Enhanced Gene Expression Following Vaccination in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Ekua W. Brenu, Gunn M. Atkinson, Mieke L. van Driel, Sanne Kreijkamp-Kaspers, Don R. Staines, Sonya M. Marshall-Gradisnik

Discipline of General Practice, School of Medicine, The University of Queensland, Brisbane, Australia..
Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Australia..
National Center for Neuroimmu- nology and Emerging Diseases, Griffith University, Gold Coast, Australia..
Queensland Health, Gold Coast Public Health Unit, Gold Coast, Australia..
School of Medical Science, Griffith Health Institute, Griffith University, Gold Coast, Australia..

DOI: 10.4236/ijcm.2013.43029                

Abstract

Vaccines have been shown to cause differential expression of genes and increase antibody titers against antigens. Influenza vaccines may have an effect on unexplained disorders such as Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). Immunological changes have been identified following immunization with trivalent influenza vaccine (TIV). The objective of this pilot study was to examine the consequences of TIV on cytokine and cytotoxic genes in CFS/ME. Peripheral blood mononuclear cells were preferentially isolated from whole blood of 7 CFS/ME patients and 8 controls. Following total RNA extraction and synthesis of cDNA, reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) was used to determine the expression levels of mRNAs for cytotoxic genes (perforin (PRF1), granzyme A (GZMA), granzyme B (GZMB) and cytokine genes. GZMB was significantly increased overall in the CFS/ME patients compared to the controls. GZMA was significantly increased 28 days after vaccination while PRF1 was reduced prevaccination but increased 14 days post-vaccination in the CFS/ME patients. There were no significant changes in cytokine genes pre or post vaccination. Administration of TIV may increase the expression of lytic genes in CFS/ME and this may contribute to the increase in cytotoxic activity we observed in these patients post vaccination.

