Aberrant T cell-mediated immunity in untreated schizophrenic patients: deficient interleukin-2 production.
ABSTRACT The authors examined the immune status at the cellular and humoral levels of 16 untreated schizophrenic patients. No abnormality in the distribution of T cell subsets (CD4+, CD8+) was detected. The proliferative response to the T cell mitogen phytohemagglutinin was normal. No increase in the number of T cells showing activation markers, such as human leukocyte antigens and interleukin-2 receptors, was noted. Conversely, function studies revealed a clear deficiency in interleukin-2 production by purified T cells. This lower production was probably intrinsic to the patients' T cells, since interleukin-2 production showed normal sensitivity to prostaglandin E2-mediated down-regulation by autologous monocytes.
Article: Psychoneuroimmunology[Show abstract] [Hide abstract]
ABSTRACT: Recent research has shown that alterations of the immune system are associated with several psychiatric disorders. Patients with schizophrenia or major depression show a number of changes including those of cellular immunity, cytokine production, and levels of cytokines, soluble cytokine receptors and acute-phase proteins that indicate an immune activation. Findings from studies of cerebrospinal fluid (CSF) also point to an activation of the immune system, at least in a subgroup of patients with schizophrenia. The relationship between clinical characteristics and immune parameters in schizophrenia suggests that immune activation plays a role in the pathogenesis of the disorder in at least one-third of schizophrenic patients. Cytokines interact with some catecholamines, and a hypersecretion of certain cytokines, such as interleukin (IL)-2 and IL-6, is hypothesised to contribute to schizophrenia and depression, possibly via an influence on the catecholaminergic system. Immune mediators can activate astrocytes and microglia, and probably also neurons, to secrete cytokines. The strong connection between cytokines and catecholamines is underlined by the finding that noradrenaline (norepinephrine) stimulates the release of IL-1 and IL-6 from astrocytes. Via these mechanisms, an immune process in the CNS seems to maintain itself by a feedback process. An increased permeability of the blood-brain barrier can reinforce the immune-activating process in the CNS. Furthermore, pharmacoimmunological investigations of antipsychotics and antidepressants point to an inhibiting influence of these agents on several cytokines. Further research is required to fully elucidate the immune process and the role of cytokines in the CNS. This may allow the development of drugs that will selectively influence certain cytokines. The development of immuno-inhibiting drugs or drugs that prevent the activation of cytokines may have implications for the drug treatment of psychiatric disorders.CNS Drugs 08/1995; 4(2). · 4.38 Impact Factor
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ABSTRACT: Accumulating evidence supports the view that deregulation of the immune system represents an important vulnerability factor for psychosis. In a subgroup of psychotic patients, the high comorbidity with autoimmune and chronic inflammatory conditions suggests a common underlying immune abnormality leading to both conditions. The reviewed data of affective and nonaffective psychosis show that if immune biomarkers exist for such immune abnormality, they may be found in raised macrophage/monocyte inflammatory activation patterns (monocytosis, high-inflammatory gene expression, raised glucocorticoid receptor β/glucocorticoid receptor α ratio, and high levels of proinflammatory and anti-inflammatory monocyte/macrophage derived cytokines in serum/plasma), reduced T cell numbers/proliferation, and TH1 skewing. This activation of the inflammatory response system may be suggestive for microglia activation, as these cells are the macrophages of the brain. Indeed, there is some evidence of activation of the microglia as detected in positron emission tomography scans and in histopathology, and it is assumed that this activation disturbs the development and function of neuronal circuits in the brain. Further, animal models of psychotic conditions (maternal stress and inflammation paradigms) suggest that such monocyte/microglia activation could be seen as the result of a combination of genetic predisposition and an immune-mediated two-hit model. Infection but also environmental stressors during gestation/early life activate microglia, perturbing neuronal development, thereby setting the stage for vulnerability for later psychotic disorders. A second hit, such as endocrine changes, stress, or infection, could further activate microglia, leading to functional abnormalities of the neuronal circuitry in the brain and psychosis.Biological psychiatry 10/2013; · 8.93 Impact Factor
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ABSTRACT: With the advent of DSM 5 criticism has generally centered on a lack of biological validity of the diagnostic criteria. Part of the problem in describing a nosology of psychosis is the tacit assumption of multiple genetic causes each with an incremental loading on the clinical picture that fails to differentiate a clear underlying pathophysiology of high impact. The aim of this paper is to consolidate a primary theory of deficient muscarinic signaling underlying key clinical features of schizophrenia and its regulation by several important genetic associations including neuregulin, DISC and dysbindin. Secondary reductions in markers for GABAergic function and changes in the levels of interneuron calcium binding proteins parvalbumin and calbindin can be attributed to dysfunctional muscarinic transduction. A parallel association exists for cytokine production. The convergent pathway hypothesis is likewise used to model dopaminergic and glutamatergic theories of schizophrenia. The negative symptom dimension is correlated with dysfunction of Akt and ERK transduction, a major point of convergence. The present paradigm predicts the importance of a recent finding of a deletion in a copy number variant of PLCB1 and its potential use if replicated, as one of the first testable biological markers differentiating schizophrenia from bipolar disorder and further subtyping of schizophrenia into deficit and non-deficit. Potential limitations of PLCB1 as a prospective marker are also discussed.Frontiers in Pharmacology 01/2014; 5:277.