RESUMEN
Memory CD4 T cells are critical to human immunity, yet it is unclear whether viral inflammation during memory formation has long-term consequences. Here, we compared transcriptional and epigenetic landscapes of Spike (S)-specific memory CD4 T cells in 24 individuals whose first exposure to S was via SARS-CoV-2 infection or mRNA vaccination. Nearly 2 years after memory formation, S-specific CD4 T cells established by infection remained enriched for transcripts related to cytotoxicity and for interferon-stimulated genes, likely because of a chromatin accessibility landscape altered by inflammation. Moreover, S-specific CD4 T cells primed by infection had reduced proliferative capacity in vitro relative to vaccine-primed cells. Furthermore, the transcriptional state of S-specific memory CD4 T cells was minimally altered by booster immunization and/or breakthrough infection. Thus, infection-associated inflammation durably imprints CD4 T cell memory, which affects the function of these cells and may have consequences for long-term immunity.
Asunto(s)
Linfocitos T CD4-Positivos , COVID-19 , Memoria Inmunológica , Inflamación , Células T de Memoria , SARS-CoV-2 , Humanos , COVID-19/inmunología , SARS-CoV-2/inmunología , Linfocitos T CD4-Positivos/inmunología , Memoria Inmunológica/inmunología , Inflamación/inmunología , Células T de Memoria/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Femenino , Masculino , Adulto , Vacunas contra la COVID-19/inmunologíaRESUMEN
The vast spectrum of clinical features of COVID-19 keeps challenging scientists and clinicians. Low resistance to infection might result in long-term viral persistence, but the underlying mechanisms remain unclear. Here, we studied the immune response of immunocompetent COVID-19 patients with prolonged SARS-CoV-2 infection by immunophenotyping, cytokine and serological analysis. Despite viral loads and symptoms comparable to regular mildly symptomatic patients, long-term carriers displayed weaker systemic IFN-I responses and fewer circulating pDCs and NK cells at disease onset. Type 1 cytokines remained low, while type-3 cytokines were in turn enhanced. Of interest, we observed no defects in antigen-specific cytotoxic T cell responses, and circulating antibodies displayed higher affinity against different variants of SARS-CoV-2 Spike protein in these patients. The identification of distinct immune responses in long-term carriers adds up to our understanding of essential host protective mechanisms to ensure tissue damage control despite prolonged viral infection.
RESUMEN
Adaptive immune responses are induced by vaccination and infection, yet little is known about how CD4+ T cell memory differs when primed in these two contexts. Notably, viral infection is generally associated with higher levels of systemic inflammation than is vaccination. To assess whether the inflammatory milieu at the time of CD4+ T cell priming has long-term effects on memory, we compared Spike-specific memory CD4+ T cells in 22 individuals around the time of the participants' third SARS-CoV-2 mRNA vaccination, with stratification by whether the participants' first exposure to Spike was via virus or mRNA vaccine. Multimodal single-cell profiling of Spike-specific CD4+ T cells revealed 755 differentially expressed genes that distinguished infection- and vaccine-primed memory CD4+ T cells. Spike-specific CD4+ T cells from infection-primed individuals had strong enrichment for cytotoxicity and interferon signaling genes, whereas Spike-specific CD4+ T cells from vaccine-primed individuals were enriched for proliferative pathways by gene set enrichment analysis. Moreover, Spike-specific memory CD4+ T cells established by infection had distinct epigenetic landscapes driven by enrichment of IRF-family transcription factors, relative to T cells established by mRNA vaccination. This transcriptional imprint was minimally altered following subsequent mRNA vaccination or breakthrough infection, reflecting the strong bias induced by the inflammatory environment during initial memory differentiation. Together, these data suggest that the inflammatory context during CD4+ T cell priming is durably imprinted in the memory state at transcriptional and epigenetic levels, which has implications for personalization of vaccination based on prior infection history.
