Decreased production of interleukin-2 (IL-2), IL-2 secreting cells and CD4+ cells in medication-free patients with schizophrenia

There are a number of indications that schizophrenia is associated with changes in the immune system. Although functional studies have mostly demonstrated decreased in vitro production of IL-2 by peripheral blood mononuclear cells (PBMCs) stimulated with mitogen, the reason is unclear. The aim of the study was to explore the relationship between IL-2 production and CD4+ cells which mainly secret IL-2 in non-Caucasian patients with schizophrenia. Blood CD4+ cells and mitogen-stimulated IL-2 secreting cells identified by an immunohistochemical study with the alkaline phosphatase/anti-alkaline phosphatase (APAAP) technique, and in vitro IL-2 production with radioimmunometric assay (RIA) were measured in 30 schizophrenic patients and 30 normal control subjects matched for sex, age and race. The results showed that blood CD4+ cells and mitogen-induced IL-2 secreting cells and IL-2 production were significantly lower in schizophrenic subjects than in the normal controls. There was significantly positive correlation between CD4+ cells and IL-2 production in normal controls but not in patients. These findings suggest that immune disturbance may be present in schizophrenic patients. The lower in vitro IL-2 production is probably related to the decreased number of T-cells that secret IL-2, as well as to the intrinsic disorder of the patients' T cells.     

Interleukin-1 beta production in dysthymia before and after pharmacotherapy.

BACKGROUND: Like major depression, dysthymia has been associated with elevated production of interleukin-1 (IL-1 beta) in mitogen-stimulated lymphocytes. In the present investigation, we assessed whether the elevated IL-1 beta production in dysthymic patients would normalize following treatment with sertraline. METHODS: The production of IL-1 beta was determined in dysthymic patients and in nondepressed control subjects. Patients then received 12 weeks of doses of either sertraline or placebo in a double-blind trial, after which cytokine production was again determined. RESULTS: Basal IL-1 beta was elevated in dysthymic patients relative to control subjects. Cytokine production was modestly correlated with the severity of symptoms and with the age of illness onset. Relative to placebo treatment, sertraline attenuated the symptoms of depression; however, this was not accompanied by normalization of IL-1 beta production. CONCLUSIONS: While dysthymia is associated with elevated IL-1 beta production, the failure for the cytokine to normalize following symptom alleviation suggests that either the IL-1 beta may be a trait marker of the illness, or that more sustained treatment is necessary to reduce cytokine production. Given the neuroendocrine and central neurochemical consequences of exogenously administered IL-1 beta, the possibility ought to be explored that increased IL-1 beta production may play a role in the pathophysiology of dysthymia.     

Innate production of interleukin-10 and tumor necrosis factor affects the risk of multiple sclerosis

Multiple sclerosis (MS) typically presents with a relapsing-remitting onset. This can be distinguished from primary progressive MS. Typical MS is characterized by a profound inflammatory reaction in which anti-inflammatory cytokine interleukin-10 (IL-10) and pro-inflammatory cytokine tumor necrosis factor (TNF) may play a pivotal role. We tested the hypothesis that patients with MS have a distinct innate cytokine production that contributes to the susceptibility for and outcome of MS. The innate cytokine production of patients was estimated as the average production of cytokines in lipopolysaccharide -stimulated whole-blood cultures of 2 to 5 first-degree healthy family members. A total of 126 family members of 50 patients with typical MS, 61 family members of 25 patients with primary progressive MS, and 129 control subjects of 54 families were enrolled in this study. We found that members of families with low IL-10 and high TNF production had a fourfold increased risk of developing typical MS compared with members of families with high IL-10 and low TNF production. Patients with MS were eightfold more likely to develop typical MS than primary progressive MS when they belonged to families with low IL-10 and high TNF production. The presence of human leukocyte antigen-DR2 was associated with MS but not with TNF production. This study shows that typical MS is associated with an innate pro-inflammatory cytokine profile in contrast to primary progressive MS.     

