RESUMEN
BACKGROUND: In a previous study, we found an up-regulated inflammatory monocyte gene expression profile in major depressive disorder (MDD) patients aged ⩾ 28 years and a down-regulated inflammatory gene expression profile in MDD patients aged<28 years. In the same sample of patients, we aimed to investigate immune dysregulation in the lymphocyte arm of the immune system, particularly in the context of the described monocyte (de-)activation states. METHODS: From deep frozen leukocytes, circulating percentages of monocytes, lymphocytes, B, T, and natural killer (NK) cells, and various functional subsets of T and T helper (Th) cells (Th1, Th2, Th17, and natural T regulatory cells) were measured in N=50 MDD patients and N=58 age- and gender-matched healthy controls (HC). In addition, serum levels of interleukin (IL)-6, sCD25, IL-7, IL-3, SCF, IGF-BP2, and EGF were evaluated. RESULTS: MDD patients were in general characterized by an impaired maturation of Th2 cells, Th17 cells, and NK cells and by decreased serum levels of IL-7 and sCD25. MDD patients aged ⩾ 28 years additionally exhibited decreased percentages of CD4(+)CD25(high)FoxP3(+) T regulatory cells, next to signs of the above described partial T cell defects. Natural T regulatory cells were inversely associated with the pro-inflammatory state of the monocytes (r=-.311; p=.034) that characterized this patient subgroup. CONCLUSIONS: Deficiencies of the NK and T (regulatory) cell system and inflammatory monocyte immune activation co-occur as partly interrelated phenomena within the same MDD patients.
Asunto(s)
Trastorno Depresivo Mayor/inmunología , Células Asesinas Naturales/inmunología , Monocitos/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Células Th2/inmunología , Adulto , Estudios de Casos y Controles , Citocinas/metabolismo , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/patología , Femenino , Humanos , Células Asesinas Naturales/patología , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Monocitos/patología , Linfocitos T Reguladores/patología , Células Th17/patología , Células Th2/patologíaRESUMEN
BACKGROUND: Dendritic cells (DC) are key regulators of the immune system, which is compromised in patients with bipolar disorder. We sought to study monocyte-derived DC in bipolar disorder. METHODS: Monocytes purified from blood collected from DSM-IV bipolar disorder outpatients (n = 53, 12 without lithium treatment) and healthy individuals (n = 34) were differentiated into DC via standard granulocyte-macrophpage colony-stimulating factor/interleukin-4 culture (with/without 1, 5, and 10 mmol/L lithium chloride). The DC were analyzed for DC-specific and functional markers and for T-cell stimulatory potency. RESULTS: Monocytes of bipolar patients showed a mild hampering in their differentiation into fully active DC, showing a weak residual expression of the monocyte marker CD14 and a relatively low potency to stimulate autologous T cells. Lithium treatment abolished this mild defect, and monocyte-derived DC of treated bipolar patients showed signs of activation (i.e., an up-regulated potency to stimulate autologous T cells and a higher expression of the DC-specific marker CD1a). This activated phenotype contrasted with the suppressed phenotype of monocyte-derived DC exposed to lithium in vitro (10 mmol/L) during culture. CONCLUSIONS: Dendritic cells show mild aberrancies in bipolar disorder that are fully restored to even activation after in vivo lithium treatment.
Asunto(s)
Trastorno Bipolar/patología , Células Dendríticas/patología , Monocitos/patología , Adulto , Antígenos CD/biosíntesis , Antígenos CD1/biosíntesis , Antimaníacos/uso terapéutico , Autoanticuerpos/análisis , Autoanticuerpos/inmunología , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/inmunología , Diferenciación Celular/fisiología , Linaje de la Célula/fisiología , Técnicas de Cocultivo , Células Dendríticas/inmunología , Femenino , Citometría de Flujo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Humanos , Inmunoglobulinas/biosíntesis , Interleucina-4/fisiología , Cloruro de Litio/uso terapéutico , Masculino , Glicoproteínas de Membrana/biosíntesis , Persona de Mediana Edad , Monocitos/inmunología , Linfocitos T/inmunología , Linfocitos T/fisiología , Antígeno CD83RESUMEN
Veiled cells (VC) present in afferent lymph transport antigen from the periphery to the draining lymph nodes. Although VC in lymph form a heterogeneous population, some of the cells clearly belong on morphological grounds to the Langerhans cell (LC)/ dendritic cell (DC) series. Here we show that culturing monocytes for 24 hrs while avoiding plastic adherence (polypropylene tubes) and avoiding the activation of NADPH oxidase (blocking agents) results in the generation of a population of veiled accessory cells. The generated VC were actively moving cells like lymph-borne VC in vivo. The monocyte (mo)-derived VC population existed of CD14(dim/-) and CD14(brighT) cells. Of these the CD14(dim/-) VC were as good in stimulating allogeneic T cell proliferation as immature DC (iDC) obtained after one week of adherent culture of monocytes in granulocyte-macrophage-colony stimulating factor (GM-CSF)/interleukin (IL)-4. This underscores the accessory cell function of the mo-derived CD14(dim/-) VC. Although the CD14(dim/-)VC had a modest expression of the DC-specific marker CD83 and were positive for S100, expression of the DC-specific markers CD1a, Langerin, DC-SIGN, and DC-LAMP were absent. This indicates that the here generated CD14(dim/-) VC can not be considered as classical LC/DC. It was also impossible to turn the CD14(dim/-) mo-derived VC population into typical DC by culture for one week in GM-CSF/IL-4 or LPS. In fact the cells died tinder such circumstances, gaining some macrophage characteristics before dying. The IL-12 production from mo-derived CD14(dim/-) VC was lower, whereas the production of IL-10 was higher as compared to iDC. Consequently the T cells that were stimulated by these mo-derived VC produced less IFN-gamma as compared with T cells stimulated by iDC. Our data indicate that it is possible to rapidly generate a population of CD14(dim/-) veiled accessory cells from monocytes. The marker pattern and cytokine production of these VC indicate that this population is not a classical DC population. The cells might earlier be related to the veiled macrophage-like cells also earlier described in afferent lymph.
