RESUMO
Elevated frequency of Th17-like cells expressing Toll-like receptors (TLRs) has been recently associated with relapsing-remitting multiple sclerosis (MS) pathogenesis, a chronic inflammatory demyelinating autoimmune disease of the central nervous system. We aimed to investigate the impact of current major depressive disorder (MDD) on the behaviour of these cells following in vitro stimulation with TLR2, TLR4, TLR5 and TLR9 agonists. Here, the level of both cell proliferation and cytokine production related to Th17/Tc17 phenotypes in response to TLR2 (Pam3C) and TLR4 (LPS) ligands was significantly higher in CD4+ and CD8+ T-cell cultures from MS/MDD patients when compared to non-depressed patients. These cytokine levels were positively associated with neurological disabilities in patients. No difference for responsiveness to TLR5 (flagellin) and TLR9 (ODN) agonists was observed. LPS, but not Pam3C, induced significant IL-10 release, mainly in patients without MDD. Interestingly, more intense expression of TLR2 and TLR4 on these cells was observed in MDD patients. Finally, in vitro addition of serotonin and treatment of MDD patients with selective serotonin reuptake inhibitors (SSRIs) reduced the production of Th17/Tc17-related cytokines by CD4+ and CD8+ T cells in response to Pam3C and LPS. However, only SSRI therapy diminished the frequency and intensity of TLR2 and TLR4 expression on circulating CD4+ and CD8+ T cells. In summary, although preliminary, our findings suggest that adverse events that elevate circulating levels of TLR2 and TLR4 ligands can affect MS pathogenesis, particularly among depressed patients.
Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Fluoxetina/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Esclerose Múltipla Recidivante-Remitente/imunologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Células Th17/efeitos dos fármacos , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Adulto , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/imunologia , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/metabolismo , Fenótipo , Células Th17/imunologia , Células Th17/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
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.
Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/imunologia , HIV-1 , Interleucinas/metabolismo , Complicações Infecciosas na Gravidez/imunologia , Células T Auxiliares Foliculares/metabolismo , Adulto , Fármacos Anti-HIV/uso terapêutico , Anticorpos Antibacterianos/sangue , Formação de Anticorpos/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Contagem de Linfócito CD4 , Células Cultivadas , Técnicas de Cocultura , Estrogênios/sangue , Feminino , Anticorpos Anti-HIV/sangue , Proteína gp41 do Envelope de HIV/imunologia , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , HIV-1/imunologia , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/imunologia , Humanos , Imunoglobulina G/sangue , Gravidez , Complicações Infecciosas na Gravidez/sangue , Progesterona/sangue , Toxoide Tetânico/imunologia , Adulto JovemRESUMO
Both obesity and low vitamin D levels have been associated with allergic asthma (AA) severity. In the present study, severity of AA was associated with obesity but to the in vitro IgE production. In those patients, higher levels of IL-5, IL-6 and IL-17 were quantified in CD4+ T-cell cultures as compared with patients with mild and moderate AA. In addition, the lowest IL-10 levels were detected in the cell cultures from patients with a worse prognosis. Interestingly, the occurrence of AA elevates the plasma levels of leptin, and this adipokine was positively correlated with the release of IL-5, IL-6 and IL-17, but inversely correlated with IL-10 production, by CD4+ T-cells from patients. In AA-derived CD4+ T-cell cultures, 1,25(OH)2D3 was less efficient at inhibiting IL-5, IL-6 and IL-17 production, and up regulating IL-10 release, as those from healthy subjects. Interestingly, the in vitro immunomodulatory effects of vitamin D were inversely correlated with serum leptin levels. In summary, our findings suggested that obesity, probably due to the overproduction of leptin, negatively impacts AA as it favors imbalance between Th2/Th17 and regulatory phenotypes. The deleterious effects of leptin may also be due to its ability to counter-regulate the immunosuppressive effects of vitamin D.
Assuntos
Asma/imunologia , Linfócitos T CD4-Positivos/imunologia , Citocinas/imunologia , Hipersensibilidade/imunologia , Leptina/metabolismo , Obesidade/metabolismo , Adulto , Asma/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Calcitriol/farmacologia , Citocinas/efeitos dos fármacos , Feminino , Humanos , Hipersensibilidade/metabolismo , Imunoglobulina E/imunologia , Técnicas In Vitro , Interleucina-10/imunologia , Interleucina-17/imunologia , Interleucina-5/imunologia , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Vitamina D/metabolismo , Vitaminas/farmacologia , Adulto JovemRESUMO
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.