RESUMEN
BACKGROUND: Mood disorders have been associated with risk of clinical relapses in multiple sclerosis (MS), a demyelinating disease mediated by myelin-specific T cells. OBJECTIVES: We aimed to investigate the impact of major depressive disorder (MDD) and cytokine profile of T-cells in relapsing remitting MS patients. METHODS: For our study, plasma and PBMC were obtained from 60 MS patients (30 with lifetime MDD) in remission phase. The PBMC cultures were stimulated with anti-CD3/anti-CD28 beads or myelin basic protein (MBP), and effector and regulatory T cell phenotypes were determined by flow cytometry. The cytokine levels, both in the plasma or in the supernatants collected from PBMC cultures, were quantified by Luminex. In some experiments, the effect of serotonin (5-HT) was investigated. RESULTS: Here, higher Th17-related cytokine levels in response to anti-CD3/anti-CD28 and MBP were quantified in the plasma and PBMC cultures of the MS/MDD group in comparison with MS patients. Further, elevated frequency of CD4+ and CD8+ T cells capable of producing IL-17, IL-22 and GM-CSF was observed in depressed patients. Interestingly, the percentage of myelin-specific IFN-γ+IL-17+ and IFN-γ+GM-CSF+ CD4+ T cells directly correlated with neurological disabilities. In contrast, the occurrence of MDD reduced the proportion of MBP-specific CD39+Tregs subsets. Notably, the severity of both neurological disorder and depressive symptoms inversely correlated with these Tregs. Finally, the addition of 5-HT downregulated the release of Th17-related cytokines in response to anti-CD3/anti-CD28 and myelin antigen. CONCLUSIONS: In summary, our findings suggested that recurrent major depression, by favoring imbalances of effector Th17 and Treg cell subsets, contributes to MS severity.
Asunto(s)
Apirasa , Autoantígenos , Trastorno Depresivo Mayor , Esclerosis Múltiple , Vaina de Mielina , Linfocitos T Reguladores , Células Th17 , Apirasa/inmunología , Autoantígenos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/inmunología , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Humanos , Interleucina-17/inmunología , Leucocitos Mononucleares/inmunología , Esclerosis Múltiple/inmunología , Vaina de Mielina/inmunología , Serotonina/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunologíaRESUMEN
Macrophages play a role in preventing inflammation in the respiratory tract. To investigate the mechanisms that lead to tolerance in macrophages, we examined the crosstalk between airway epithelial cells (AECs) and macrophages using a 2D coculture model. Culture of macrophages with AECs led to a significant inhibition of LPS induced pro-inflammatory responses. More importantly, AECs induced the secretion of TGF-ß and IL-10 from macrophages even in the absence of LPS stimulation. In addition, the expression of inhibitory molecule, CD200R was also upregulated on AEC exposed macrophages. Furthermore, the AECs exposed macrophages induced significantly increased level of T regulatory cells. Investigation into the possible mechanisms indicated that a combination of growth factor, G-CSF, and metabolites, Kynurenine and lactic acid produced by AECs is responsible for inducing tolerance in macrophages. Interestingly, all these molecules had differential effect on macrophages with G-CSF inducing TGF-ß, Kynurenine elevating IL-10, and lactic acid upregulating CD200R. Furthermore, a cocktail of these factors/metabolites induced similar changes in macrophages as AEC exposure. Altogether, these data identify factors secreted by AECs that enhance tolerance in the respiratory tract. These mediators thus have the potential to be used for therapeutic purposes to modulate respiratory inflammation following local viral infections and lung diseases.
