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Title: Neural, endocrine and immune interactions at the level of circulating leucocytes in multiple sclerosis
Author: Zoukos, Ioannis Antonios
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1994
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Interactions between the neural, endocrine and immune systems at the level of peripheral blood mononuclear cells (PBMCs) have been investigated in multiple sclerosis (MS). An increased density of β-adrenoceptors was demonstrated on PBMCs in patients with progressive or relapsing-remitting disease. The same observation was made in patients with chronic rheumatoid arthritis (RA), but not in myasthenia gravis (MG). The affinity of the receptors was within the normal range and there was a positive correlation between density and function as determined by intracellular cAMP production after stimulation. In vitro. functional increased expression of β-adrenoceptors was observed when PBMCs from normal controls were cultured in the presence of the soluble mediators interleukin-1 (IL-1) and hydrocortisone, whereas the already up-regulated receptors on PBMCs from MS patients remained unchanged. Further support for the role of those mediators in β-adrenoceptor expression was given by the observation that plasma cortisol levels were high in patients during relapse. The link between high density of β-adrenoceptors and inflammation was further elucidated in a serial monthly assessment of relapsing-remitting MS patients, where it was demonstrated that the increase in β-adrenoceptors on PBMCs was correlated with expression of high affinity IL-2 receptors (IL-2Rs) and disease activity as determined by clinical and magnetic resonance imaging (MRI). Furthermore, plasma levels of cytokines such as tumour necrosis factor alpha (TNFα) and interleukin-1 beta (IL1β), appeared to be increased during the active phase of the disease. The hypothesis that β-adrenoceptor increased expression may be due to autonomic dysfunction was tested in a comparative study of MS patients, normal subjects and two models of autonomic dysfunction, pure autonomic failure (PAF) and multiple system atrophy (MSA). Only in PAF did β-adrenoceptor up-regulation correlate with low plasma levels of noradrenaline (NA) and adrenaline (Ad). Central autonomic function and neurohormonal responses to the centrally acting sympatholytic agent, clonidine, were studied. Although the haemodynamic and neurohormonal responses to clonidine, suggest a central autonomic dysfunction in progressive MS patients, the disparity between MS and PAF patients, when considering their plasma levels of NA and Ad, indicate that high density of β-adrenoceptors on PBMCs in S is more likely to be due to the inflammatory process than autonomic dysfunction. A link between β-adrenoceptor increased expression on PBMCs and recovery has been suggested by in vitro studies in which β-agonist stimulation was found to reduce the IL-2R density and suppress cell proliferation following mitogenic stimulation. The therapeutic importance of adrenoceptor up-regulation in MS remains to be tested by appropriate trials using either β-agonists or agents activating the second messenger system, adenylate cyclase, in lymphocytes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available