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Rubella vaccine-induced cellular immunity: evidence of associations with polymorphisms in the Toll-like, vitamin A and D receptors, and innate immune response genes

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Abstract

Toll-like, vitamin A and D receptors and other innate proteins participate in various immune functions. We determined whether innate gene-sequence variations are associated with rubella vaccine-induced cytokine immune responses. We genotyped 714 healthy children (11–19 years of age) after two doses of rubella-containing vaccine for 148 candidate SNP markers. Rubella virus-induced cytokines were measured by ELISA. Twenty-two significant associations (range of P values 0.002–0.048) were found between SNPs in the vitamin A receptor family (RARA, RARB, TOP2B and RARG), vitamin D receptor and downstream mediator of vitamin D signaling (RXRA) genes and rubella virus-specific (IFN-γ, IL-2, IL-10, TNF-α, and GM-CSF) cytokine immune responses. A TLR3 gene promoter region SNP (rs5743305, −8441A > T) was associated with rubella-specific GM-CSF secretion. Importantly, SNPs in the TRIM5 gene coding regions, rs3740996 (His43Tyr) and rs10838525 (Gln136Arg), were associated with an allele dose-related secretion of rubella virus-specific TNF-α and IL-2/GM-CSF, respectively, and have been previously shown to have functional consequences regarding the antiviral activity and susceptibility to HIV-1 infection. We identified associations between individual SNPs and haplotypes in, or involving, the RIG-I (DDX58) gene and rubella-specific TNF-α secretion. This is the first paper to present evidence that polymorphisms in the TLR, vitamin A, vitamin D receptor, and innate immunity genes can influence adaptive cytokine responses to rubella vaccination.

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References

  • Arai H, Miyamoto KI, Yoshida M, Yamamoto H, Taketani Y, Morita K, Kubota M, Yoshida S, Ikeda M, Watabe F, Kanemasa Y, Takeda E (2001) The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene. J Bone Miner Res 16:1256–1264

    Article  PubMed  CAS  Google Scholar 

  • Bahl R, Bhandari N, Kant S, Molbak K, Ostergaard E, Bhan MK (2002) Effect of vitamin A administered at Expanded Program on Immunization contacts on antibody response to oral polio vaccine. Eur J Clin Nutr 56:321–325

    Article  PubMed  CAS  Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  PubMed  CAS  Google Scholar 

  • Benn CS, Balde A, George E, Kidd M, Whittle H, Lisse IM, Aaby P (2002) Effect of vitamin A supplementation on measles-specific antibody levels in Guinea-Bissau. Lancet 359:1313–1314

    Article  PubMed  CAS  Google Scholar 

  • Biacchesi S, LeBerre M, Lamoureux A, Louise Y, Lauret E, Boudinot P, Bremont M (2009) Mitochondrial antiviral signaling protein plays a major role in induction of the fish innate immune response against RNA and DNA Viruses. J Virol 83:7815–7827

    Article  PubMed  CAS  Google Scholar 

  • Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E (2006) Epidemic influenza and vitamin D. Epidemiol Infect 134:1129–1140

    Article  PubMed  CAS  Google Scholar 

  • Cantorna MT, Mahon BD (2005) D-hormone and the immune system. J Rheumatol Suppl 76:11–20

    PubMed  CAS  Google Scholar 

  • Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA (2004) Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 74:106–120

    Article  PubMed  CAS  Google Scholar 

  • Couper KN, Blount DG, Riley EM (2008) IL-10: the master regulator of immunity to infection. J Immunol 180:5771–5777

    PubMed  CAS  Google Scholar 

  • de la Torre MS, Torres C, Nieto G, Vergara S, Carrero AJ, Macias J, Pineda JA, Caruz A, Fibla J (2008) Vitamin D receptor gene haplotypes and susceptibility to HIV-1 infection in injection drug users. J Infect Dis 197:405–410

