Evidence for abnormal cytokine expression in Gulf War Illness: A preliminary analysis of daily immune monitoring data

BMC Immunology

Jarred Younger²  Katharine Baker³  Stephanie Middleton¹  Luke Parkitny² 

[1] Department of Anesthesia, Perioperative, and Pain Medicine, Stanford University, Palo Alto, CA, USA;Neuroinflammation, Pain & Fatigue Lab, University of Alabama at Birmingham, Birmingham, AL, USA;Experimental Neuropsychology Research Unit, School of Psychological Sciences, Monash University, Melbourne, Australia

关键词: Immune;    Longitudinal;    Daily;    Cytokine;    Inflammation;    Fatigue;    Gulf War;   

Others  :  1228737
DOI  :  10.1186/s12865-015-0122-z

 received in 2015-08-06, accepted in 2015-09-22,  发布年份 2015

【 摘 要 】

Background

Gulf War Illness (GWI) is a clinically heterogeneous chronic condition that affects many veterans of the 1990–1991 Persian Gulf War. One of the most prevalent and debilitating symptoms of GWI is abnormal fatigue. The mechanisms underlying GWI generally, and fatigue symptoms specifically, have yet to be conclusively identified, although immune system abnormalities are suspected to be involved. The first goal of this immune monitoring study was to determine if GWI is associated with higher absolute levels and daily variability of pro-inflammatory immune factors. The second goal was to explore the relationship between day-to-day immune marker fluctuations and daily self-reported fatigue severity.

Methods

We recruited veterans with GWI and healthy veteran control (HV) participants to provide self-reported fatigue severity data and blood samples, over 25 consecutive days. We profiled inflammatory processes by using a longitudinal, daily immune-monitoring approach. For each day, serum cytokine and chemokine concentrations were determined using multiplex assays.

Results

Seven veterans with GWI and eight healthy veteran control (HV) participants completed the study protocol. We found that GWI was associated with higher variability in the expression of eotaxin-1 (p < 0.001). For GWI participants, higher fatigue severity days were associated with greater IL-1β (p = 0.008) and IL-15 (p < 0.001).

Conclusions

Our findings provide preliminary evidence that the immune system is involved in the pathophysiology of GWI. Longitudinal immune profiling approaches may be helpful in discovering targets for novel therapies in conditions such as GWI.

【 授权许可】

   
2015 Parkitny et al.

【 图 表 】

Fig. 1.

