The ex vivo production of IL-6 and IL-21 by CD4+ T cells is directly associated with neurological disability in neuromyelitis optica patients.

Neuromyelitis optica (NMO), also known as Devic's disease, is an autoimmune, inflammatory disorder of the central nervous system (CNS) in which the immune system attacks myelin of the neurons located at the optic nerves and spinal cord, thus producing a simultaneous or sequential optic neuritis and myelitis. The objective of this study was evaluated the background T-cell function of patients suffering from neuromyelitis optica (NMO), an autoimmune disorder of the central nervous system. In our study, the in vitro T cell proliferation and the production of Th1 cytokines were significantly lower in cell cultures from NMO patients, as compared with healthy individuals. In contrast, a dominant Th17-like phenotype, associate with higher IL-23 and IL-6 production by LPS-activated monocytes, was observed among NMO patients. The release of IL-21 and IL-6 by polyclonally activated CD4+ T cells was directly correlated to neurological disability. In addition, the in vitro release of IL-21, IL-6 and IL-17 was significantly more resistant to glucocorticoid inhibition in NMO patients. In conclusion, the results indicate dominant Th17-related response in NMO patients that was directly proportional to neurological disability. Furthermore, our results can help to explain why NMO patients trend to be more refractory to corticoid treatment.

The impact of pregnancy on the HIV-1-specific T cell function in infected pregnant women.

Evidences indicate that pregnancy can alter the Ag-specific T-cell responses. This work aims to evaluate the impact of pregnancy on the in vitro HIV-1-specific immune response. As compared with non-pregnant patients, lower T-cell proliferation and higher IL-10 production were observed in T-cell cultures from pregnant patients following addition of either mitogens or HIV-1 antigens. In our system, the main T lymphocyte subset involved in producing IL-10 was CD4(+)FoxP3(-). Depletion of CD4(+) cells elevated TNF-α and IFN-γ production. Interestingly, the in vitro HIV-1 replication was lower in cell cultures from pregnant patients, and it was inversely related to IL-10 production. In these cultures, the neutralization of IL-10 by anti-IL-10 mAb elevated TNF-α release and HIV-1 replication. In conclusion, our results reveal that pregnancy-related events should favor the expansion of HIV-1-specific IL-10-secreting CD4(+) T-cells in HIV-1-infected women, which should, in the scenario of pregnancy, help to reduce the risk of vertical HIV-1 transmission.

High IL-10 production by aged AIDS patients is related to high frequency of Tr-1 phenotype and low in vitro viral replication.

This work aims to elucidate the effects of age and HIV-1 infection on the frequency and function of T cell subsets in response to HIV-specific and non-specific stimuli. As compared with the younger AIDS group, the frequencies of naive and central memory T cells were significantly lower in aged AIDS patients. Although there was also a dramatic loss of classical CD4(+)FoxP3(+)CD25(+)Treg cells in this patient group, high frequencies of IL-10-producing CD4(+)FoxP3(-) T cells were observed. In our system, the increased production of IL-10 in aged AIDS patients was mainly derived from Env-specific CD4(+)FoxP3(-)CD152(+) T cells. Interestingly, while the blockade of IL-10 activity by monoclonal antibody clearly enhanced the release of IL-6 and IL-1ß by Env-stimulated PBMC cultures from aged AIDS patients, this monoclonal antibody enhanced in vitro HIV-1-replication. In conclusion, HIV infection and aging undoubtedly contribute synergistically to a complex immune dysfunction in T cell compartment of HAART-treated older HIV-infected individuals.

Dopamine up-regulates Th17 phenotype from individuals with generalized anxiety disorder.

Our objective was to evaluate the effect of stress-related dose of dopamine (DA) on the in vitro proliferation and cytokine production in polyclonally-activated T cells from healthy individuals or individuals with generalized anxiety disorder (GAD). Our results demonstrated that cell cultures from GAD group proliferated less following T cell activation, as compared with control group. The addition of DA reduced the proliferative response in cell cultures from healthy but not from GAD individuals. The cytokine profile in GAD individuals revealed Th1 and Th2 deficiencies associated with a dominant Th17 phenotype, which was enhanced by DA. A similar DA-induced immunomodulation was also observed in PPD-activated cell cultures from GAD individuals. Unlike the control, DA-enhanced Th17 cytokine production in GAD individuals was not affected by glucocorticoid. In conclusion, our results show that the T cell functional dysregulation in GAD individuals is significantly amplified by DA. These immune abnormalities can have impact in increasing the susceptibility of individuals with anxiety disorders to infectious diseases and inflammatory/autoimmune disorders.

Substance P enhances Th17 phenotype in individuals with generalized anxiety disorder: an event resistant to glucocorticoid inhibition.