    Article  CAS  Google Scholar 

  • den Dunnen JT, Antonarakis SE (2001) Nomenclature for the description of human sequence variations. Hum Genet 109:121–124

    Article  CAS  Google Scholar 

  • Dhiman N, Ovsyannikova IG, Vierkant RA, Ryan JE, Pankratz VS, Jacobson RM, Poland GA (2008a) Associations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine: preliminary results. Vaccine 26:1731–1736

    Article  PubMed  CAS  Google Scholar 

  • Dhiman N, Ovsyannikova IG, Vierkant RA, Pankratz VS, Jacobson RM, Poland GA (2008b) Associations between cytokine/cytokine receptor SNPs and humoral immunity to measles, mumps and rubella in a Somali population. Tissue Antigens 72:211–220

    Article  PubMed  CAS  Google Scholar 

  • Dhiman N, Ovsyannikova IG, Cunningham JM, Vierkant RA, Kennedy RB, Pankratz VS, Poland GA, Jacobson RM (2007) Associations between measles vaccine immunity and single nucleotide polymorphisms in cytokine and cytokine receptor genes. J Infect Dis 195:21–29

    Article  PubMed  CAS  Google Scholar 

  • Eldin P, Papon L, Oteiza A, Brocchi E, Lawson TG, Mechti N (2009) TRIM22 E3 ubiquitin ligase activity is required to mediate antiviral activity against encephalomyocarditis virus. J GenVirol 90:536–545

    CAS  Google Scholar 

  • Geissmann F, Revy P, Brousse N, Lepelletier Y, Folli C, Durandy A, Chambon P, Dy M (2003) Retinoids regulate survival and antigen presentation by immature dendritic cells. J Exp Med 198:623–634

    Article  PubMed  CAS  Google Scholar 

  • Goldschmidt V, Bleiber G, May M, Martinez R, Ortiz M, Telenti A (2006) Role of common human TRIM5alpha variants in HIV-1 disease progression. Retrovirology 3:54

    Article  PubMed  CAS  Google Scholar 

  • Grenet J, Teitz T, Wei T, Valentine V, Kidd VJ (1999) Structure and chromosome localization of the human CASP8 gene. Gene 226:225–232

    Article  PubMed  CAS  Google Scholar 

  • Hope-Simpson RE (1981) The role of season in the epidemiology of influenza. J Hyg (London) 86:35–47

    CAS  Google Scholar 

  • Hu J, Sealfon SC, Hayot F, Jayaprakash C, Kumar M, Pendleton AC, Ganee A, Fernandez-Sesma A, Moran TM, Wetmur JG (2007) Chromosome-specific and noisy IFNB1 transcription in individual virus-infected human primary dendritic cells. Nucleic Acids Res 35:5232–5241

    Article  PubMed  CAS  Google Scholar 

  • Javanbakht H, An P, Gold B, Petersen DC, O’Huigin C, Nelson GW, O’Brien SJ, Kirk GD, Detels R, Buchbinder S, Donfield S, Shulenin S, Song B, Perron MJ, Stremlau M, Sodroski J, Dean M, Winkler C (2006) Effects of human TRIM5alpha polymorphisms on antiretroviral function and susceptibility to human immunodeficiency virus infection. Virology 354:15–27

    Article  PubMed  CAS  Google Scholar 

  • Jones SA (2005) Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol 175:3463–3468

    PubMed  CAS  Google Scholar 

  • Katze MG, Fornek JL, Palermo RE, Walters KA, Korth MJ (2008) Innate immune modulation by RNA viruses: emerging insights from functional genomics. Nat Rev Immunol 8:644–654

    Article  PubMed  CAS  Google Scholar 

  • Kishimoto T (2006) Interleukin-6: discovery of a pleiotropic cytokine. Arthritis Res Ther 8(Suppl 2):S2

    Article  PubMed  CAS  Google Scholar 

  • Ling C, Poulsen P, Simonsson S, Ronn T, Holmkvist J, Almgren P, Hagert P, Nilsson E, Mabey AG, Nilsson P, Vaag A, Groop L (2007) Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle. J Clin Invest 117:3427–3435