【 参考文献 】

• [1]Fukuda K, Straus S, Hickie I, Sharpe M, Dobbins J, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International chronic fatigue syndrome study group. Ann Intern Med. 1994; 121:953-959.
• [2]Wolfe J, Proctor SP, Davis JD, Borgos MS, Friedman MJ. Health symptoms reported by Persian Gulf War veterans two years after return. Am J Ind Med. 1998; 33(2):104-113.
• [3]Fukuda K, Nisenbaum R, Stewart G, Thompson WW, Robin L, Washko RM et al.. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. Jama. 1998; 280(11):981-988.
• [4]Gronseth GS. Gulf war syndrome: a toxic exposure? A systematic review. Neurol Clin. 2005; 23(2):523-540.
• [5]Hotopf M, David A, Hull L, Ismail K, Unwin C, Wessely S. Role of vaccinations as risk factors for ill health in veterans of the Gulf war: cross sectional study. BMJ. 2000; 320(7246):1363-1367.
• [6]Peakman M, Skowera A, Hotopf M. Immunological dysfunction, vaccination and Gulf War illness. Philos Trans R Soc B. 2006; 361(1468):681-687.
• [7]Rijpkema SG, Adams T, Rigsby P, Xing DK, Corbel MJ. Investigation in a Model System of the Effects of Combinations of Anthrax and Pertussis Vaccines Administered to Service Personnel in the 1991Gulf War. Hum Vaccin. 2005; 1(4):165-169.
• [8]Rook GA, Zumla A. Gulf War syndrome: is it due to a systemic shift in cytokine balance towards a Th2 profile? Lancet. 1997; 349(9068):1831-1833.
• [9]Skowera A, Hotopf M, Sawicka E, Varela-Calvino R, Unwin C, Nikolaou V et al.. Cellular Immune Activation in Gulf War Veterans. J Clin Immunol. 2004; 24(1):66-73.
• [10]Zhang Q, Zhou X-D, Denny T, Ottenweller JE, Lange G, LaManca JJ et al.. Changes in immune parameters seen in Gulf War veterans but not in civilians with chronic fatigue syndrome. Clin Diagn Lab Immunol. 1999; 6(1):6-13.
• [11]Ferguson E, Cassaday HJ. The Gulf War and illness by association. Br J Psychol. 1999; 90(4):459-475.
• [12]Kelley KW, Bluthé R-M, Dantzer R, Zhou J-H, Shen W-H, Johnson RW et al.. Cytokine-induced sickness behavior. Brain Behav Immun. 2003; 17(1):112-118.
• [13]Everson MP, Shi K, Aldridge P, Bartolucci AA, Blackburn WD. Immunological responses are not abnormal in symptomatic Gulf War veterans. Ann N Y Acad Sci. 2002; 966(1):327-342.
• [14]Bregenholt S, Ishøy T, Skovgaard LT, Suadicani P, Appleyard M, Guldager B et al.. No evidence for altered cellular immune functions in personnel deployed in the Persian Gulf during and after the Gulf War‐The Danish Gulf War study. Apmis. 2001; 109(7–8):517-524.
• [15]Broderick G, Ben-Hamo R, Vashishtha S, Efroni S, Nathanson L, Barnes Z et al.. Altered immune pathway activity under exercise challenge in Gulf War Illness: an exploratory analysis. Brain Behav Immun. 2013; 28:159-169.
• [16]Broderick G, Fletcher MA, Gallagher M, Barnes Z, Vernon SD, Klimas NG. Exploring the diagnostic potential of immune biomarker coexpression in Gulf War illness. Springer, Psychoneuroimmunology; 2012.
• [17]Broderick G, Kreitz A, Fuite J, Fletcher MA, Vernon SD, Klimas N. A pilot study of immune network remodeling under challenge in Gulf War Illness. Brain Behav Immun. 2011; 25(2):302-313.
• [18]Vojdani A, Thrasher JD. Cellular and humoral immune abnormalities in Gulf War veterans. Environ Health Perspect. 2004; 112(8):840-846.
• [19]Whistler T, Fletcher MA, Lonergan W, Zeng XR, Lin JM, Laperriere A et al.. Impaired immune function in Gulf War Illness. BMC Med Genomics. 2009; 2:12. BioMed Central Full Text
• [20]O'Bryan TA, Romano PJ, Zangwill BC. Human leukocyte antigens in Gulf War veterans with chronic unexplained multiple symptoms. Mil Med. 2003; 168(12):1015-1018.
• [21]Skowera A, Stewart E, Davis ET, Cleare AJ, Unwin C, Hull L et al.. Antinuclear autoantibodies (ANA) in Gulf War-related illness and chronic fatigue syndrome (CFS) patients. Clin Exp Immunol. 2002; 129(2):354-358.
• [22]Stringer EA, Baker KS, Carroll I, Montoya J, Chu L, Maecker H et al.. Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. J Transl Med. 2013; 11(1):93. BioMed Central Full Text
• [23]Steele L. Prevalence and patterns of Gulf War illness in Kansas veterans: association of symptoms with characteristics of person, place, and time of military service. Am J Epidemiol. 2000; 152(10):992-1002.
• [24]Doebbeling BN, Clarke WR, Watson D, Torner JC, Woolson RF, Voelker MD et al.. Is there a Persian Gulf War syndrome? Evidence from a large population-based survey of veterans and nondeployed controls. Am J Med. 2000; 108(9):695-704.
