Mathematical modeling of the circadian rhythm of key neuroendocrine-immune system players in rheumatoid arthritis: a systems biology approach.

Full Abstract

OBJECTIVE: Healthy subjects and patients with rheumatoid arthritis (RA) exhibit circadian rhythms of the neuroendocrine-immune system. Understanding circadian dynamics is complex due to the nonlinear behavior of the neuroendocrine-immune network. This study was undertaken to seek and test a mathematical model for studying this network. METHODS: We established a quantitative computational model to simulate nonlinear interactions between key factors in the neuroendocrine-immune system, such as plasma tumor necrosis factor (TNF), plasma cortisol (and adrenal cholesterol store), and plasma noradrenaline (NA) (and presynaptic NA store). RESULTS: The model was nicely fitted with measured reference data on healthy subjects and RA patients. Although the individual circadian pacemakers of cortisol, NA, and TNF were installed without a phase shift, the relative phase shift between these factors evolved as a consequence of the modeled network interactions. Combined long-term and short-term TNF increase (the "RA model") increased cortisol plasma levels for only a few days, and cholesterol stores started to become markedly depleted. This nicely demonstrated the phenomenon of inadequate cortisol secretion relative to plasma TNF levels, as a consequence of adrenal deficiency. Using the RA model, treatment with glucocorticoids between midnight and 2:00 AM was found to have the strongest inhibitory effect on TNF secretion, which supports recent studies on RA therapy. Long-term reduction of TNF levels by simulation of anti-TNF therapy normalized cholesterol stores under "RA" conditions. CONCLUSION: These first in silico studies of the neuroendocrine-immune system in rheumatology demonstrate that computational biology in medicine, making use of large collections of experimental data, supports understanding of the pathophysiology of complex nonlinear systems.

Author information

Author/s: Meyer-Hermann, Michael (M); Figge, Marc Thilo (MT); Straub, Rainer H (RH);

Affiliation: Systems Immunology, Frankfurt Institute for Advanced Studies, Ruth-Moufang-Strasse 1, Frankfurt/Main, Germany. m.meyer-hermann(-atsign-)fias.uni-frankfurt.de

Journal and publication information

Publication Type: Journal Article

Journal: Arthritis and rheumatism (Arthritis Rheum), published in United States. (Language: eng)

Reference: 2009-Sep; vol 60 (issue 9) : pp 2585-94

Dates: Created 2009/09/21; Completed 2009/10/19;

PMID: 19714618, status: MEDLINE (last retrieval date: 10/19/2009, IMS Date: )

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Arthritis, Rheumatoid - blood; drug therapy; physiopathology
Cholesterol - blood
Circadian Rhythm - physiology
Glucocorticoids - therapeutic use
Humans
Hydrocortisone - blood

Associated Chemicals: Glucocorticoids (0) ; Tumor Necrosis Factor-alpha (0) ; Hydrocortisone (50-23-7) ; Norepinephrine (51-41-2) ; Cholesterol (57-88-5)

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