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Interleucina-10 , Lipopolisacáridos , Humanos , Interleucina-10/metabolismo , Lipopolisacáridos/farmacología , Lipopolisacáridos/metabolismo , Quinurenina/metabolismo , Células Epiteliales/metabolismo , Macrófagos , Mucosa Respiratoria/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Inflamación/metabolismo , Factor Estimulante de Colonias de Granulocitos/metabolismo , Ácido Láctico/metabolismoRESUMEN
BACKGROUND: Recent evidences have suggested the involvement of toll-like receptor (TLR)-4 in the pathogenesis of cerebral cavernous malformations (CCM). Elevated frequency of TLR+T-cells has been associated with neurological inflammatory disorders. As T-cells and B-cells are found in CCM lesions, the objective of the present study was to evaluate the cytokine profile of T-cells expressing TLR2 and TLR4, as well as B-cell subsets, in asymptomatic (CCMAsympt) and symptomatic (CCMSympt) patients. METHODS: For our study, the cytokine profile from TLR2+ and TLR4+ T-cell and B-cell subsets in CCMAsympt and CCMSympt patients was investigated using flow cytometry and ELISA. T-cells were stimulated in vitro with anti-CD3/anti-CD28 beads or TLR2 (Pam3C) and TLR4 (LPS) ligands. RESULTS: CCMSymptc patients presented a higher frequency of TLR4+(CD4+ and CD8+) T-cells and greater density of TLR4 expression on these cells. With regard to the cytokine profile, the percentage of TLR2+ and TLR4+ Th17 cells was higher in CCMSympt patients. In addition, an elevated proportion of TLR4+ Tc-1 cells, as well as Tc-17 and Th17.1 cells expressing TLR2 and TLR4, was observed in the symptomatic patients. By contrast, the percentage of TLR4+ IL-10+CD4+ T cells was higher in the CCMAsympt group. Both Pam3C and LPS were more able to elevate the frequency of IL-6+CD4+T cells and Th17.1 cells in CCMSympt cell cultures. Furthermore, in comparison with asymptomatic patients, purified T-cells from the CCMSympt group released higher levels of Th17-related cytokines in response to Pam3C and, mainly, LPS, as well as after activation via TCR/CD28. Concerning the B-cell subsets, a higher frequency of memory and memory activated B-cells was observed in CCMSympt patients. CONCLUSIONS: Our findings reveal an increase in circulating Th17/Tc-17 cell subsets expressing functional TLR2 and, mainly, TLR4 molecules, associated with an increase in memory B-cell subsets in CCM patients with clinical activity of the disease.
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Hemangioma Cavernoso del Sistema Nervioso Central , Receptor Toll-Like 2 , Hemangioma Cavernoso del Sistema Nervioso Central/metabolismo , Humanos , Células B de Memoria , Células Th17/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
Circulating TFH (cTFH ) cells express CXCR5, PD-1, and, when activated, ICOS, and release IL-21. According to the production of IFN-γ, IL-4, and IL-17 and expression of FoxP3, these cells are also classified as cTFH 1, cTFH 2, cTFH 17, and cTFR cells, respectively. This CD4+ T-cell subset is pivotal to efficient humoral immunity, and pregnancy appears to favor IgG production. Here, not only pregnancy amplified the in vivo production of anti-HBsAg IgG in HBV immunized women, but the frequency of cTFH cells was directly correlated with estradiol levels. In vitro, pregnancy-related dose of 17-ß-estradiol (E2) directly increased the percentage of different cTFH subsets. While E2 and progesterone (P4) increased the proportion of differentiated TFH cells derived from naïve CD4+ T-cells, only E2 amplified the release of IL-21 in those cell cultures. In addition, E2 and P4 increased the proportion of memory B cells and plasma cells, respectively. In SEB-activated B/TFH cell co-cultures, E2, in the presence of P4, increased the production of total IgG. Finally, among the hormones, P4 was stronger in upregulating the percentage of IL-10+ TFR cells. Collectively, our findings suggested that E2 and P4 cooperate in the humoral immune response by favoring the expansion of different cTFH and B cell subsets.
