Succumbing to the laws of attraction

Fritsch, Paul; Craddock, Travis J. A.; Rosario, Ryan M. del; Rice, Mark; Smylie, AnneLiese; Folcik, Virginia A; Vries, Gerda de; Fletcher, Mary A; Klimas, Nancy G.; Broderick, Gordon

doi:10.4161/sysb.28948

Cited by 16 publications

(20 citation statements)

References 94 publications

(99 reference statements)

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“…We found that even this coarse-grained model could support multiple steady states, 2 of which were proximal to immune marker profiles exhibited by patients with ME/CFS. 26,27 Although useful in showing the potential involvement of endocrineeimmune coregulatory control in supporting the persistence of this condition, these initial models remained coarse in resolution.…”

Section: Introductionmentioning

confidence: 99%

Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome

Morris

Cooney

Sedghamiz

et al. 2019

Clinical Therapeutics

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Purpose: The complex and varied presentation of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has made it difficult to diagnose, study, and treat. Its symptoms and likely etiology involve multiple components of endocrine and immune regulation, including the hypothalamic-pituitaryadrenal axis, the hypothalamic-pituitary-gonadal axis, and their interactive oversight of immune function. We propose that the persistence of ME/CFS may involve changes in the regulatory interactions across these physiological axes. We also propose that the robustness of this new pathogenic equilibrium may at least in part explain the limited success of conventional single-target therapies. Methods: A comprehensive model was constructed of female endocrineeimmune signaling consisting of 28 markers linked by 214 documented regulatory interactions. This detailed model was then constrained to adhere to experimental measurements in a subset of 17 candidate immune markers measured in peripheral blood of patients with ME/ CFS and healthy control subjects before, during, and after a maximal exercise challenge. A set of 26 competing numerical models satisfied these data to within 5% error. Findings: Mechanistically informed predictions of endocrine and immune markers that were either unmeasured or exhibited high subject-to-subject variability pointed to possible context-specific overexpression in ME/CFS at rest of corticotropinreleasing hormone, chemokine (C-X-C motif) ligand 8, estrogen, follicle-stimulating hormone (FSH), gonadotropin-releasing hormone 1, interleukin (IL)-23, and luteinizing hormone, and underexpression of adrenocorticotropic hormone, cortisol, interferon-g, IL-10, IL-17, and IL-1a. Simulations of rintatolimod and rituximab treatment predicted a shift in the repertoire of available endocrineeimmune regulatory regimens. Rintatolimod was predicted to make available substantial remission in a significant subset of subjects, in particular those with low levels of IL-1a, IL-17, and cortisol; intermediate levels of progesterone and FSH; and high estrogen levels. Rituximab treatment was predicted to support partial remission in a smaller subset of patients with ME/ CFS, specifically those with low norepinephrine, IL-1a, chemokine (C-X-C motif) ligand 8, and cortisol

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Section: Introductionmentioning

confidence: 99%

Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome

Morris

Cooney

Sedghamiz

et al. 2019

Clinical Therapeutics

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“…In previous work, our group updated and further developed the network of documented immune signaling interactions used by the agent-based Basic Immune Simulator (Folcik et al, 2007) to create an augmented model of innate and adaptive immune cell signaling (Fritsch et al, 2013). In this model, various adaptive immune cell subsets were aggregated into functional groups (namely, T helper cell populations Th1, Th2, Th17, and cytotoxic T lymphocytes CTL) as were sub-populations of innate immune cells (natural killer cells NK and dendritic cells DC).…”

