases TGF-ß, which restrains Th1 lineage development. Blocking TGF-ß along with ICT increases Th1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression of bone CRPC and improves survival.

Asunto(s)

Linaje de la Célula , Inmunoterapia , Linfocitos T Colaboradores-Inductores/citología , Microambiente Tumoral , Animales , Antígenos/metabolismo , Neoplasias Óseas/secundario , Antígeno CTLA-4/metabolismo , Linaje de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Clonales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Memoria Inmunológica/efectos de los fármacos , Ipilimumab/farmacología , Masculino , Ratones , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/inmunología , Neoplasias de la Próstata Resistentes a la Castración/patología , Análisis de Supervivencia , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Células TH1/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Microambiente Tumoral/efectos de los fármacos

RESUMEN

Asthma is a common chronic inflammatory disease which severely reduces the quality of life in patients. Studies have demonstrated that both PM2.5 and cold stress contribute to the development of asthma. However, the combined effects of these two risking factors are unknown. In this study, we investigated the combined effects of PM2.5 exposure and cold stress (PMCS) on asthma, as well as the underlying mechanisms by using a murine model. After different exposures, the immune-pathological changes and redox states in groups were evaluated. Besides, the balance of TH1/TH2 cells and the acetylation levels of H3K9 and H3K14 in IL-4 gene promotor were detected. Our results showed that, compared with other exposures, PMCS led to an increased inflammation and redox levels in mice. It also significantly increased the percentage of TH2 T cells, which was correlated with hyperacetylation of H3K9 and H3K14 in IL-4 gene promoter in CD4+T cells. Furthermore, a significantly increased P300 and decreased HDAC1 were detected in CD4 + T cells in PMCS group. In conclusion, our findings demonstrated that PMCS exacerbated asthma in mice by increasing H3K9 and H3K14 acetylation in IL-4 gene promoter in CD4 + T cells, and P300 and HDAC1 might contribute to their combined effects.

Asunto(s)

Asma/inducido químicamente , Frío/efectos adversos , Histonas/metabolismo , Interleucina-4/metabolismo , Pulmón/efectos de los fármacos , Material Particulado/toxicidad , Regiones Promotoras Genéticas , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Acetilación , Animales , Asma/genética , Asma/inmunología , Asma/metabolismo , Modelos Animales de Enfermedad , Proteína p300 Asociada a E1A/metabolismo , Histona Desacetilasa 1/metabolismo , Interleucina-4/genética , Interleucina-4/inmunología , Pulmón/inmunología , Pulmón/metabolismo , Masculino , Ratones Endogámicos BALB C , Ovalbúmina , Tamaño de la Partícula , Procesamiento Proteico-Postraduccional , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo

RESUMEN

The peripheral activation of autoreactive T cells and subsequent central nervous system (CNS) immune cell infiltration are key events relevant for experimental autoimmune encephalomyelitis (EAE), a commonly employed multiple sclerosis (MS) model, influenced by TH1 and TH17 mediated immunity. The phosphoinositide-3-kinase (PI3K)-AKT kinase pathway modulates outcome during EAE, with direct actions of PI3K on adaptive immunity implicated in deleterious and effects on antigen presenting cells involved in beneficial responses during EAE. Here, by genetically deleting the regulatory subunit of Class Ia PI3K, p85α, in selective myeloid cells, we aimed to resolve the impact of PI3K in EAE. While genetically deleting PI3K in LysM expressing cells exerted unremarkable effects, attenuating PI3K function in CD11c+ dendritic cells (DCs), promoted secretion of pathogenic EAE promoting cytokines, particularly skewing TH1 and TH17 immunity, while notably, improving health in EAE. Neutralizing IFN-γ activity using blocking antibodies revealed a prolonged TH1 response was critical for the decreased disease of these animals. Thus, PI3K-AKT signaling in DCs acts in a paradoxical manner. While attenuating EAE associated TH1 and TH17 responses, it impairs health during autoimmune inflammation.