Decreased in vitro production of interferon-gamma and interleukin-2 in whole blood of patients with schizophrenia during treatment

A pattern of aberrations in the T-cell cytokine system that is typical for autoimmune disorders has also been reported in patients with schizophrenia, namely a decreased interleukin-2 (IL-2) production and increased levels of the soluble IL-2 receptor (sIL-2R). It has also been reported that the production of interferon-gamma (IFN-gamma) may be lowered. In a longitudinal design, we studied the production of both IFN-gamma and IL-2 and their correlation in patients with schizophrenia during treatment and investigated whether associations exist between cytokine production and clinical variables. The production of IFN-gamma and IL-2 was measured in equal numbers (n = 29) of patients with schizophrenia (DSM-IV) and controls who were matched for age and gender. Patients were measured 1 day after admission (T1), after 14 (T2) and 28 (T2) days of treatment. Psychopathology was assessed after these times. The production of both IFN-gamma and IL-2 was significantly lower in patients than in controls throughout the whole investigation period (T1-T3). The productions of both cytokines were significantly correlated in controls (r = 0.60, P 相似文献   

An imbalance in the production of IL-1beta and IL-6 by monocytes of bipolar patients: restoration by lithium treatment

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.     

Salivary production in Parkinson's disease.

Hypersialorrhea is a common phenomenon in Parkinson disease (PD). The objective of this study was to determine whether patients with PD had an abnormally increased production of saliva and whether the production of saliva could be associated to factors related to either the disease characteristics or to its treatment. A total of 83 patients with PD and 55 control subjects participated in this study. Because of the age difference between the two groups, comparisons were made on a +/-2-year age-matched sample of 44 PD patients and 44 control subjects. PD patients produced significantly less saliva than control subjects. Correlations were obtained with the 83 PD patients between unstimulated salivary flow and patients characteristics. When controlling for age, sex, and Hoehn and Yahr scale, decreased production of saliva correlated significantly with the dose of levodopa and the symptoms of xerostomia. When controlling for medications, there was no relationship between the production of saliva and the evolution of the disease. This study shows that patients with PD produce less saliva than normal. Factors influencing the production of saliva include the use of levodopa and female gender. Our results may have implications for the treatment of drooling in PD.     

The prevalence of autoantibodies among right and left handed schizophrenic patients and control subjects.

Sera from schizophrenic patients (n = 186) and healthy control subjects (n = 346) were tested for the presence of seven common autoantibodies by standard immunological methods. The association between handedness and autoantibodies was tested in a multi-way contingency table using a log-linear model. For men, but not women, nondextrals (patients and controls) were twice as likely to test positive for autoantibodies than dextrals (p = 0.0002). Although more women (33%) than men (24%) tested positive for autoantibodies, handedness was not a distinguishing factor among women. These data suggest that sinistrality and gender are associated with autoantibodies in a subgroup of schizophrenic patients and healthy control subjects.     

Interleukin-1 and interleukin-2 production by peripheral blood mononuclear cells in multiple sclerosis patients

The production of interleukin-1 (IL-1) and interleukin-2 (IL-2) by peripheral blood mononuclear cells (PBM) was assessed in multiple sclerosis (MS) patients in relapse, chronic progressive MS patients, patients with other neurological diseases (OND) and healthy subjects. Production was defined as the level of IL-1 and IL-2 in PBM supernatants. Neither spontaneous nor LPS-induced IL-1 production differed significantly in MS, OND patients or healthy individuals. On the other hand PHA-induced PBM IL-2 production was significantly less in MS patients in relapse (130 +/- 10.0 U/ml) than in chronic progressive MS patients (172 +/- 9.8 U/ml), OND patients (192 +/- 11.5 U/ml) and healthy subjects (215 +/- 13.8 U/ml) (P less than 0.02). Spontaneous IL-2 production was also diminished in MS patients in relapse (31 +/- 7.2 U/ml) as compared to chronic progressive MS patients (46 +/- 8.8 U/ml) and healthy subjects (49 +/- 11.1 U/ml) (P less than 0.01). Anti-Tac monoclonal antibody was used to study IL-2 receptor expression on the same sample of PBM that was used for IL-2 study. MS patients in relapse had significantly higher levels of IL-2 receptor-positive unstimulated PBM (6.0 +/- 2.2%) as compared to chronic progressive MS (2.0 +/- 0.9%), OND (2.5 +/- 1.1%) and healthy subjects (1.5 +/- 0.7%) (P less than 0.002). We postulate that reduced apparent IL-2 production by PBM of MS patients in relapse may result from immediate IL-2 binding to receptor expressed on activated T lymphocytes and internalization of IL-2-receptor complex.     

