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

Matthew C Morris; Katherine E Cooney; Hooman Sedghamiz; Maria Abreu; Fanny Collado; Elizabeth G Balbin; Travis Craddock; Nancy G Klimas; Gordon Broderick; Mary Ann Fletcher

doi:10.1016/j.clinthera.2019.03.002

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

Matthew C Morris
, Katherine E Cooney
, Hooman Sedghamiz
, Maria Abreu
, Fanny Collado
, Elizabeth G Balbin
, Travis Craddock
, Nancy G Klimas
, Gordon Broderick
, Mary Ann Fletcher

College of Psychology

Research output: Contribution to journal › Article › peer-review

Abstract

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-pituitary-adrenal 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 endocrine–immune 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 corticotropin-releasing 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-γ, IL-10, IL-17, and IL-1α. Simulations of rintatolimod and rituximab treatment predicted a shift in the repertoire of available endocrine–immune regulatory regimens. Rintatolimod was predicted to make available substantial remission in a significant subset of subjects, in particular those with low levels of IL-1α, 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-1α, chemokine (C-X-C motif) ligand 8, and cortisol levels; intermediate FSH and gonadotropin-releasing hormone 1 levels; and elevated expression of tumor necrosis factor-α, luteinizing hormone, IL-12, and B-cell activation. Implications: Applying a rigorous filter of known signaling mechanisms to experimentally measured immune marker expression in ME/CFS has highlighted potential new context-specific markers of illness. These novel endocrine and immune markers may offer useful candidates in delineating new subtypes of ME/CFS and may inform on refinements to the inclusion criteria and instrumentation of new and ongoing trials involving rintatolimod and rituximab treatment protocols.

Original language	American English
Pages (from-to)	656-674.e4
Journal	Clinical Therapeutics
Volume	41
Issue number	4
DOIs	https://doi.org/10.1016/j.clinthera.2019.03.002
State	Published - Apr 1 2019

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Inc.

Funding

This research was supported by National Institutes of Health awards R01 NS090200-01 (Dr. Fletcher, principal investigator [PI]); R56 AI065723-06A1 (Dr. Fletcher, PI); and R01AR057853-01 (Dr. Klimas, PI). It was also supported by the US Department of Defense Congressionally Directed Medical Research Program ( http://cdmrp.army.mil/ ) under award GW140142 (Drs. Broderick/Craddock, PIs; Whitley, Partnering PI), where Dr. Darrell Whitley and his team contributed to the development of the computational framework used to support this analysis. Finally, this work was also supported by this agency under previous award GW093042 (Dr. Broderick, PI). This research was supported by National Institutes of Health awards R01 NS090200-01 (Dr. Fletcher, principal investigator [PI]); R56 AI065723-06A1 (Dr. Fletcher, PI); and R01AR057853-01 (Dr. Klimas, PI). It was also supported by the US Department of Defense Congressionally Directed Medical Research Program (http://cdmrp.army.mil/) under award GW140142 (Drs. Broderick/Craddock, PIs; Whitley, Partnering PI), where Dr. Darrell Whitley and his team contributed to the development of the computational framework used to support this analysis. Finally, this work was also supported by this agency under previous award GW093042 (Dr. Broderick, PI). Dr. Morris and Ms. Cooney developed and evaluated the mathematical model, conducted the analyses, prepared graphics, and drafted the initial manuscript. Mr. Sedghamiz assisted with model parameterization and analysis as well as manuscript editing. Dr. Broderick oversaw the design of the mathematical tools and the analyses and co-wrote the initial manuscript. Dr. Craddock reviewed the design of the methods, consulted on the methodology, and co-wrote and edited the manuscript. Dr. Abreu oversaw the collection, filtering, and normalization of the raw data. Ms. Collado and Ms. Balbin oversaw study coordination, recruitment, and processing of all subjects. Dr. Fletcher designed the study; oversaw all laboratory assessments, sample collection, and processing; and contributed directly to the interpretation of the results. Dr. Klimas designed the study; directed all clinical and scientific aspects of the overall study; and contributed directly to the study design and the interpretation of results. All authors have read and approved the final manuscript. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Defense.

Funders	Funder number
National Institutes of Health	R01 NS090200-01, R01AR057853-01
U.S. Department of Defense
National Institute of Allergy and Infectious Diseases	R01AI065723
Congressionally Directed Medical Research Programs	GW140142, GW093042

ASJC Scopus Subject Areas

Pharmacology (medical)
Pharmacology

Keywords

chronic fatigue syndrome
endocrine regulation
immune regulation
numerical modeling
rintatolimod
rituximab

Disciplines

Psychology

Access to Document

10.1016/j.clinthera.2019.03.002

https://doi.org/10.1016/j.clinthera.2019.03.002

Cite this

Morris, M. C., Cooney, K. E., Sedghamiz, H., Abreu, M., Collado, F., Balbin, E. G., Craddock, T., Klimas, N. G., Broderick, G., & Fletcher, M. A. (2019). Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome. Clinical Therapeutics, 41(4), 656-674.e4. https://doi.org/10.1016/j.clinthera.2019.03.002