    Article  PubMed  CAS  Google Scholar 

  • Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311:1770–1773

    Article  PubMed  CAS  Google Scholar 

  • Loo YM, Fornek J, Crochet N, Bajwa G, Perwitasari O, Martinez-Sobrido L, Akira S, Gill MA, Garcia-Sastre A, Katze MG, Gale M Jr (2008) Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J Virol 82:335–345

    Article  PubMed  CAS  Google Scholar 

  • Mora RJ, Iwata M, Von Andrian UH (2008) Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 8:685–698

    Article  CAS  Google Scholar 

  • Mosmann TR (1991) Cytokine secretion patterns and cross-regulation of T cell subsets. Immunol Res 10:183–188

    Article  PubMed  CAS  Google Scholar 

  • Mosmann TR, Coffman RL (1989) Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol 46:111–147

    Article  PubMed  CAS  Google Scholar 

  • Ovsyannikova IG, Jacobson RM, Vierkant RA, Jacobsen SJ, Pankratz VS, Poland GA (2004) The contribution of HLA class I antigens in immune status following two doses of rubella vaccination. Hum Immunol 65:1506–1515

    Article  PubMed  CAS  Google Scholar 

  • Ovsyannikova IG, Ryan JE, Vierkant RA, O’Byrne MM, Jacobson RM, Poland GA (2009a) Influence of host genetic variation on rubella-specific T cell cytokine responses following rubella vaccination. Vaccine 27:3359–3366

    Article  PubMed  CAS  Google Scholar 

  • Ovsyannikova IG, Vierkant RA, Pankratz VS, O’Byrne MM, Jacobson RM, Poland GA (2009b) HLA haplotype and supertype associations with cellular immune responses and cytokine production in healthy children after rubella vaccine. Vaccine 27:3349–3358

    Article  PubMed  CAS  Google Scholar 

  • Pichlmair A, Schulz O, Tan CP, Naslund TI, Liljestrom P, Weber F, Reis e Sousa C (2006) RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314:997–1001

    Article  PubMed  CAS  Google Scholar 

  • Rahman MM, Mahalanabis D, Hossain S, Wahed MA, Alvarez JO, Siber GR, Thompson C, Santosham M, Fuchs GJ (1999) Simultaneous vitamin A administration at routine immunization contact enhances antibody response to diphtheria vaccine in infants younger than six months. J Nutr 129:2192–2195

    PubMed  CAS  Google Scholar 

  • Ryan JE, Ovsyannikova IG, Poland GA (2005) Detection of measles virus-specific IFN-gamma-secreting T-cells by ELISPOT. In: Kalyuzhyny AE (ed) Handbook of ELISPOT: methods and protocols. Humana Press Inc, Totowa, pp 207–217

    Google Scholar 

  • Sawyer SL, Wu LI, Akey JM, Emerman M, Malik HS (2006) High-frequency persistence of an impaired allele of the retroviral defense gene TRIM5alpha in humans. Curr Biol 16:95–100

    Article  PubMed  CAS  Google Scholar 

  • Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 70:425–434

    Article  PubMed  Google Scholar 

  • Schroder NW, Schumann RR (2005) Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis 5:156–164

    PubMed  Google Scholar 

  • Sewram S, Singh R, Kormuth E, Werner L, Mlisana K, Karim SS, Ndung’u T (2009) Human TRIM5alpha expression levels and reduced susceptibility to HIV-1 infection. J Infect Dis 199:1657–1663

    Article  PubMed  CAS  Google Scholar 

  • Smith AJ, Humphries SE (2009) Cytokine and cytokine receptor gene polymorphisms and their functionality. Cytokine Growth Factor Rev 20:43–59