Impaired cytokine production by peripheral blood mononuclear cells and monocytes/macrophages in Parkinson's disease

OBJECTIVE: Although the pathogenesis of Parkinson's disease (PD) is still unknown, several reports suggest the presence of immunological abnormalities in the patients with PD such as impaired T cell responses or cytokine production by the peripheral immune system. MATERIAL AND METHOD: In this study, we examined cytokine production by peripheral blood mononuclear cells (PBMC) and monocyte/macrophages (PBM) in the patients with idiopathic PD, using age-related healthy donors as a normal control and cerebrovascular diseases (CVD) as a disease control. RESULTS: Production of TNF-alpha, IL-1alpha, IL-1beta and IL-6 by PBMC and TNF-alpha by PBM were significantly lower in the patients with PD as compared to the control groups. IFN-gamma production by LPS-stimulated PBMC in the patients with PD was also significantly lower than that in control groups. Cytokine production by PBMC from the patients with CVD who had a similar disability as the patient group was not significantly different from those in normal controls. Thus, impaired production of inflammatory cytokines may not be due to the mental and physical stress caused by their disability. CONCLUSION: In the patients with PD, a significant negative correlation was noted in 1alpha-1beta, IL-1beta and IL-6 levels produced by LPS-stimulated PBMC and Hoehn Yahr disability score of the patients, suggesting that the impaired cytokine production may progress with disease progression. These abnormalities in cytokine production may not be primary but may affect the prognosis of PD.     

Anticardiolipin and antinuclear antibodies in epilepsy--a population-based cross-sectional study

Increased prevalence of autoantibodies has been suggested in patients with epilepsy. This study determined the presence of autoantibodies in a representative cohort of 960 patients with epilepsy. The frequency of antinuclear antibodies (ANA), immunoglobulin G class anticardiolipin antibodies (aCL) and anti-B2-glycoprotein I antibodies were studied in 960 consenting adult patients with epilepsy and in 580 population-based reference subjects identified from the Finnish Population Registry. Overall the frequencies of the autoantibodies studied did not differ between patients with epilepsy and reference subjects. aCL were present in 4.5% of the patients and in 5.0% of the reference subjects and 17% of both the patients and the reference subjects had antinuclear antibodies. However, patients with partial epilepsy for > or =30 years were three times more likely to have aCL than patients with partial epilepsy for <10 years. Patients with partial epilepsy and > or=1 seizure per month were 2.2 times more likely to have aCL than patients with partial epilepsy with <1 seizure per month. Moreover, ANA tended to be more frequent among patients with > or =1 seizure per month. No association was found between the major antiepileptic drugs and autoantibodies. Overall the frequencies of the autoantobodies studied were similar in the large epilepsy cohort and in matched reference subjects from the general population. However, a long duration of epilepsy and poor seizure control were associated with an increased presence of aCL in patients with partial epilepsy.     

Serum autoantibodies in patients with Alzheimer's disease and vascular dementia and in nondemented control subjects.