Morris, MC, Cooney, KE, Sedghamiz, H, Abreu, M, Collado, F, Balbin, EG, Craddock, T, Klimas, NG, Broderick, G & Fletcher, MA 2019, 'Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome', Clinical Therapeutics, vol. 41, no. 4, pp. 656-674.e4. https://doi.org/10.1016/j.clinthera.2019.03.002

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

abstract = "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-pituitary-adrenal 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 endocrine–immune 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 corticotropin-releasing 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-γ, IL-10, IL-17, and IL-1α. Simulations of rintatolimod and rituximab treatment predicted a shift in the repertoire of available endocrine–immune regulatory regimens. Rintatolimod was predicted to make available substantial remission in a significant subset of subjects, in particular those with low levels of IL-1α, 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-1α, chemokine (C-X-C motif) ligand 8, and cortisol levels; intermediate FSH and gonadotropin-releasing hormone 1 levels; and elevated expression of tumor necrosis factor-α, luteinizing hormone, IL-12, and B-cell activation. Implications: Applying a rigorous filter of known signaling mechanisms to experimentally measured immune marker expression in ME/CFS has highlighted potential new context-specific markers of illness. These novel endocrine and immune markers may offer useful candidates in delineating new subtypes of ME/CFS and may inform on refinements to the inclusion criteria and instrumentation of new and ongoing trials involving rintatolimod and rituximab treatment protocols.",

keywords = "chronic fatigue syndrome, endocrine regulation, immune regulation, numerical modeling, rintatolimod, rituximab",

author = "Morris, \{Matthew C\} and Cooney, \{Katherine E\} and Hooman Sedghamiz and Maria Abreu and Fanny Collado and Balbin, \{Elizabeth G\} and Travis Craddock and Klimas, \{Nancy G\} and Gordon Broderick and Fletcher, \{Mary Ann\}",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = apr,

day = "1",

doi = "10.1016/j.clinthera.2019.03.002",

language = "American English",

volume = "41",

pages = "656--674.e4",

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T1 - Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome

AU - Morris, Matthew C

AU - Cooney, Katherine E

AU - Sedghamiz, Hooman

AU - Abreu, Maria

AU - Collado, Fanny

AU - Balbin, Elizabeth G

AU - Craddock, Travis

AU - Klimas, Nancy G

AU - Broderick, Gordon

AU - Fletcher, Mary Ann

PY - 2019/4/1

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N2 - 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-pituitary-adrenal 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 endocrine–immune 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 corticotropin-releasing 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-γ, IL-10, IL-17, and IL-1α. Simulations of rintatolimod and rituximab treatment predicted a shift in the repertoire of available endocrine–immune regulatory regimens. Rintatolimod was predicted to make available substantial remission in a significant subset of subjects, in particular those with low levels of IL-1α, 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-1α, chemokine (C-X-C motif) ligand 8, and cortisol levels; intermediate FSH and gonadotropin-releasing hormone 1 levels; and elevated expression of tumor necrosis factor-α, luteinizing hormone, IL-12, and B-cell activation. Implications: Applying a rigorous filter of known signaling mechanisms to experimentally measured immune marker expression in ME/CFS has highlighted potential new context-specific markers of illness. These novel endocrine and immune markers may offer useful candidates in delineating new subtypes of ME/CFS and may inform on refinements to the inclusion criteria and instrumentation of new and ongoing trials involving rintatolimod and rituximab treatment protocols.

AB - 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-pituitary-adrenal 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 endocrine–immune 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 corticotropin-releasing 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-γ, IL-10, IL-17, and IL-1α. Simulations of rintatolimod and rituximab treatment predicted a shift in the repertoire of available endocrine–immune regulatory regimens. Rintatolimod was predicted to make available substantial remission in a significant subset of subjects, in particular those with low levels of IL-1α, 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-1α, chemokine (C-X-C motif) ligand 8, and cortisol levels; intermediate FSH and gonadotropin-releasing hormone 1 levels; and elevated expression of tumor necrosis factor-α, luteinizing hormone, IL-12, and B-cell activation. Implications: Applying a rigorous filter of known signaling mechanisms to experimentally measured immune marker expression in ME/CFS has highlighted potential new context-specific markers of illness. These novel endocrine and immune markers may offer useful candidates in delineating new subtypes of ME/CFS and may inform on refinements to the inclusion criteria and instrumentation of new and ongoing trials involving rintatolimod and rituximab treatment protocols.

KW - chronic fatigue syndrome

KW - endocrine regulation

KW - immune regulation

KW - numerical modeling

KW - rintatolimod

KW - rituximab

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UR - https://doi.org/10.1016/j.clinthera.2019.03.002

U2 - 10.1016/j.clinthera.2019.03.002

DO - 10.1016/j.clinthera.2019.03.002

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SN - 1879-114X

VL - 41

SP - 656-674.e4

JO - Clinical Therapeutics

JF - Clinical Therapeutics

IS - 4

ER -

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

Abstract

Bibliographical note

Funding

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Keywords

Disciplines

Access to Document

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