• [25]Kang HK, Natelson BH, Mahan CM, Lee KY, Murphy FM. Post-Traumatic Stress Disorder and Chronic Fatigue Syndrome-like Illness among Gulf War Veterans: A Population-based Survey of 30,000 Veterans. Am J Epidemiol. 2003; 157(2):141-148.
• [26]McCauley LA, Joos SK, Barkhuizen A, Shuell T, Tyree WA, Bourdette DN. Chronic Fatigue in a Population-Based Study of Gulf War Veterans. Arch Environ Health. 2002; 57(4):340.
• [27]Rothwell NJ, Luheshi GN. Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci. 2000; 23(12):618-625.
• [28]Dantzer R, Kelley KW. Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun. 2007; 21(2):153-160.
• [29]Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA. A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav Immun. 2010; 24(7):1209-1217.
• [30]Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG. Plasma cytokines in women with chronic fatigue syndrome. J Transl Med. 2009; 7(1):96. BioMed Central Full Text
• [31]Maes M, Twisk FN, Kubera M, Ringel K. Evidence for inflammation and activation of cell-mediated immunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin. J Affect Disord. 2012; 136(3):933-939.
• [32]Cavelti-Weder C, Furrer R, Keller C, Babians-Brunner A, Solinger AM, Gast H, et al. Inhibition of IL-1β improves fatigue in type 2 diabetes. Diabetes Care. 2011;34(10):e158–8.
• [33]Omdal R, Gunnarsson R. The effect of interleukin-1 blockade on fatigue in rheumatoid arthritis—a pilot study. Rheumatol Int. 2005; 25(6):481-484.
• [34]Angiolillo AL, Kanegane H, Sgadari C, Reaman GH, Tosato G. Interleukin-15 promotes angiogenesis in vivo. Biochem Biophys Res Commun. 1997; 233(1):231-237.
• [35]Quinn LS, Haugk KL, Grabstein KH. Interleukin-15: a novel anabolic cytokine for skeletal muscle. Endocrinology. 1995; 136(8):3669-3672.
• [36]Weng NP, Liu K, Catalfamo M, Li Y, Henkart PA. IL-15 is a growth factor and an activator of CD8 memory T cells. Ann N Y Acad Sci. 2002; 975:46-56.
• [37]Lee YB, Nagai A, Kim SU. Cytokines, chemokines, and cytokine receptors in human microglia. J Neurosci Res. 2002; 69(1):94-103.
• [38]Brenu EW, van Driel ML, Staines DR, Ashton KJ, Ramos SB, Keane J et al.. Immunological abnormalities as potential biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis. J Transl Med. 2011; 9(1):81. BioMed Central Full Text
• [39]Smylie AL, Broderick G, Fernandes H, Razdan S, Barnes Z, Collado F et al.. A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome. BMC Immunol. 2013; 14:29. BioMed Central Full Text
• [40]Barker E, Fujimura SF, Fadem MB, Landay AL, Levy JA. Immunologic Abnormalities Associated with Chronic Fatigue Syndrome. Clin Infect Dis. 1994; 18(1):S136-S141.
• [41]Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G et al.. The aging systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011; 477(7362):90-94.
• [42]Iikuni N, Nakajima A, Inoue E, Tanaka E, Okamoto H, Hara M et al.. What's in season for rheumatoid arthritis patients? Seasonal fluctuations in disease activity. Rheumatology. 2007; 46(5):846-848.
• [43]Latman NS. Relation of menstrual cycle phase to symptoms of rheumatoid arthritis. Am J Med. 1983; 74(6):957-960.
• [44]Schanberg LE, Anthony KK, Gil KM, Maurin EC. Daily pain and symptoms in children with polyarticular arthritis. Arthritis Rheum. 2003; 48(5):1390-1397.
• [45]Zautra AJ, Fasman R, Parish BP, Davis MC. Daily fatigue in women with osteoarthritis, rheumatoid arthritis, and fibromyalgia. Pain. 2007; 128(1):128-135.
• [46]Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983; 67(6):361-370.
• [47]Weathers FW, Litz BT, Herman DS, Huska JA, Keane TM. The PTSD Checklist (PCL): Reliability, validity, and diagnostic utility, Proceedings of the Annual Convention of the International Society for Traumatic Stress Studies: International Society for Traumatic Stress Studies San Antonio, 1993.
• [48]Saad M, Riad-Gabriel M, Khan A, Sharma A, Michael R, Jinagouda S et al.. Diurnal and ultradian rhythmicity of plasma leptin: effects of gender and adiposity. J Clin Endocrinol Metab. 1998; 83:453-459.
• [49]Schoeller D, Cella L, Sinha M, Caro JF. Entrainment of the diurnal rhythm of plasma leptin to meal timing. J Clin Invest. 1997; 100:1882-1887.
• [50]Dünki RM, Keller E, Meier PF, Ambühl B. Temporal patterns of human behaviour: are there signs of deterministic 1/f scaling? Physica A: Statistical Mechanics and its Applications. 2000; 276(3):596-609.
• [51]Savitzky A, Golay MJ. Smoothing and differentiation of data by simplified least squares procedures. Anal Chem. 1964; 36(8):1627-1639.