BACKGROUND AND PURPOSE: In this study we sought to evaluate the clinical significance of serum autoantibodies to dementing processes. METHODS: We assessed 40 age-matched subjects: 10 patients with probable Alzheimer's disease, 10 with possible Alzheimer's disease with cerebrovascular disease, 10 with vascular dementia, and 10 nondemented control subjects. Serum from each subject was tested for the presence of antithyroglobulin antibody, thyroid antimicrosomal antibody, gastric anti-parietal cell antibody, anti-smooth muscle antibody, antinuclear antibody, rheumatoid factor, antineuronal antibody, and anticardiolipin antibody. In addition, we investigated the sera of these patients for the presence of an antivascular antibody directed against the vascular basement membrane proteoglycan antigen and for circulating immune complexes. RESULTS: Autoantibodies were present in 100% of the patients with possible Alzheimer's disease with cerebrovascular disease, 80% of those with vascular dementia, 40% of those with probable Alzheimer's disease, and 30% of the nondemented control subjects. The highest number of autoantibodies was observed in patients with vascular dementia and possible Alzheimer's disease with cerebrovascular disease. Antinuclear antibody was present in 60% of vascular dementia patients and antineuronal antibody in 50% of these patients. However, no individual autoantibody could differentiate Alzheimer's disease from cerebrovascular disorders. Immune complexes were detected in the serum of 20-30% of each patient group. Neither the patient nor the control sera was found to contain antiendothelial antibody. CONCLUSIONS: Despite the relatively small number of individuals examined in each category, the elevated number of autoantibodies associated with possible Alzheimer's disease with cerebrovascular disease and vascular dementia indicates a possible link between the presence of autoantibodies and cerebrovascular disorders in dementia.     

IL-2 and IL-6 secretion in dementia: correlation with type and severity of disease

The production of interleukin-2 (IL-2) and interleukin-6 (IL-6) by peripheral blood mononuclear cells (MNC) was assessed in patients with Alzheimer's disease (AD) who were subdivided into two groups — mild and moderately-severe — according to the severity of the disease, probable vascular dementia (VaD) patients and elderly control subjects. No differences in IL-2 secretion were found between mild AD patients and controls. However, there was a significant increase in IL-2 production both in the moderately-severe AD group and in the VaD group. IL-6 levels in AD patients of both groups were similar and significantly higher than those of VaD and controls. Our results suggest that increased levels of IL-2-production correlate with severity of the dementia, whereas increased levels of IL-6 production seem to be related to AD and thus may play a role in AD pathogenesis.     

Hypocortisolism and increased glucocorticoid sensitivity of pro-Inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with dysregulation of the hypothalamus pituitary adrenal (HPA) axis. Alterations include various responses to HPA axis stimulation, different basal hormone levels, and changes in glucocorticoid receptor (GR) numbers on lymphocytes. The functional significance of these latter changes remains elusive. METHODS: Twelve Bosnian war refugees with PTSD and 13 control subjects were studied. On 2 consecutive days, they collected saliva samples after awakening and at 11, 15, and 20 hours. Glucocorticoid (GC) sensitivity was measured by dexamethasone (DEX) inhibition of lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) production in whole blood. RESULTS: The PTSD patients showed no cortisol response after awakening and had lower daytime cortisol levels (F = 14.57, p <.001). Less DEX was required for cytokine suppression in PTSD patients (IL-6: t = -2.82, p =.01; TNF-alpha: t = 5.03, p <.001), reflecting higher GC sensitivity of pro-inflammatory cytokine production. The LPS-stimulated production of IL-6, but not TNF-alpha, was markedly increased in patients (IL-6: F = 10.01, p <.004; TNF-alpha: F =.89, p =.34). CONCLUSIONS: In refugees with PTSD, hypocortisolism is associated with increased GC sensitivity of immunologic tissues. Whether this pattern reflects an adaptive mechanism and whether this is sufficient to protect from detrimental effects of low cortisol remains to be investigated.     