Asunto(s)

Enfermedades Autoinmunes/inmunología , Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Inflamación/inmunología , Fosfatidilinositol 3-Quinasas/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Sistema Nervioso Central/inmunología , Citocinas/inmunología , Modelos Animales de Enfermedad , Interferón gamma/inmunología , Ratones , Esclerosis Múltiple/inmunología , Células Mieloides/inmunología , Células TH1/inmunología , Células Th17/inmunología

RESUMEN

BACKGROUND: GBR 830 is a humanized mAb against OX40, a costimulatory receptor on activated T cells. OX40 inhibition might have a therapeutic role in T cell-mediated diseases, including atopic dermatitis (AD). OBJECTIVE: This exploratory phase 2a study investigated the safety, efficacy, and tissue effects of GBR 830 in patients with AD. METHODS: Patients with moderate-to-severe AD (affected body surface area, ≥10%; Eczema Area and Severity Index score, ≥12; and inadequate response to topical treatments) were randomized 3:1 to 10 mg/kg intravenous GBR 830 or placebo on day 1 (baseline) and day 29. Biopsy specimens were collected (n = 40) at days 1, 29, and 71. Primary end points included treatment-emergent adverse events (TEAEs) and changes from baseline in biomarkers (epidermal hyperplasia/cytokines) at days 29 and 71. RESULTS: GBR 830 was well tolerated, with equal TEAE distribution (GBR 830, 63.0% [29/46]; placebo, 63.0% [10/16]). One serious TEAE in the GBR 830 group was deemed unrelated to study drug. At day 71, the proportion of intent-to-treat subjects achieving 50% or greater improvement in Eczema Area and Severity Index score was greater with GBR 830 (76.9% [20/26]) versus placebo (37.5% [3/8]). GBR 830 induced significant progressive reductions in TH1 (IFN-γ/CXCL10), TH2 (IL-31/CCL11/CCL17), and TH17/TH22 (IL-23p19/IL-8/S100A12) mRNA expression in lesional skin. Significant progressive reductions until day 71 in the drug group were seen in OX40+ T cells and OX40L+ dendritic cells (P < .001). Hyperplasia measures (thickness/keratin 16/Ki67) showed greater reductions with GBR 830 (P < .001). CONCLUSIONS: Two doses of GBR 830 administered 4 weeks apart were well tolerated and induced significant progressive tissue and clinical changes until day 71 (42 days after the last dose), highlighting the potential of OX40 targeting in patients with AD.

Asunto(s)

Anticuerpos Monoclonales Humanizados/administración & dosificación , Citocinas/inmunología , Dermatitis Atópica/tratamiento farmacológico , Regulación de la Expresión Génica/efectos de los fármacos , Receptores OX40/antagonistas & inhibidores , Piel/inmunología , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Hiperplasia/inmunología , Hiperplasia/patología , Masculino , Persona de Mediana Edad , Receptores OX40/inmunología , Piel/patología

RESUMEN

BACKGROUND: Atopic dermatitis (AD) shows differential clinical presentation in older compared with younger patients. Nevertheless, changes in the AD molecular profile with age are unknown. OBJECTIVE: We sought to characterize age-related changes in the AD profile. METHODS: We evaluated age-specific changes in lesional and nonlesional tissues and blood from patients with moderate-to-severe AD (n = 246) and age-matched control subjects (n = 71) using immunohistochemistry, quantitative real-time PCR, and Singulex in a cross-sectional study. Patients were analyzed by age group (18-40, 41-60, and ≥61 years). RESULTS: Although disease severity/SCORAD scores were similar across AD age groups (mean, approximately 60 years; P = .873), dendritic cell infiltrates (CD1b+ and FcεRI+, P < .05) decreased with age. TH2 measures (IL5, IL13, CCL13, CCL18, and CCL26) significantly decreased with age in patients with AD, despite increasing with age in control subjects. Consistent with TH2 axis decreases, serum IgE levels and eosinophil counts negatively correlated with age in patients with AD (r = -0.24 and r = -0.23, respectively; P < .05). TH22-secreted IL22 expression levels also decreased with age uniquely in patients with AD (P < .05). Expression of TH1-related (IFNG, IL12/23p40, STAT1, and CXCL9; P < .05 for CXCL9) and TH17-related (IL17A and IL20; P < .05 for IL20) markers increased with age in both patients with AD and control subjects. Expression of terminal differentiation measures significantly increased in older patients with AD (loricrin [LOR] and filaggrin [FLG], P < .05), whereas expression of S100As (S100A8, P < .01) and hyperplasia markers (epidermal thickness, keratin 16, and Ki67; P < .05 for keratin 16) decreased. Serum trends in AD mimicked skin findings, with TH2 downregulation (CCL26; r = -0.32, P < .1) and TH1 upregulation (IFN-γ; r = 0.48, P < .01) with age. CONCLUSION: The adult AD profile varies with age. Although TH1/TH17 skewing increases in both patients with AD and control subjects, patients with AD show unique decreases in TH2/TH22 polarization and normalization of epithelial abnormalities. Thus age-specific treatment approaches might be beneficial for AD.