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Linfocitos B/inmunología , Estradiol/sangre , Estradiol/inmunología , Inmunidad Humoral , Embarazo/sangre , Embarazo/inmunología , Progesterona/sangre , Progesterona/inmunología , Células T Auxiliares Foliculares/inmunología , Adulto , Subgrupos de Linfocitos B/efectos de los fármacos , Subgrupos de Linfocitos B/inmunología , Diferenciación Celular , Citocinas/metabolismo , Estradiol/farmacología , Femenino , Vacunas contra Hepatitis B/inmunología , Humanos , Inmunoglobulina G/biosíntesis , Técnicas In Vitro , Interleucinas/biosíntesis , Progesterona/farmacología , Células T Auxiliares Foliculares/clasificación , Células T Auxiliares Foliculares/citología , Adulto JovenRESUMEN
This study examines the link between peripheral immune changes in perpetuation of the Alzheimer's disease (AD) neuropathology and cognitive deficits. Our research design using human AD patients and rodent model is supported by past evidence from genomic studies. We observed an active immune response against Aß as indicated by the increased Aß specific IgG antibody in the serum of AD and patients with mild cognitive impairments as compared to healthy controls. A similar increase in IgG and decrease in IgM antibody against Aß was also confirmed in the 5xFAD mouse model of AD. More importantly, we observed a negative correlation between reduced IgM levels and cognitive dysfunction that manifested as impaired memory consolidation. Strong peripheral immune activation was supported by increased activation of microglia in the brain and macrophages in the spleen of AD mice compared to wild type control littermates. Furthermore, inflammatory cytokine IL-21 that is involved in antibody class switching was elevated in the plasma of AD patients and correlated positively with the IgG antibody levels. Concurrently, an increase in IL-21 and IL-17 was observed in spleen cells from AD mice. Further investigation revealed that proportions of T follicular helper (Tfh) cells that secrete IL-21 are increased in the spleen of AD mice. In contrast to Tfh, the frequency of B1 cells that produce IgM antibodies was reduced in AD mice. Altogether, these data indicate that in AD the immune tolerance to Aß is compromised leading to chronic immune/inflammatory responses against Aß that are detrimental and cause neuropathology. Graphical Abstract Healthy subjects are tolerant to Aß and usually react weakly to it resulting the in the production of IgM class of antibodies that are efficient at clearing up self-antigens such as Aß without causing inflammation. In contrast, Alzheimer's disease patients mount a strong immune response against Aß probably in an effort to clear up excessive Aß. There is enhanced production of inflammatory cytokines such as IL-21 as well as an increase in Tfh cells that cause antibody class switching form IgM to IgG. The strong immune response is inefficient at clearing up Aß and instead exacerbates inflammation that causes AD neuropathology and cognitive dysfunction.
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Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Inmunidad/inmunología , Mediadores de Inflamación/inmunología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/inmunología , Péptidos beta-Amiloides/metabolismo , Animales , Disfunción Cognitiva/inmunología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismoRESUMEN
PROBLEM: Pregnancy appears to favor maternal antibody production. In contrast, by damaging follicular helper T cells (TFH ), HIV-1 infection compromises protective humoural immune response. Therefore, we aimed to investigate the frequency of different TFH -like cells in HIV-infected pregnant women (PW) before and after antiretroviral (ARV) therapy. METHOD OF STUDY: Peripheral blood mononuclear cells, CD4+ T and B cells, were obtained from asymptomatic HIV-1-infected non-PW and PW just before and after ARV therapy. In some experiments, healthy HIV-1-negative PW were also tested. The frequency of different TFH -like cell subsets was determined by flow cytometry. The plasma titers of IgG anti-tetanus toxoid (TT), anti-HBsAg, and anti-gp41 were determined by ELISA. The in vitro production of total IgG, IL-21, and hormones (estrogen and progesterone) was quantified also by ELISA. RESULTS: Our results demonstrate that antiretroviral (ARV) therapy was more efficient in elevating the percentage of circulating IL-21-secreting TFH cells in HIV-1-infected pregnant women (PW) than in non-pregnant patients (nPW). Moreover, in co-culture systems, CD4+ T cells from ART-treated PW were more efficient in assisting B cells to produce IgG production. The in vivo anti-HBsAg IgG titers after ARV therapy were also significantly higher in PW, and their levels were directly associated with both IL-21+ TFH frequency and plasma concentration of estrogen. CONCLUSION: In summary, our results suggest that pregnancy favors the recovery of TFH -like cells after ARV therapy in HIV-1-infected women, which could help these mothers to protect their newborns from infectious diseases by transferring IgG across the placenta.