Our objective was to evaluate the effect of stress-related dose of substance P (SP) on the in vitro proliferation and cytokine production in polyclonally activated T cells from healthy individuals or individuals with generalized anxiety disorder (GAD). Our results demonstrated that cell cultures from GAD group proliferated less following T cell activation, as compared with control group. The addition of SP enhanced, while the glucocorticoid (GC) reduced, the proliferative response in activated cell cultures from healthy but not from GAD individuals. The cytokine profile in GAD individuals revealed Th1 and Th2 deficiencies were associated with dominate Th17 phenotype which was enhanced by SP. Differently from control, the production of Th17 cytokines in GAD individuals was not affected by GC. In conclusion, our results show that complex T cell functional dysregulation in GAD individuals is significantly amplified by SP. These immune abnormalities can have impact in increasing the susceptibility to infectious diseases and inflammatory/autoimmune disorders in anxious individuals.

Enhanced Th17 phenotype in uninfected neonates born from viremic HIV-1-infected pregnant women.

Our objective was to evaluate the in vitro functional profile of T cells from uninfected neonates born from HIV-1-infected pregnant women who controlled (G1) or not (G2) the virus replication. We demonstrated that the lymphoproliferation of T cell to polyclonal activators was higher in the G2 as compared with G1. Nevertheless, no detectable proliferative response was observed in response to HIV-1 antigens in both neonate groups. Cytokine dosage in the supernatants of these polyclonally activated T cell cultures demonstrated that, while IL-10 was the dominant cytokine produced in G1, Th17-related cytokines were significantly higher in G2 neonates. The higher Th17 phenotype tendency in G2 was related to high production of IL-23 by lipopolysaccharide-activated monocyte-derived dendritic cells from these neonates. Our results demonstrated immunological disorders in uninfected neonates born from viremic HIV-1-infected mothers that can help to explain why some of these children have elevated risk of clinical morbidity and mortality due to pathological hypersensitivity.

Enhanced Th17 phenotype in individuals with generalized anxiety disorder.

The generalized anxiety disorder (GAD) is often a debilitating chronic condition, characterized by long-lasting anxiety that is not focused on any object or situation. Besides being clearly linked to increased susceptibility to infectious diseases, anxiety is also known to contribute to the pathogenesis of many inflammatory/autoimmune disorders. The present work aimed to explore the T cell profile following in vitro activation in cultures obtained from a group of individuals with GAD, comparing them with healthy control individuals. Our results demonstrated that cell cultures from GAD group proliferated less following T cell activation as compared with the control group. The analysis of the cytokine profile revealed Th1 and Th2 cytokine deficiencies in the anxious group, as compared with the control subjects. On the other hand, this cellular and humoral immune damage was followed by enhanced production of Th17-derived cytokines. In particular, the levels of TNF-α and IL-17 were significantly higher in cell cultures containing activated T cells from GAD individuals. Therefore, besides a deficiency on Th1 phenotype, an elevated proinflammatory status of these individuals might be related to both glucocorticoid immune resistance and lower IL-10 levels produced by activated T cells. In conclusion, our results demonstrated a T cell functional dysregulation in individuals with GAD, and can help to explain the mechanisms of immune impairment in these subjects and their relationship with increased susceptibility to infections and autoimmune diseases.

Failure of highly active antiretroviral therapy in reconstituting immune response to Clostridium tetani vaccine in aged AIDS patients.

The purpose of this study was to evaluate the impact of age on tetanus-specific immune response in successfully highly active antiretroviral therapy-treated AIDS patients, using healthy age-matched individuals as controls. Whole Peripheral blood mononuclear cells or CD8(+) cell-depleted peripheral blood mononuclear cells from previously tetanus toxoid (TT)-immunized individuals were activated with TT plus IL-2, and cell proliferation, cytokine production, and in vitro HIV-1 replication were measured. The in vivo magnitude of the humoral immune response was also assessed by antibody measurements. Our results showed that, compared with other groups, both in vitro TT-specific lymphoproliferation and serum antibody concentration were lower in older AIDS patients. Although the IL-1beta and tumour necrosis factor alpha (TNF-alpha) production were higher in cultures from aged HIV-1-infected patients, a dramatic damage on the interferon gamma (IFN-gamma) release was observed, when compared with younger patients. CD8(+) T lymphocytes depletion reduced IL-1beta and TNF-alpha release in the older groups, however, it did not significantly alter their IFN-gamma production. Furthermore, the neutralization of endogenous IL-10 did not change the IFN-gamma deficiency in older AIDS patients. Finally, the lower cellular immune response in this patient group was not related to in vitro HIV-1 replication. The results suggest that successfully highly active antiretroviral therapy-treated aged AIDS patients do not reconstitute the immune response to TT, making them probably more susceptible to tetanus even after vaccination.