Asunto(s)

Envejecimiento , Dermatitis Atópica , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/sangre , Envejecimiento/genética , Envejecimiento/inmunología , Citocinas/genética , Citocinas/inmunología , Dermatitis Atópica/sangre , Dermatitis Atópica/genética , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Femenino , Proteínas Filagrina , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Índice de Severidad de la Enfermedad , Piel/inmunología , Piel/patología , Adulto Joven

RESUMEN

BACKGROUND: Peripheral blood skin-homing/cutaneous lymphocyte antigen (CLA)+ T cells emerge as biomarkers of cutaneous immune activation in patients with inflammatory skin diseases (atopic dermatitis [AD] and alopecia areata [AA]). However, blood phenotyping across these subsets is not yet available in patients with vitiligo. OBJECTIVE: We sought to measure cytokine production by circulating skin-homing (CLA+) versus systemic (CLA-) "polar" CD4+/CD8+ ratio and activated T-cell subsets in patients with vitiligo compared with patients with AA, AD, or psoriasis and control subjects. METHODS: Flow cytometry was used to measure levels of the cytokines IFN-γ, IL-13, IL-9, IL-17, and IL-22 in CD4+/CD8+ T cells in the blood of 19 patients with moderate-to-severe nonsegmental/generalized vitiligo, moderate-to-severe AA (n = 32), psoriasis (n = 24), or AD (n = 43) and control subjects (n = 30). Unsupervised clustering differentiated subjects into groups based on cellular frequencies. RESULTS: Patients with Vitiligo showed the highest CLA+/CLA- TH1/type 1 cytotoxic T-cell polarization, with parallel TH2/TH9/TH17/TH22 level increases to levels often greater than those seen in patients with AA, AD, or psoriasis (P < .05). Total regulatory T-cell counts were lower in patients with vitiligo than in control subjects and patients with AD or psoriasis (P < .001). Vitiligo severity correlated with levels of multiple cytokines (P < .1), whereas duration was linked with IFN-γ and IL-17 levels (P < .04). Patients and control subjects grouped into separate clusters based on blood biomarkers. CONCLUSIONS: Vitiligo is characterized by a multicytokine polarization among circulating skin-homing and systemic subsets, which differentiates it from other inflammatory/autoimmune skin diseases. Future targeted therapies should delineate the relative contribution of each cytokine axis to disease perpetuation.

Asunto(s)

Alopecia Areata/diagnóstico , Biomarcadores/sangre , Citocinas/sangre , Dermatitis Atópica/diagnóstico , Piel/inmunología , Células TH1/inmunología , Vitíligo/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Diagnóstico Diferencial , Progresión de la Enfermedad , Femenino , Citometría de Flujo , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Oligosacáridos/metabolismo , Antígeno Sialil Lewis X/análogos & derivados , Antígeno Sialil Lewis X/metabolismo , Células Th2/inmunología

RESUMEN

Intestinal reovirus infection can trigger T helper 1 (TH1) immunity to dietary antigen, raising the question of whether other viruses can have a similar impact. Here we show that the acute CW3 strain of murine norovirus, but not the persistent CR6 strain, induces TH1 immunity to dietary antigen. This property of CW3 is dependent on its major capsid protein, a virulence determinant. Transcriptional profiling of mesenteric lymph nodes following infection reveals an immunopathological signature that does not segregate with protective immunity but with loss of oral tolerance, in which interferon regulatory factor 1 is critical. These data show that viral capacity to trigger specific inflammatory pathways at sites where T cell responses to dietary antigens take place interferes with the development of tolerance to an oral antigen. Collectively, these data provide a foundation for the development of therapeutic strategies to prevent TH1-mediated complex immune disorders triggered by viral infections.

Asunto(s)

Infecciones por Caliciviridae/inmunología , Dieta , Norovirus/inmunología , Norovirus/patogenicidad , Ovalbúmina/inmunología , Células TH1/inmunología , Administración Oral , Animales , Infecciones por Caliciviridae/virología , Proteínas de la Cápside/inmunología , Enfermedad Celíaca/inmunología , Modelos Animales de Enfermedad , Femenino , Células HEK293 , Humanos , Inmunidad , Inflamación , Factor 1 Regulador del Interferón/inmunología , Ganglios Linfáticos , Ratones , Ratones Endogámicos C57BL , Ovalbúmina/administración & dosificación , Esparcimiento de Virus

