Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War Illness
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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-04-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphys.2020.00358/full |
| _version_ | 1818485939776782336 |
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| author | Saurabh Vashishtha Saurabh Vashishtha Gordon Broderick Gordon Broderick Travis J. A. Craddock Travis J. A. Craddock Zachary M. Barnes Zachary M. Barnes Fanny Collado Elizabeth G. Balbin Elizabeth G. Balbin Mary Ann Fletcher Mary Ann Fletcher Mary Ann Fletcher Nancy G. Klimas Nancy G. Klimas Nancy G. Klimas |
| author_facet | Saurabh Vashishtha Saurabh Vashishtha Gordon Broderick Gordon Broderick Travis J. A. Craddock Travis J. A. Craddock Zachary M. Barnes Zachary M. Barnes Fanny Collado Elizabeth G. Balbin Elizabeth G. Balbin Mary Ann Fletcher Mary Ann Fletcher Mary Ann Fletcher Nancy G. Klimas Nancy G. Klimas Nancy G. Klimas |
| author_sort | Saurabh Vashishtha |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T16:16:13Z |
| format | Article |
| id | doaj.art-a197383a35a24d9995f77376f71ae033 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-10T16:16:13Z |
| publishDate | 2020-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-a197383a35a24d9995f77376f71ae0332022-12-22T01:41:58ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2020-04-011110.3389/fphys.2020.00358449576Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War IllnessSaurabh Vashishtha0Saurabh Vashishtha1Gordon Broderick2Gordon Broderick3Travis J. A. Craddock4Travis J. A. Craddock5Zachary M. Barnes6Zachary M. Barnes7Fanny Collado8Elizabeth G. Balbin9Elizabeth G. Balbin10Mary Ann Fletcher11Mary Ann Fletcher12Mary Ann Fletcher13Nancy G. Klimas14Nancy G. Klimas15Nancy G. Klimas16Department of Medicine, University of Alberta, Edmonton, AB, CanadaCenter for Clinical Systems Biology, Rochester General Hospital, Rochester, NY, United StatesCenter for Clinical Systems Biology, Rochester General Hospital, Rochester, NY, United StatesDepartment of Biomedical Engineering, Kate Gleason College of Engineering, Rochester Institute of Technology, Rochester, NY, United StatesInstitute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL, United StatesDepartments of Psychology & Neuroscience, Computer Science and Clinical Immunology, Nova Southeastern University, Fort Lauderdale, FL, United StatesDiabetes Research Institute, University of Miami, Miami, FL, United StatesMiami Veterans Affairs Medical Center, Miami, FL, United StatesMiami Veterans Affairs Medical Center, Miami, FL, United StatesInstitute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL, United StatesMiami Veterans Affairs Medical Center, Miami, FL, United StatesInstitute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL, United StatesDepartments of Psychology & Neuroscience, Computer Science and Clinical Immunology, Nova Southeastern University, Fort Lauderdale, FL, United StatesMiami Veterans Affairs Medical Center, Miami, FL, United StatesInstitute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL, United StatesDepartments of Psychology & Neuroscience, Computer Science and Clinical Immunology, Nova Southeastern University, Fort Lauderdale, FL, United StatesMiami Veterans Affairs Medical Center, Miami, FL, United StatesPotentially 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.https://www.frontiersin.org/article/10.3389/fphys.2020.00358/fullGulf War Illnesscytokinesimmune signalingTh1Th17network biology |
| spellingShingle | Saurabh Vashishtha Saurabh Vashishtha Gordon Broderick Gordon Broderick Travis J. A. Craddock Travis J. A. Craddock Zachary M. Barnes Zachary M. Barnes Fanny Collado Elizabeth G. Balbin Elizabeth G. Balbin Mary Ann Fletcher Mary Ann Fletcher Mary Ann Fletcher Nancy G. Klimas Nancy G. Klimas Nancy G. Klimas Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War Illness Frontiers in Physiology Gulf War Illness cytokines immune signaling Th1 Th17 network biology |
| title | Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War Illness |
| title_full | Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War Illness |
| title_fullStr | Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War Illness |
| title_full_unstemmed | Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War Illness |
| title_short | Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War Illness |
| title_sort | leveraging prior knowledge to recover characteristic immune regulatory motifs in gulf war illness |
| topic | Gulf War Illness cytokines immune signaling Th1 Th17 network biology |
| url | https://www.frontiersin.org/article/10.3389/fphys.2020.00358/full |
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