Assuntos
Interferon gama/metabolismo , Interleucina-17/metabolismo , Esclerose Múltipla/patologia , Serotonina/metabolismo , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Adulto , Encéfalo/patologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/fisiologia , Células Cultivadas , Feminino , Humanos , Ativação Linfocitária/imunologia , Masculino , Esclerose Múltipla/imunologiaRESUMO
Multiple sclerosis (MS) is thought to be an autoimmune disorder. It is believed that immunological events in the early stages have great impact on the disease course. Therefore, we aimed to evaluate the cytokine profile of myelin basic protein (MBP)-specific T cells from MS patients in the early phase of the disease and correlate it to clinical parameters, as well as to the effect of in vitro corticoid treatment. Peripheral T cells from MS patients were stimulated with MBP with our without hydrocortisone for 5 days. The cytokines level were determined by ELISA. The number of active brain lesions was determined by MRI scans, and the neurological disabilities were assessed by Expanded Disability Status Scale scores. Our results demonstrated that MS-derived T cells responded to MBP by producing high levels of T helper type 1 (Th1) and Th17 cytokines. Although the production of interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor, IL-17 and IL-22 was less sensitive to hydrocortisone inhibition, only IL-17 and IL-22 levels correlated with active brain lesions. The ability of hydrocortisone to inhibit IL-17 and IL-22 production by MBP-specific CD4(+) T cells was inversely related to the number of active brain lesions. Finally, the production of both cytokines was significantly higher in cell cultures from Afrodescendant patients and it was less sensitive to hydrocortisone inhibition. In summary, our data suggest that IL-17- and IL-22-secreting CD4(+) T cells resistant to corticoids are associated with radiological activity of the MS in early stages of the disease, mainly among Afrodescendant patients who, normally, have worse prognosis.
Assuntos
Corticosteroides/farmacologia , Encéfalo/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Resistência a Medicamentos , Hidrocortisona/farmacologia , Interleucina-17/imunologia , Interleucinas/imunologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Proteína Básica da Mielina/imunologia , Adolescente , Adulto , Negro ou Afro-Americano , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Avaliação da Deficiência , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-17/metabolismo , Interleucinas/metabolismo , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/etnologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Proteína Básica da Mielina/metabolismo , Fatores de Tempo , Adulto Jovem , Interleucina 22RESUMO
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.
Assuntos
Envelhecimento/imunologia , Fármacos Anti-HIV/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/imunologia , Adulto , Fatores Etários , Envelhecimento/patologia , Anticorpos Antivirais/biossíntese , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Estudos de Casos e Controles , Feminino , Infecções por HIV/patologia , Infecções por HIV/virologia , Humanos , Interleucina-10/biossíntese , Interleucina-10/imunologia , Interleucina-17/biossíntese , Interleucina-17/imunologia , Interleucinas/biossíntese , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Peptídeos/farmacologia , Cultura Primária de Células , Toxoide Tetânico/farmacologia , Carga Viral/efeitos dos fármacos , Proteínas Virais/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
Interleukin-6 (IL-6) has been implicated in the induction of pathogenic IL-17-producing T cells in autoimmune diseases, and studies evaluating the role of this cytokine in T-cell function in patients with multiple sclerosis (MS) are lacking. Our objective was to evaluate the role of IL-6 receptor (IL-6R) signalling on in vitro functional status of T cells from patients with relapsing-remitting MS during clinical remission. Our results demonstrated that, even during the remission phase, activated T cells from patients produce higher levels of IL-17, and this cytokine was positively correlated with disease severity, as determined by Expanded Disability Status Scale score. In the MS group, the blockade of IL-6R signalling by anti-IL-6R monoclonal antibody reduced IL-17 production and elevated IL-10 release by activated CD4(+) T cells, but it did not alter the production of these cytokines by activated CD8(+) T cells. Blockade of IL-6R signalling also reduced the ability of monocytes to up-regulate T helper type 17 phenotype in patients with MS. Finally, both cell proliferation and IL-17 release by CD4(+) and, mainly, CD8(+) T cells from patients with MS were less sensitive to hydrocortisone inhibition than control group. Interestingly, IL-6R signalling blockade restored the ability of hydrocortisone to inhibit both T-cell proliferation and IL-17 production. Collectively, these results suggest that IL-6 might be involved in MS pathogenesis by enhancing IL-17 production and reducing corticoid inhibitory effects on activated T cells.