Section: Aggregating Cytokines Into Functional Setsmentioning

confidence: 99%

“…Toward this we have extended sampling to include 8 blood draws collected prior to, during and up to 4 h after peak exercise in n = 12 veterans with GWI and n = 11 healthy control veterans (HC). In an effort to cast this data in the context of a priori knowledge, we apply as a mechanistic scaffold an extension of a literaturebased model of immune signaling (Fritsch et al, 2013) previously reported by our group. We group individual cytokine and chemokine measurements into the functional sets reported by Folcik et al (2007Folcik et al ( , 2011 and apply a rate equation framework which leverages the basic topological features of biological networks to infer regulatory control actions rather than rely on a more conventional structurally naïve fit to data (Vashishtha et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War Illness

et al. 2020

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Potentially linked to the basic physiology of stress response, Gulf War Illness (GWI) is a debilitating condition presenting with complex immune, endocrine and neurological symptoms. Here we interrogate the immune response to physiological stress by measuring 16 blood-borne immune markers at 8 time points before, during and after maximum exercise challenge in n = 12 GWI veterans and n = 11 healthy veteran controls deployed to the same theater. Immune markers were combined into functional sets and the dynamics of their joint expression described as classical rate equations. These empirical networks were further informed structurally by projection onto prior knowledge networks mined from the literature. Of the 49 literature-informed immune signaling interactions, 21 were found active in the combined exercise response data. However, only 4 signals were common to both subject groups while 7 were uniquely active in GWI and 10 uniquely active in healthy veterans. Feedforward mediation of IL-23 and IL-17 by IL-6 and IL-10 emerged as distinguishing control elements that were characteristically active in GWI versus healthy subjects. Simulated restructuring of the regulatory circuitry in GWI as a result of applying an IL-6 receptor antagonist in combination with either a Th1 (IL-2, IFNγ, and TNFα) or IL-23 receptor antagonist predicted a partial rescue of immune response elements previously associated with illness severity. Overall, results suggest that pharmacologically altering the topology of the immune response circuitry identified as active in GWI can inform on strategies that while not curative, may nonetheless deliver a reduction in symptom burden. A lasting and more complete remission in GWI may therefore require manipulation of a broader physiology, namely one that includes endocrine oversight of immune function.

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“…Recent studies have indicated that the 'normal' immune and physiological homeostatic states (involving inflammatory / anti-inflammatory balance), which arises from feedback between the immune and endocrine systems (being different between males / females), lies in three equilibrium positions. Illnesses such as Gulf War Syndrome (GWI) and chronic-fatigue syndrome (CFS) establish alternative (and sub-optimal) equilibrium positions [214]. The evidence for one of these sub-optimal positions usually lies in immune activation and cytokine production.…”

Section: Disease Time Cascadesmentioning

confidence: 99%

“…This is exactly what has been described in this review for the effects of cytomegalovirus against certain 'sensitive' members of the population. Some 14% of soldiers experienced GWS [214], and CMV studies indicate that around 20% of persons have high CMV IgG (with elevated IL-6 or CRP). This proportion is higher in those with CMV-mediated disease as in CAD, diabetes, etc.…”

Section: Disease Time Cascadesmentioning

confidence: 99%

Is Cytomegalovirus Involved in Recurring Periods of Higher than Expected Death and Medical Admissions, Occurring as Clustered Outbreaks in the Northern and Southern Hemispheres?

Jones¹

2016

BJMMR

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A series of clustered infectious-like events have been recently documented in both the northern hemisphere (Canada, UK [England, Northern Ireland, Scotland and Wales], all countries in the European Union, and the USA) and the southern hemisphere (Australia and New Zealand), in which both deaths and emergency admissions for a range of medical conditions appear to simultaneously rise in a step-like manner, stay high for a period of 12 to 18 months, and then revert back to the expected time trajectory. These unique events are also observed in very small geographical areas within the population area of a single hospital or Primary Care Organisation (PCO), and this precludes explanations based on acute thresholds to admission or to PCO funding, procedures and practice. These events have been overlooked by traditional health surveillance methodologies, simply because it was assumed that neither deaths nor medical admissions could behave in this unique way. Indeed, in the UK it has been widely assumed that the increases in medical admissions arising from these events are solely due to deficiencies in the organization and delivery of health and social care, often labelled as 'failure to manage demand'. Based on the spectrum of medical conditions which are associated with the increased admissions

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Succumbing to the laws of attraction

Cited by 16 publications

References 94 publications

Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome

Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome

Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War Illness

Is Cytomegalovirus Involved in Recurring Periods of Higher than Expected Death and Medical Admissions, Occurring as Clustered Outbreaks in the Northern and Southern Hemispheres?

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