Keywords

Chronic Fatigue Syndrome; Perforin; Granzymes; Cytokines

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	P. R. Dormitzer, G. Galli, F. Castellino, H. Golding, S. Khurana, G. Del Giudice and R. Rappuoli, “Influenza Vaccine Immunology,” Immunological Reviews, Vol. 239, No. 1, 2011, pp. 167-77. doi:10.1111/j.1600-065X.2010.00974.x
[2]	N. E. Basta, M. E. Halloran, L. Matrajt and I. M. Longini Jr., “Estimating Influenza Vaccine Efficacy from Challenge and Community-Based Study Data,” American Journal of Epidemiology, Vol. 168, No. 12, 2008, pp. 1343- 1352. doi:10.1093/aje/kwn259
[3]	H. I. Nakaya, J. Wrammert, E. K. Lee, L. Racioppi, S. Marie-Kunze, W. N. Haining, A. R. Means, S. P. Kasturi, N. Khan, G. M. Li, M. McCausland, V. Kanchan, K. E. Kokko, S. Li, R. Elbein, A. K. Mehta, A. Aderem, K. Subbarao, R. Ahmed and B. Pulendran, “Systems Biology of Vaccination for Seasonal Influenza in Humans,” Nature Immunology, Vol. 12, 2011, pp. 786-95. doi:10.1038/ni.2067
[4]	C. A. Siegrist, “Vaccinology Update for 2008: What’s New in Switzerland?” Revue Médicale Suisse, Vol. 4, No. 139, 2008, pp. 72-75.
[5]	M. Bijl, C. G. Kallenberg and S. van Assen, “Vaccination of the Immune-Compromised Patients with Focus on Patients with Autoimmune-Inflammatory Diseases,” The Netherlands Journal of Medicine, Vol. 69, No. 1, 2011, pp. 5-13.
[6]	W. C. Reeves, D. Wagner, R. Nisenbaum, J. F. Jones, B. Gurbaxani, L. Solomon, D. A. Papanicolaou, E. R. Unger, S. D. Vernon and C. Heim, “Chronic Fatigue Syndrome—A Clinically Empirical Approach to Its Definition and Study,” BMC Medicine, Vol. 3, 2005, p. 19. doi:10.1186/1741-7015-3-19
[7]	E. W. Brenu, M. L. van Driel, D. R. Staines, K. J. Ashton, S. B. Ramos, J. Keane, N. G. Klimas and S. M. Marshall-Gradisnik, “Immunological Abnormalities as Potential Biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis,” Journal of Translational Medicine, Vol. 9, 2011, p. 81. doi:10.1186/1479-5876-9-81
[8]	E. W. Brenu, M. van Driel, D. R. Staines, S. Kreijkamp-Kaspers, S. L. Hardcastle and S. Marshall-Gradisnik, “The Effects of Influenza Vaccination on Immune Function in Patients with Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis,” International Journal of Clinical Medicine, Vol. 3, No. 6, 2012, pp. 544-551.
[9]	J. R. Kerr, R. Petty, B. Burke, J. Gough, D. Fear, L. I. Sinclair, D. L. Mattey, S. C. Richards, J. Montgomery, D. A. Baldwin, P. Kellam, T. J. Harrison, G. E. Griffin, J. Main, D. Enlander, D. J. Nutt and S. T. Holgate, “Gene Expression Subtypes in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis,” The Journal of Infectious Diseases, Vol. 197, No. 8, 2008, pp. 1171-1184. doi:10.1086/533453
[10]	K. Fukuda, S. E. Straus, I. Hickie, M. C. Sharpe, J. G. Dobbins and A. Komaroff, “The Chronic Fatigue Syndrome: A Comprehensive Approach to Its Definition and Study. International Chronic Fatigue Syndrome Study Group,” Annals of Internal Medicine, Vol. 121, No. 12, 1994, pp. 953-959.
[11]	E. W. Brenu, D. R. Staines, O. K. Baskurt, K. J. Ashton, S. B. Ramos, R. M. Christy and S. M. Marshall-Gradisnik, “Immune and Hemorheological Changes in Chronic Fatigue Syndrome,” Journal of Translational Medicine, Vol. 8, 2010, p. 1. doi:10.1186/1479-5876-8-1
[12]	“The Australian Immunisation Handbook,” 9th Edition, 2008. http://www.health.gov.au/internet/immunise/publishing.nsf/Content/Handbook-influenza
[13]	K. L. Bucasas, L. M. Franco, C. A. Shaw, M. S. Bray, J. M. Wells, D. Nino, N. Arden, J. M. Quarles, R. B. Couch and J. W. Belmont, “Early Patterns of Gene Expression Correlate with the Humoral Immune Response to Influenza Vaccination in Humans,” Journal of Infectious Diseases, Vol. 203, No. 7, 2011, pp. 921-929. doi:10.1093/infdis/jiq156
[14]	J. Stein-Streilein, M. Bennett, D. Mann and V. Kumar, “Natural Killer Cells in Mouse Lung: Surface Phenotype, Target Preference, and Response to Local Influenza Virus Infection,” Journal of Immunology, Vol. 131, No. 6, 1983, pp. 2699-2704.
[15]	P. C. Doherty, D. J. Topham, R. A. Tripp, R. D. Cardin, J. W. Brooks and P. G. Stevenson, “Effector CD4+ and CD8+ T-Cell Mechanisms in the Control of Respiratory Virus Infections,” Immunological Reviews, Vol. 159, No. 1, 1997, pp. 105-117. doi:10.1111/j.1600-065X.1997.tb01010.x