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Fármacos Anti-VIH/farmacología , Infecciones por VIH/inmunología , VIH-1 , Interleucinas/metabolismo , Complicaciones Infecciosas del Embarazo/inmunología , Células T Auxiliares Foliculares/metabolismo , Adulto , Fármacos Anti-VIH/uso terapéutico , Anticuerpos Antibacterianos/sangre , Formación de Anticuerpos/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Recuento de Linfocito CD4 , Células Cultivadas , Técnicas de Cocultivo , Estrógenos/sangre , Femenino , Anticuerpos Anti-VIH/sangre , Proteína gp41 de Envoltorio del VIH/inmunología , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , VIH-1/inmunología , Anticuerpos contra la Hepatitis B/sangre , Antígenos de Superficie de la Hepatitis B/inmunología , Humanos , Inmunoglobulina G/sangre , Embarazo , Complicaciones Infecciosas del Embarazo/sangre , Progesterona/sangre , Toxoide Tetánico/inmunología , Adulto JovenRESUMEN
Chronic hepatitis C (CHC) is frequently related to liver fibrosis, and several studies have suggested that the immunological activity of HCV antigens contributes to hepatic damage. In the present study, among structural and non-structural HCV antigens, elevatedIL-1ß, IL-6, IL-17 levels were secreted by PBMC cultures obtained from CHC patients following stimulation with core antigen. Moreover, the percentage of core-specific IL-6+IL-17+(CD4+ and CD8+) T cells was significantly higher in patients with worsehepatic lesions, determined on the Metavir scale. When compared with healthy subjects, the percentage of circulating Treg cells was elevated in CHC patients, mainly among those with advanced liver fibrosis. Nevertheless, in this last group of patients, the proportion of CD39+ Treg subsets was very low. Finally, the percentage of senescent (CD57+ CD28-) and exhausted (PD-1+CD28+) core-specific T cells in CHC patients was also found to be a result of fibrotic hepatic status. In summary, imbalances between different core-specific T cell subsets are associated with liver fibrosis severity.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Hepatitis C Crónica/inmunología , Cirrosis Hepática/inmunología , Subgrupos de Linfocitos T/inmunología , Adulto , Anciano , Apirasa/metabolismo , Antígenos CD28/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Antígenos CD57/metabolismo , Linfocitos T CD8-positivos/metabolismo , Femenino , Hepacivirus , Humanos , Interleucina-17/sangre , Interleucina-6/sangre , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Hígado/patología , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
Due to their function in assisting B cells, TFH cells may be involved in the production of pathogenic IgG in neuromyelitis optica spectrum disorder (NMOSD). In the present study, the proportion of IL-6+ and IL-17+ TFH cell subsets was higher in NMOSD patients than healthy individuals. The frequency of both TFH cell subsets were directly associated with disease activity. By contrast, NMOSD patients with a higher proportion of IL-10+ TFH cell subsets showed a lower neurological disabilities score. In summary, all findings suggest that expansion of peripheral IL-6+ and IL-17+ TFH cells may be involved in the severity of NMOSD.
Asunto(s)
Interleucina-17/sangre , Interleucina-6/sangre , Neuromielitis Óptica/sangre , Neuromielitis Óptica/diagnóstico , Índice de Severidad de la Enfermedad , Linfocitos T Colaboradores-Inductores/metabolismo , Adulto , Biomarcadores/sangre , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Excessive levels of proinflammatory cytokines in the CNS are associated with reduced serotonin (5-HT) synthesis, a neurotransmitter with diverse immune effects. In this study, we evaluated the ability of exogenous 5-HT to modulate the T-cell behavior of patients with MS, a demyelinating autoimmune disease mediated by Th1 and Th17 cytokines. Here, 5-HT attenuated, in vitro, T-cell proliferation and Th1 and Th17 cytokines production in cell cultures from MS patients. Additionally, 5-HT reduced IFN-γ and IL-17 release by CD8+ T cells. By contrast, 5-HT increased IL-10 production by CD4+ T cells from MS patients. A more accurate analysis of these IL-10-secreting CD4+ T cells revealed that 5-HT favors the expansion of FoxP3+ CD39+ regulatory T cells (Tregs) and type 1 regulatory T cells. Notably, this neurotransmitter also elevated the frequency of Treg17 cells, a novel regulatory T-cell subset. The effect of 5-HT in upregulating CD39+ Treg and Treg17 cells was inversely correlated with the number of active brain lesions. Finally, in addition to directly reducing cytokine production by purified Th1 and Th17 cells, 5-HT enhanced in vitro Treg function. In summary, our data suggest that serotonin may play a protective role in the pathogenesis of MS.