Assuntos
Interleucina-17/biossíntese , Interleucina-6/metabolismo , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Corticosteroides/metabolismo , Corticosteroides/farmacologia , Adulto , Citocinas/biossíntese , Resistência a Medicamentos , Feminino , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Receptores de Interleucina-6/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Adulto JovemRESUMO
Dopamine (DA) is a neurotransmitter produced mainly in the central nervous system (CNS) that has immunomodulatory actions on T cells. As the multiple sclerosis (MS) has long been regarded as an autoimmune disease of CNS mediated by T cells, the objective of this study was to evaluate the impact of DA on in vitro functional status of T cells from relapsing-remitting (RR)-MS patients. Peripheral T-cells from RR-MS patients were activated by mitogens and cell proliferation and cytokine production were assayed by [(3)H]-thymidine uptake and ELISA, respectively. Our results demonstrated that DA enhanced in vitro T cell proliferation and Th17-related cytokines in MS-derived cell cultures. In addition, this catecholamine reduced Treg-related cytokines (IL-10 and TGF-ß) release by activated CD4(+) T cells. These DA-induced effects on T cells were mainly dependent on IL-6 production by both polyclonally-activated CD4(+) T cells and LPS-stimulated monocytes. Furthermore, the production of IL-17 and IL-6 by MS-derived T cells was directly related with neurological disability (EDSS score), and the release of these cytokines was less sensitive to glucocorticoid inhibition in MS patients than in control group, mainly after DA addition. In conclusion, our data suggest that DA amplifies glucocorticoid-resistant Th17 phenotype in MS patients, and this phenomenon could be, at least in part, due to its ability to induce IL-6 production by monocytes and CD4(+) T cells.
Assuntos
Dopamina/farmacologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Neuroimunomodulação/fisiologia , Células Th17/imunologia , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Divisão Celular , Células Cultivadas , Resistência a Medicamentos , Feminino , Humanos , Interleucina-10/biossíntese , Interleucina-10/genética , Interleucina-6/biossíntese , Interleucina-6/genética , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Esclerose Múltipla Recidivante-Remitente/metabolismo , Fito-Hemaglutininas/farmacologia , Índice de Gravidade de Doença , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/genética , Adulto JovemRESUMO
The pathogenesis of neuromyelitis optica (NMO) is influenced by a combination of genetic and environmental factors, including infectious agents. Several infectious diseases can both trigger or exacerbate autoimmunity. The objective of the present work was to evaluate the in vitro immune responsiveness to Escherichia coli (EC), Staphylococcus aureus (SA) and Candida albicans (CA) in remittent-recurrent NMO patients, and correlate it with the level of neurological disability. Our results revealed that the extent of lymphoproliferation and cytokine profile in response to SA- and CA-stimulated PBMC cultures was similar between NMO patients and healthy individuals. Nevertheless, a higher in vitro CD4(+) T cell proliferation associated with elevated IL-1ß, IL-6 and IL-17 release was observed in NMO-derived EC-stimulated cell cultures. Additionally, in these last cultures, the IL-10 production was significantly lower as compared with control group. The in vitro EC-induced levels of IL-6 and IL-17 were positively related with neurological disabilities. This higher tendency to produce Th17-related cytokines was proportional to the production of IL-23 and IL-6 by LPS-activated monocytes. Interestingly, elevated LPS levels were quantified in the plasma of NMO patients. The results suggest that a higher Th17-responsiveness to E. coli could be involved in the NMO pathogenesis.
Assuntos
Candida albicans/imunologia , Escherichia coli/imunologia , Neuromielite Óptica/imunologia , Staphylococcus aureus/imunologia , Células Th17/imunologia , Adulto , Antígenos de Bactérias/imunologia , Proliferação de Células , Células Cultivadas , Citocinas/metabolismo , Feminino , Humanos , Imunidade Celular , Lipopolissacarídeos/sangue , Lipopolissacarídeos/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/microbiologia , Neuromielite Óptica/fisiopatologia , Adulto JovemRESUMO
Exogenous glucocorticoid plays an important role in controlling clinical relapses of multiple sclerosis (MS), but the response to this treatment differs among patients. In this study, T-cell proliferation and IL-17 production were less sensitive to hydrocortisone (HC) inhibition in MS patients than healthy individuals, mainly in CD8(+) compartment. Furthermore, in vitro IL-17 production was positively related with neurological disability and its release was proportional to IL-23 and IL-6 productions by LPS-activated monocytes. Interestingly, elevated LPS levels were quantified in the plasma of MS patients, and their levels were directly related to in vivo IL-6 production. Finally, HC-resistance in reducing IL-17 production by polyclonally-activated CD8(+) T cells was particularly observed among MS patients with higher in vivo LPS levels. In summary, the results indicate that T-cells derived from MS patients show an enhanced Th17-like phenotype that is directly associated with neurological disability, resistance to glucocorticoid inhibition and elevated bacterial translocation.