[16]	M. G. Lichtenheld, K. J. Olsen, P. Lu, D. M. Lowrey, A. Hameed, H. Hengartner and E. R. Podack, “Structure and Function of Human Perforin,” Nature, Vol. 335, 1988, pp. 448-451. doi:10.1038/335448a0
[17]	M. G. Lichtenheld and E. R. Podack, “Structure of the Human Perforin Gene. A Simple Gene Organization with Interesting Potential Regulatory Sequences,” Journal of Immunology, Vol. 143, No. 12, 1989, pp. 4267-4274.
[18]	S. Hoves, J. A. Trapani and I. Voskoboinik, “The Battlefield of Perforin/Granzyme Cell Death Pathways,” Journal of Leukocyte Biology, Vol. 87, No. 2, 2010, pp. 237-243. doi:10.1189/jlb.0909608
[19]	J. Zhang, I. Scordi, M. J. Smyth and M. G. Lichtenheld, “Interleukin 2 Receptor Signaling Regulates the Perforin Gene through Signal Transducer and Activator of Transcription (Stat)5 Activation of Two Enhancers,” Journal of Experimental Medicine, Vol. 190, No. 9, 1999, pp. 1297-1308. doi:10.1084/jem.190.9.1297
[20]	M. E. Pipkin, A. Rao and M. G. Lichtenheld, “The Transcriptional Control of the Perforin Locus,” Immunological Reviews, Vol. 235, No. 1, 2010, pp. 55-72.
[21]	Y. F. Wu, B. H. Zhang, D. Y. Cen, J. Wei and C. Chen, “Expression of Perforin in Cord Blood NK Cells after IL-2/IL-15 Stimulation and Its Relation with Cytotoxicity,” Journal of Experimental Hematology, Vol. 19, No. 4, 2011, pp. 1015-1018.
[22]	J. Zhou, J. Zhang, M. G. Lichtenheld and G. G. Meadows, “A Role for NF-Kappa B Activation in Perforin Expression of NK Cells upon IL-2 Receptor Signaling,” Journal of Immunology, Vol. 169, No. 3, 2002, pp. 1319-1325.
[23]	T. W. Salcedo, L. Azzoni, S. F. Wolf and B. Perussia, “Modulation of Perforin and Granzyme Messenger RNA Expression in Human Natural Killer Cells,” Journal of Immunology, Vol. 151, No. 5, 1993, pp. 2511-2520.
[24]	S. Jost, H. Quillay, J. Reardon, E. Peterson, R. P. Simmons, B. A. Parry, N. N. Bryant, W. D. Binder and M. Altfeld, “Changes in Cytokine Levels and NK Cell Activation Associated with Influenza,” PLoS One, Vol. 6, No. 9, 2011, Article ID: e25060. doi:10.1371/journal.pone.0025060
[25]	A. N. Naikhin, A. R. Rekstin, I. B. Barantseva, S. A. Donina, A. Desheva Iu, E. P. Grigor’eva, I. V. Kiseleva and L. G. Rudenko, “Immune Response to Live Influenza Vaccine,” Vestnik Rossiiskoi Akademii Meditsinskikh Nauk, Vol. 12, 2002, pp. 24-28.
[26]	A. N. Naikhin, A. R. Rekstin, J. Katz, S. A. Donina, E. P. Grigor’eva, A. Desheva Iu, N. Arden, L. G. Rudenko and N. Cox, “Production of Interleukin-2 in Vitro and in Vivo in Elderly People, Vaccinated with Live and Inactivated Flu Vaccines Separately and Combined,” Voprosy Viru- sologii, Vol. 45, No. 1, 2000, pp. 25-29.
[27]	B. Liu, I. Mori, M. J. Hossain, L. Dong, Z. Chen and Y. Kimura, “Local Immune Responses to Influenza Virus Infection in Mice with a Targeted Disruption of Perforin Gene,” Microbial Pathogenesis, Vol. 34, No. 4, 2003, pp. 161-167. doi:10.1016/S0882-4010(02)00191-2
[28]	J. Pardo, J. I. Aguilo, A. Anel, P. Martin, L. Joeckel, C. Borner, R. Wallich, A. Mullbacher, C. J. Froelich and M. M. Simon, “The Biology of Cytotoxic Cell Granule Exocytosis Pathway: Granzymes Have Evolved to Induce Cell Death and Inflammation,” Microbes and Infection, Vol. 11, No. 4, 2009, pp. 452-459. doi:10.1016/j.micinf.2009.02.004
[29]	T. Saiki, T. Kawai, K. Morita, M. Ohta, T. Saito, K. Rokutan and N. Ban, “Identification of Marker Genes for Differential Diagnosis of Chronic Fatigue Syndrome,” Molecular Medicine, Vol. 14, No. 9-10, 2008, pp. 599-607. doi:10.2119/2007-00059.Saiki
[30]	J. E. McElhaney, S. Gravenstein, C. M. Upshaw, J. W. Hooton, P. Krause, P. Drinka and R. C. Bleackley, “Granzyme B: A Marker of Risk for Influenza in Institutionalized Older Adults,” Vaccine, Vol. 19, No. 27, 2001, pp. 3744-3751. doi:10.1016/S0264-410X(01)00087-1
[31]	E. Szyszko, K. Brokstad, R. J. Cox, A. O. Hovden, A. Madhun and L. R. Haaheim, “Impact of Influenza Vaccine Formulation with a Detailed Analysis of the Cytokine Response,” Scandinavian Journal of Immunology, Vol. 64, No. 5, 2006, pp. 467-475. doi:10.1111/j.1365-3083.2006.01805.x