RESUMEN

In this study, we investigated IL-10 and IL-17 specific immunomodulatory potential of S-nitrosoglutathione (GSNO), a physiological nitric oxide carrier molecule, in experimental autoimmune encephalomyelitis (EAE). In active EAE model, GSNO treatment attenuated EAE severity and splenic CD4+ T cells isolated from these mice exhibited decreased IL-17 expression without affecting the IFN-γ expression compared to the cells from untreated EAE mice. Similarly, adoptive transfer of these cells to nave mice resulted in reduction in IL-17 expression in the spinal cords of recipient mice with milder EAE severity. CD4+ T cells isolated from GSNO treated EAE mice, as compared to untreated EAE mice, still expressed lower levels of IL-17 under TH17 skewing conditions, but expressed similar levels of IFN-γ under TH1 skewing condition. Interestingly, under both TH17 and TH1 skewing condition, CD4+ T cells isolated from GSNO treated EAE mice, as compared to untreated EAE mice, expressed higher levels of IL-10 and adoptive transfer of these TH17 and TH1 skewed cells seemingly exhibited milder EAE disease. In addition, adoptive transfer of CD4+ T cells from GSNO treated EAE mice to active EAE mice also ameliorated EAE disease with induction of spinal cord expression of IL-10 and reduction in of IL-17, thus suggesting the participation of IL-10 mechanism in GSNO mediated immunomodulation. GSNO treatment of mice passively immunized with CD4+ T cells either from GSNO treated EAE mice or untreated mice further ameliorated EAE disease, supporting efficacy of GSNO for prophylaxis and therapy in EAE. Overall, these data document a modulatory role of GSNO in IL-17/IL-10 axis of EAE and other autoimmune diseases.

Asunto(s)

Traslado Adoptivo , Encefalomielitis Autoinmune Experimental/terapia , Inmunomodulación , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Donantes de Óxido Nítrico/farmacología , S-Nitrosoglutatión/farmacología , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/trasplante , Encefalomielitis Autoinmune Experimental/inmunología , Ratones , Ratones Endogámicos C57BL , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/trasplante , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/trasplante

Asunto(s)

Células Th2 , Proteína p53 Supresora de Tumor , Humanos , Inflamación , Monoéster Fosfórico Hidrolasas , Sistema Respiratorio

RESUMEN

BACKGROUND: Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked neutropenia, which are caused by WAS mutations affecting Wiskott-Aldrich syndrome protein (WASp) expression or activity, manifest in immunodeficiency, autoimmunity, genomic instability, and lymphoid and other cancers. WASp supports filamentous actin formation in the cytoplasm and gene transcription in the nucleus. Although the genetic basis for XLT/WAS has been clarified, the relationships between mutant forms of WASp and the diverse features of these disorders remain ill-defined. OBJECTIVE: We sought to define how dysfunctional gene transcription is causally linked to the degree of TH cell deficiency and genomic instability in the XLT/WAS clinical spectrum. METHODS: In human TH1- or TH2-skewing cell culture systems, cotranscriptional R-loops (RNA/DNA duplex and displaced single-stranded DNA) and DNA double-strand breaks (DSBs) were monitored in multiple samples from patients with XLT and WAS and in normal T cells depleted of WASp. RESULTS: WASp deficiency provokes increased R-loops and R-loop-mediated DSBs in TH1 cells relative to TH2 cells. Mechanistically, chromatin occupancy of serine 2-unphosphorylated RNA polymerase II is increased, and that of topoisomerase 1, an R-loop preventing factor, is decreased at R-loop-enriched regions of IFNG and TBX21 (TH1 genes) in TH1 cells. These aberrations accompany increased unspliced (intron-retained) and decreased spliced mRNA of IFNG and TBX21 but not IL13 (TH2 gene). Significantly, increased cellular load of R-loops and DSBs, which are normalized on RNaseH1-mediated suppression of ectopic R-loops, inversely correlates with disease severity scores. CONCLUSION: Transcriptional R-loop imbalance is a novel molecular defect causative in TH1 immunodeficiency and genomic instability in patients with WAS. The study proposes that cellular R-loop load could be used as a potential biomarker for monitoring symptom severity and prognostic outcome in the XLT-WAS clinical spectrum and could be targeted therapeutically.

Asunto(s)

Inestabilidad Genómica/genética , Células TH1/patología , Síndrome de Wiskott-Aldrich/genética , Células Cultivadas , Daño del ADN/genética , Humanos , Transcripción Genética , Síndrome de Wiskott-Aldrich/patología