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Interferón gamma/metabolismo , Interleucina-17/metabolismo , Esclerosis Múltiple/patología , Serotonina/metabolismo , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Células Th17/inmunología , Adulto , Encéfalo/patología , Linfocitos T CD8-positivos/inmunología , Proliferación Celular/fisiología , Células Cultivadas , Femenino , Humanos , Activación de Linfocitos/inmunología , Masculino , Esclerosis Múltiple/inmunologíaRESUMEN
Pregnancy favors antibody production, and some evidence has suggested a direct effect of estrogen on B cells. The impact of pregnancy on circulating follicular helper T (TFH) cells, typically identified by the expression of CD45RO and CXCR5, has not been previously investigated. Here, the percentage of TFH cells, co-expressing or not PD-1, ICOS, or CXCR3 markers was significantly higher in pregnant women (PW) as compared with non-pregnant ones (nPW). Furthermore, the percentage of CXCR3+ TFH cells able to produce IL-6, IL-21, and IL-10 was significantly higher in PW than nPW. Interestingly, anti-CMV and anti-HBs antibody titers were significantly higher in the plasma of PW and were directly correlated with IL-21-producing CXCR3+ TFH cells. Finally, peripheral estrogen levels, but not progesterone, were positively related to either PD-1+ CXCR3+ TFH cells or plasma anti-CMV and anti-HBs IgG antibodies. In summary, our data suggests a positive effect of pregnancy on the proportion of CD4+ T cell subset specialized in helping B cells. This phenomenon, which could be related to the high estrogen levels produced during pregnancy, may help to explain why pregnancy favor humoral immunity.
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Linfocitos B/inmunología , Citomegalovirus/inmunología , Centro Germinal/inmunología , Virus de la Hepatitis B/inmunología , Linfocitos T Colaboradores-Inductores/fisiología , Adolescente , Adulto , Anticuerpos Antivirales/sangre , Formación de Anticuerpos , Circulación Sanguínea , Células Cultivadas , Estrógenos/metabolismo , Femenino , Humanos , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Interleucinas/metabolismo , Embarazo , Receptor de Muerte Celular Programada 1/metabolismo , Receptores CXCR3/metabolismo , Adulto JovenRESUMEN
Studies have suggested the pivotal role of T helper type 1 (Th1) -related cytokines on the outcome of hepatitis C virus (HCV) infection. Nevertheless, the role of different interleukin-17 (IL-17) -secreting T cells on chronic hepatitis C (CHC) is less clear. Here, the in vivo IL-1ß, IL-6, and IL-17 levels were positively correlated with both alanine transaminase (ALT) levels and hepatic lesions. When compared with the control group, CHC patients showed a lower proportion of IL-17-secreting (CD4+ and CD8+ ) T cells capable of simultaneously producing IL-21. Moreover, the percentage of IL-10-secreting Th17 cells was also lower in CHC patients. Notably, advanced liver lesions were observed among those patients with lower percentage levels of IL-17-producing T cells positive for IL-21, interferon-γ (IFN-γ) and IL-10. In contrast, the severity of hepatic damage was associated with peripheral single IL-17+ T cells. The percentage of IL-17+ IL-21- IFN-γ+ (CD4+ and CD8+ ) T-cell phenotypes was positively associated with plasma CD14 levels. Finally, elevated levels of circulating CD14 were detected among CHC patients with extensive liver damage. In summary, although preliminary, our results suggest that a balance between different IL-17-producing T cells, associated with peripheral levels of CD14, may be a progress marker for liver disease in chronically HCV-infected patients.
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Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/inmunología , Interleucina-17/inmunología , Cirrosis Hepática/etiología , Cirrosis Hepática/inmunología , Subgrupos de Linfocitos T/inmunología , Adulto , Anciano , Células Cultivadas , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Fatigue is a common "ghost" symptom in patients with multiple sclerosis (MS), an autoimmune disease mediated by T cells that target myelin antigens of the central nervous system. As fatigue has been associated with inflammatory states, its occurrence may negatively impact MS progression. The aim of this study was to evaluate the impact of fatigue on the cytokine profile of patients with relapsing-remitting (RR) MS. For our study, blood were collected from MS patients in clinical remission phase with (n=15) and without (n=15) fatigue. Cytokines were detected by ELISA in the plasma and supernatant collected from anti-CD3/anti-CD28-activated T cells or LPS-stimulated monocytes. In some wells, different doses of hydrocortisone (HC) were added at the beginning of the culture. Here, peripheral levels of IL-6 and TNF-α, as well as in vitro production of cytokines related to Th17 (IL-6, IL-17, IL-22, and GM-CSF) or Th1 (IFN-γ) phenotypes, were elevated in fatigued patients and their levels were associated with fatigue severity. The same phenomenon was observed between the production of IL-6, TNF-α, IL-1ß, and IL-23 by monocytes and fatigue. Moreover, HC was less efficient in inhibiting in vitro inflammatory cytokine production in patients with fatigue, mainly those produced by both CD8+ T cells and monocytes. Our data, although preliminary, suggests that the occurrence of fatigue, by favoring the in vitro production of Th1/Th17-related cytokines and corticoid resistance, may negatively impact the course of MS.