Asunto(s)
Células Presentadoras de Antígenos/fisiología , Movimiento Celular/fisiología , Células Dendríticas/fisiología , NADPH Oxidasas/metabolismo , Células Presentadoras de Antígenos/citología , Células Presentadoras de Antígenos/inmunología , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Dendríticas/citología , Células Dendríticas/inmunología , Activación Enzimática/fisiología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Humanos , Interleucina-4/farmacología , Monocitos/citología , Monocitos/inmunología , Monocitos/fisiologíaRESUMEN
OBJECTIVES: To study the ex vivo interleukin (IL)-1beta and IL-6 production of monocytes in bipolar disorder (BD) patients in the absence/presence of lithium. METHODS: Monocytes of outpatients with DSM-IV BD (n=80, of whom 64 were lithium-treated) and of healthy control subjects (n=59) were cultured in vitro and exposed (24 h) or not exposed to lipopolysaccharide (LPS) and/or graded concentrations of lithium chloride (LiCl). IL-1beta and IL-6 production was assessed by enzyme-linked immunosorbent assay (ELISA) (supernatants). RESULTS: Monocytes stimulated by LPS from non-lithium-treated bipolar patients were characterized by an abnormal IL-1beta/IL-6 production ratio, i.e., low IL-1beta and high IL-6 production. Lithium treatment increased IL-1beta and decreased IL-6 production and thus restored the aberrant ratio. In vitro exposure of monocytes to LiCl did not have the same effects as lithium treatment: the procedure decreased IL-1beta production and had minimal effects on IL-6 production. CONCLUSIONS: Blood monocytes have an altered proinflammatory status in BD. Lithium treatment restores this altered status. Short-term in vitro exposure of monocytes to lithium has other effects than lithium treatment.
Asunto(s)
Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/metabolismo , Interleucina-1beta/biosíntesis , Interleucina-6/biosíntesis , Compuestos de Litio/uso terapéutico , Adulto , Atención Ambulatoria , Trastorno Bipolar/sangre , Células Cultivadas , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Técnicas In Vitro , Lipopolisacáridos/farmacología , Cloruro de Litio/farmacología , Masculino , Persona de Mediana Edad , Monocitos/efectos de los fármacos , Monocitos/inmunología , Monocitos/metabolismo , Escalas de Valoración Psiquiátrica , Psicotrópicos/uso terapéuticoRESUMEN
OBJECTIVE: A relative resistance of immune cells to steroids has been established in patients with major depression (MD). In this study, we investigated the in vitro responsiveness of T cells to dexamethasone (DEX) of patients with bipolar disorder (BD). METHODS: T cells of outpatients with DSM-IV BD (n = 54) and of healthy control subjects (HC; n = 29) were isolated, cultured and stimulated with phytohemagglutinin (PHA) for 72 h. The suppressive effect of graded concentrations of DEX (5 x 10(-9)-10(-5) M) on PHA-induced CD25 (IL-2R) expression was measured by fluorescence-activated cell sorting (FACS) analysis. Data were correlated to the T-cell activation status in the peripheral blood of the same patients and to their diagnosis, current mood state, ultradian cycling pattern and current use of medication, including lithium. RESULTS: T cells of patients with BD were less sensitive to DEX-induced suppressive effects as compared with T cells of HC. These data were particularly evident at 10(-7) M DEX (mean % suppression +/- SEM BD: 18.9% +/- 3.5 versus HC: 35.8% +/- 4.7, p = 0.001). We found no correlations of this relative in vitro DEX resistance of T cells neither with the previously mentioned clinical characteristics nor with the actual activation status of the T cells in the BD patients. CONCLUSION: A relative T-cell resistance to steroids, as has been observed in MD previously, may be a trait phenomenon of BD, independent of mood state.