Cytokine production in panic disorder patients

Based on findings that stress and anxiety may modulate immune function, we compared the production of interleukin-2 (IL-2) and interleukin-3 (IL-3) by peripheral blood mononuclear cells between 24 patients with nonmajor depressed panic disorders, 9 with agoraphobia and 15 without, and 19 healthy volunteers. No differences in the production of these cytokines was noted between the patients with panic disorders and the volunteers or between the patients with and without agoraphobia. However, in the patients, a negative correlation was found for interleukin-3 production with severity of state anxiety, but not with trait anxiety or depression. This finding indicates that interleukin-3 levels may be sensitive to the presence of anxiety and stress.     

alpha-Adrenergic receptor function in schizophrenia. Receptor number, cyclic adenosine monophosphate production, adenylate cyclase activity, and effect of drugs

alpha-Adrenergic receptor function was assessed in platelets from drug-free schizophrenic patients and control subjects. The number of alpha-receptors was similar in platelet membranes from schizophrenic patients and control subjects. In intact platelets from schizophrenic male, but not female, patients, prostaglandin E1 (PGE1)-stimulated cyclic adenosine monophosphate (cAMP) level was less than in control subjects. This defect may be due, at least in part, to decreased adenylate cyclase activity. In platelet lysates from schizophrenic patients, but not from normal control subjects, adenylate cyclase activity was diminished and PGE1-stimulated adenylate cyclase activity could be restored partially by the addition of guanosine triphosphate. Treatment with neuroleptic drugs or lithium carbonate did not change alpha-receptor number or cAMP production in platelets from schizophrenic patients, but high doses of propranolol hydrochloride increased cAMP production without affecting the number of alpha-receptors. If the production of cAMP in neurons is similar to that in platelets, diminished cAMP production may be associated with a vulnerability to schizophrenia.     

Cytokine secretion and nitric oxide production by mononuclear cells of patients with multiple sclerosis

Several experimental findings suggest a potential role of excessive nitric oxide (NO) production by macrophages, microglia and astrocytes in the pathogenesis of demyelinating lesions in MS. We assessed the production of nitrites by peripheral blood mononuclear cells (PBMCs) of 15 MS patients (10 F and 5 M) with the R–R form (EDSS: 1–3.0) and in 15 age-matched control subjects. 9 out of the 15 MS patients showed active lesions in MRI at the time of examination. 7 patients were also monitored at the onset, during and following a clinical relapse. Secretion of cytokines by PBMCs was assessed at the basal time and after 24 h of incubation with lipopolysaccharide (LPS). The production of nitrites in the supernatants of PBMCs stimulated and not stimulated with lipopolysaccharide was evaluated. The secretion of IL1β, IFN-γ, TNF-, IL-6 IL-10 and TGF-β by PBMCs was detected using ELISA methods. The production of NO, both basal and stimulated, was significantly higher in the patients with active lesions than in those without active lesions (p<0.01). No significant difference was evident between the basal and LPS-stimulated production of NO between control subjects and MS patients without active lesions. During relapses there was a significant increase in NO production by PBMCs compared to the clinical stable stage of the disease (p<0.0001). This increase was significantly greater in the early stage of relapse than in the late stage (p<0.04). A decline of NO levels was observed during recovery. Steroid treatment induced a significant decrease in the PBMC NO production of MS patients during exacerbations (p<0.01). The levels of IL-1β, IFN-γ and TNF- are significantly higher in the supernatants of the PBMCs which produced greater amounts of NO (p<0.02, p<0.03, p<0.01, respectively). On the other hand, NO levels were negatively related to IL-10 and TGF-β production (R=−75, p<0.0001 and R=−0.79, p<0.0001, respectively). The increase production of NO by peripheral blood mononuclear cells demonstrated in our study to be associated with increased production of proinflammatory cytokines could therefore be considered to be a marker of mononuclear cell activation in the peripheral blood of MS patients and, indirectly, of disease activity. Its increased secretion during T cell and monocyte homing in the CNF could contribute to the damage to the blood–brain barrier and the subsequent cytokine-mediated cytotoxic effect to myelin and oligodendrocytes in the white matter of MS patients.     