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Fatiga/sangre , Hidrocortisona/farmacología , Mediadores de Inflamación/sangre , Esclerosis Múltiple Recurrente-Remitente/sangre , Células TH1/metabolismo , Células Th17/metabolismo , Adulto , Células Cultivadas , Fatiga/inmunología , Femenino , Humanos , Mediadores de Inflamación/inmunología , Masculino , Esclerosis Múltiple Recurrente-Remitente/inmunología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th17/inmunología , Adulto JovenRESUMEN
Vitamin D deficiency is an environmental risk factor for MS, a Th17 cell-mediated autoimmune disease that results in demyelination in the CNS. Therefore, we aimed to evaluate the ability of in vitro 1,25(OH)2D in modulating different Th17 cell subsets in MS patients in remission phase. In the present study, the production of Th17-related cytokines (IL-1ß, IL-6, IL-17, IL-22), as well as GM-CSF, was significantly higher in cell cultures from MS patients than in healthy subjects (HS). The 1,25(OH)2D reduced all pro-inflammatory cytokines essayed, mainly those released from HS cell cultures. The proportion of both IL-17+IFN-γ+ (CD4+ and CD8+) T cells and IL-17+IFN-γ-CD8+ T cells was positively related with neurological disorders, determined by EDSS score. The addition of 1,25(OH)2D reduced not only these pathogenic T cell subsets but elevated the percentage of IL-10-secreting conventional (FoxP3+CD25+CD127-CD4+) and non-conventional (IL-17+) regulatory-like T cells. Taken together, the results indicate that the active form of vitamin D should benefit MS patients by attenuating the percentage of pathogenic T cells. This effect could be direct and/or indirect, by enhancing classical and non-classical regulatory T cells.
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Interleucina-17/metabolismo , Esclerosis Múltiple/sangre , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/metabolismo , Vitamina D/farmacología , Adolescente , Adulto , Células Cultivadas , Femenino , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Esclerosis Múltiple/tratamiento farmacológico , Vitamina D/uso terapéutico , Adulto JovenRESUMEN
AIM: review the literature for studies that describe the language development of children after they receive cochlear implants. RESEARCH STRATEGIES: Literature review on the PubMed, Web of Science, Scopus, and Science Direct databases, tracing the selection and critical analysis stages in the journals found and selected. SELECTION CRITERIA: We selected original articles looking at children with cochlear implants, which mentioned language development after surgery. Case studies, dissertations, books chapters, editorials, and original articles that did not mention aspects of oral communication development, perception of sounds and speech, and other stages of human development, in the title, abstract, or text, were excluded. DATA ANALYSIS: A protocol was created for this study including the following points: author, year, location, sample, type of study, objectives, methods used, main results, and conclusion. RESULTS: 5,052 articles were found based on the search descriptors and free terms. Of this total, 3,414 were excluded due to the title, 1,245 due to the abstract, and 358 from reading the full text; we selected 35, of which 28 were repeated. In the end, seven articles were analyzed in this review. CONCLUSION: We conclude that cochlear implant users have slower linguistic and educational development than their peers with normal hearing - though they are better than conventional prostheses users - and they are able to match them over time. There is great variability in the test methodologies, thus reducing the effectiveness and reliability of the results found.