    Article  PubMed  CAS  Google Scholar 

  • Sonderegger I, Iezzi G, Maier R, Schmitz N, Kurrer M, Kopf M (2008) GM-CSF mediates autoimmunity by enhancing IL-6-dependent Th17 cell development and survival. J Exp Med 205:2281–2294

    Article  PubMed  CAS  Google Scholar 

  • Speelmon EC, Livingston-Rosanoff D, Li SS, Vu Q, Bui J, Geraghty DE, Zhao LP, McElrath MJ (2006) Genetic association of the antiviral restriction factor TRIM5alpha with human immunodeficiency virus type 1 infection. J Virol 80:2463–2471

    Article  PubMed  CAS  Google Scholar 

  • van Manen D, Rits MA, Beugeling C, van Dort K, Schuitemaker H, Kootstra NA (2008) The effect of Trim5 polymorphisms on the clinical course of HIV-1 infection. PLoS Pathog 4:e18

    Article  PubMed  CAS  Google Scholar 

  • Villamor E, Fawzi WW (2005) Effects of vitamin a supplementation on immune responses and correlation with clinical outcomes. Clin Microbiol Rev 18:446–464

    Article  PubMed  CAS  Google Scholar 

  • Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-Mendoza L, Lin R, Hanrahan JW, Mader S, White JH (2004) Cutting edge: 1, 25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 173:2909–2912

    PubMed  CAS  Google Scholar 

  • Weir BS (1996) Genetic data Analysis II: methods for discrete population genetic data. Sinauer Associates, Inc., pp 98–99

  • Wetmur JG, Voho A, Ding Y, Ganee A, Kumar M, Pendleton A, Hu J (2007) A common polymorphism in the CARD domain of RIG-I modifies the innate iummune response of human dendritic cells. In: HUGO’s 12th annual genome meeting human genome meeting 2007 (Poster 18)

  • Yamamoto H, Miyamoto K, Li B, Taketani Y, Kitano M, Inoue Y, Morita K, Pike JW, Takeda E (1999) The caudal-related homeodomain protein Cdx-2 regulates vitamin D receptor gene expression in the small intestine. J Bone Miner Res 14:240–247

    Article  PubMed  CAS  Google Scholar 

  • Yoneyama M, Fujita T (2007) Function of RIG-I-like receptors in antiviral innate immunity. J Biol Chem 282:15315–15318

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank the Mayo Clinic Vaccine Research Group staff and subjects who participated in our studies. We thank V. Shane Pankratz and Tiffany J. Phan for their assistance with this manuscript. This work was supported by NIH grants AI 48793, AI 33144 and 5UL1RR024150-03 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health, and the NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Dr. Poland is the chair of a safety evaluation committee for novel non-rubella vaccines undergoing clinical studies by Merck Research Laboratories. Dr. Jacobson serves on a Safety Review Committee for a post-licensure study of Gardasil for Kaiser-Permanente.

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Authors and Affiliations

  1. Mayo Vaccine Research Group, Mayo Clinic, Guggenheim 611C, 200 1st Street S.W., Rochester, MN, 55905, USA

    Inna G. Ovsyannikova, Neelam Dhiman, Iana H. Haralambieva, Robert M. Jacobson & Gregory A. Poland

  2. Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, 55905, USA

    Robert M. Jacobson

  3. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA

    Robert A. Vierkant & Megan M. O’Byrne

  4. Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, MN, 55905, USA

    Inna G. Ovsyannikova & Gregory A. Poland

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  1. Inna G. Ovsyannikova
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  2. Neelam Dhiman
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  3. Iana H. Haralambieva
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  4. Robert A. Vierkant
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Correspondence to Gregory A. Poland.

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Ovsyannikova, I.G., Dhiman, N., Haralambieva, I.H. et al. Rubella vaccine-induced cellular immunity: evidence of associations with polymorphisms in the Toll-like, vitamin A and D receptors, and innate immune response genes. Hum Genet 127, 207–221 (2010). https://doi.org/10.1007/s00439-009-0763-1

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