Prosodic disturbance in aphasia: speech timing versus intonation production

Temporal control has often been suspected to be a critical factor in intonation production. In particular, disturbance in the production of fundamental frequency (F0) associated with intonation in patients with aphasia has been attributed to a primary underlying deficit in speech timing. The present study examined the speech timing abilities of two groups of patients with fluent and nonfluent aphasia who were found in a companion study to have relatively normal intonation production ability. Results indicated severe temporal control abnormalities for the patients with nonfluent aphasia. The fluent aphasic patients performed at comparable levels with the normal subjects, although in absolute terms their durations were also generally longer than normal. These findings do not support the view that intonation production depends critically on speech timing, and that its disturbance in aphasia is due to underlying temporal control deficit.     

Soluble interleukin-2 receptors in cerebrospinal fluid from individuals with various neurological disorders

Soluble interleukin-2 (IL-2R) levels in the cerebrospinal fluid (CSF) were studied in infectious, inflammatory, degenerative, and neoplastic disorders to evaluate their usefulness as a marker for the presence of activated T cells, thus indicating an inflammatory process. CSF from control subjects and patients with stationary, progressive, and treated multiple sclerosis (MS); aseptic meningitis; lymphoid and nonlymphoid central nervous system (CNS) tumors; Alzheimer's disease, as well as serum from MS patients and control subjects were studied for levels of soluble IL-2R. A significant increase in CSF IL-2R levels was observed in patients with MS, meningitis, and lymphoid CNS tumors; the MS group showed the highest values. CSF from individuals with Alzheimer's disease and from patients with nonlymphoid tumors did not show significantly elevated values. Serum IL-2R levels were significantly higher in MS patients than in control subjects, but there was no significant correlation between individual serum and CSF IL-2R levels. This study suggests the presence of activated T-lymphocytes in the CNS of patients with MS.     

Prosodic disturbance in aphasia: speech timing versus intonation production

Temporal control has often been suspected to be a critical factor in intonation production. In particular, disturbance in the production of fundamental frequency (F0) associated with intonation in patients with aphasia has been attributed to a primary underlying deficit in speech timing. The present study examined the speech timing abilities of two groups of patients with fluent and nonfluent aphasia who were found in a companion study to have relatively normal intonation production ability. Results indicated severe temporal control abnormalities for the patients with nonfluent aphasia. The fluent aphasic patients performed at comparable levels with the normal subjects, although in absolute terms their durations were also generally longer than normal. These findings do not support the view that intonation production depends critically on speech timing, and that its disturbance in aphasia is due to underlying temporal control deficit.     

Are peripheral blood cells from patients with Alzheimer disease more sensitive to apoptotic stimuli?

One of the reasons for the increased susceptibility to infections in patients with Alzheimer disease may be enhanced apoptotic death of their peripheral leukocytes. If this is the case, the enhanced apoptosis may be due to components in the patients' sera or to an increased sensitivity of the cells to apoptotic stimuli. To examine this possibility, the percentage of apoptotic cells in the peripheral blood mononuclear cells (PBMC) from 12 patients with Alzheimer disease was compared with that of 12 age-matched non-demented persons and 12 middle-aged healthy control subjects. In addition, the effect of sera from subjects in the three groups on the apoptosis, interleukin (IL)-1beta, IL-2, IL-6, IL-10, and tumor necrosis factor (TNF)alpha production by peripheral blood cells from healthy control subjects was examined. It was found that the percentage of apoptotic PBMC from patients with Alzheimer disease was higher than that from the remaining two groups. However, incubation of control cells with sera from patients with Alzheimer disease and non-demented elderly persons did not affect the number of apoptotic cells. Sera from patients with Alzheimer disease and non-demented elderly subjects caused an increase in IL-2 and a decrease in IL-10 production by PBMC from middle-aged control subjects but did not affect IL-1beta, IL-6, and TNFalpha secretion, indicating alterations of the immune system related to aging.