Asunto(s)
Lenguaje Infantil , Implantes Cocleares , Pérdida Auditiva/terapia , Trastornos del Desarrollo del Lenguaje/rehabilitación , Niño , Desarrollo Infantil , Humanos , Trastornos del Desarrollo del Lenguaje/cirugía , Resultado del TratamientoRESUMEN
RESUMO Objetivo Levantar na literatura a descrição do desenvolvimento de linguagem de crianças usuárias de implante coclear. Estratégias de pesquisa Buscas na plataforma Pubmed e nas bases de dados Web of Science, Scopus e Science Direct, seguindo etapas de seleção e análise crítica dos periódicos encontrados e escolhidos. Critérios de seleção Selecionados artigos originais que abordavam crianças usuárias de implante coclear, nos quais eram mencionados o desenvolvimento de linguagem após a cirurgia. Excluídos artigos de estudo de caso, dissertações, capítulos de livros, editoriais e artigos originais que não referenciavam no título, no resumo ou no texto aspectos de desenvolvimento da comunicação oral, percepção dos sons e da fala e outras fases do desenvolvimento humano. Análise dos dados Foi criado um fichamento protocolar contemplando os seguintes pontos: autor, ano, local, amostra, tipo de estudo, objetivos, métodos utilizados, resultados principais e conclusão. Resultados Encontrados 5.052 artigos a partir da busca de descritores e termos livres. Desses, 3.414 foram excluídos pelo título, 1.245, pelo resumo e 358, pela leitura do texto completo, sendo selecionados 35, dos quais, 28 estavam repetidos. Ao final, sete artigos foram analisados nesta revisão. Conclusão Verifica-se que os usuários de implante coclear apresentam desenvolvimento linguístico e educacional aquém de seus pares com audição normal, porém melhor que os usuários de próteses convencionais, podendo igualar-se a eles com o passar do tempo. Há uma grande variabilidade nas metodologias dos testes, diminuindo, portanto, a efetividade e a confiabilidade dos resultados encontrados.
ABSTRACT Aim review the literature for studies that describe the language development of children after they receive cochlear implants. Research strategies Literature review on the PubMed, Web of Science, Scopus, and Science Direct databases, tracing the selection and critical analysis stages in the journals found and selected. Selection criteria We selected original articles looking at children with cochlear implants, which mentioned language development after surgery. Case studies, dissertations, books chapters, editorials, and original articles that did not mention aspects of oral communication development, perception of sounds and speech, and other stages of human development, in the title, abstract, or text, were excluded. Data analysis A protocol was created for this study including the following points: author, year, location, sample, type of study, objectives, methods used, main results, and conclusion. Results 5,052 articles were found based on the search descriptors and free terms. Of this total, 3,414 were excluded due to the title, 1,245 due to the abstract, and 358 from reading the full text; we selected 35, of which 28 were repeated. In the end, seven articles were analyzed in this review. Conclusion We conclude that cochlear implant users have slower linguistic and educational development than their peers with normal hearing - though they are better than conventional prostheses users - and they are able to match them over time. There is great variability in the test methodologies, thus reducing the effectiveness and reliability of the results found.
Asunto(s)
Humanos , Niño , Implantes Cocleares , Pérdida Auditiva/terapia , Trastornos del Desarrollo del Lenguaje/rehabilitación , Desarrollo Infantil , Lenguaje Infantil , Resultado del Tratamiento , Trastornos del Desarrollo del Lenguaje/cirugíaRESUMEN
Aging is now a well-recognized characteristic of the HIV-infected population and both AIDS and aging are characterized by a deficiency of the T-cell compartment. The objective of the present study was to evaluate the impact of antiretroviral (ARV) therapy in recovering functional response of T cells to both HIV-1-specific ENV peptides (ENV) and tetanus toxoid (TT), in young and aged AIDS patients who responded to ARV therapy by controlling virus replication and elevating CD4(+) T cell counts. Here, we observed that proliferative response of T-cells to either HIV-1-specific Env peptides or tetanus toxoid (TT) was significantly lower in older antiretroviral (ARV)-treated patients. With regard to cytokine profile, lower levels of IFN-γ, IL-17 and IL-21, associated with elevated IL-10 release, were produced by Env- or TT-stimulated T-cells from older patients. The IL-10 neutralization by anti-IL-10 mAb did not elevate IFN-γ and IL-21 release in older patients. Finally, even after a booster dose of TT, reduced anti-TT IgG titers were quantified in older AIDS patients and it was related to both lower IL-21 and IFN-γ production and reduced frequency of central memory T-cells. Our results reveal that ARV therapy, despite the adequate recovery of CD4(+) T cell counts and suppression of viremia, was less efficient in recovering adequate immune response in older AIDS patients.