IDENTIFICATION OF HLA II CLASS GENE ASSOCIATIONS OF THE MAIN HISTOCOMPATIBILITY COMPLEX WITH PECULIARITIES OF IMMUNE RESPONSE IN PERSONS VACCINATED WITH LIVE PLAGUE VACCINE IN THE REPUBLIC OF KALMYKIA

Objective of the study was to determine allelic variants of HLA II class haplotypes in persons living in the Republic of Kalmykia in the territory of Pre-Caspian sandy natural focus of the plague, immunized for epidemic reasons with live plague vaccine and search for associations of HLA class II haplotypes with peculiarities of post-vaccinal immunity development.

Materials and methods. 20 individuals took part in the study. HLA typing was performed applying multiplex PCR. Production of immune-regulatory cytokines and antibody titers to fraction 1 of the plague microbe was determined using enzyme immunoassay. Statistical processing of the results was carried out using standard programs.

Results and conclusions. Allelic variants of haplotypes HLA-DQA1, HLA-DQB1 and HLA-DRB1 class II of the main histocompatibility complex of 20 persons residing in Lagansky and Chernozemelsky districts of the Republic of Kalmykia have been identified. Determined have been the differences in the ratio of allelic variants of HLA-DQA1 and cytokine production INF-γ, TNF-α, IL-4 and IL-10 by the areas of residence. Association of the HLA-DRB1*01 allele with a high level of spontaneous and induced IL-10 cytokine production has been revealed at various times after booster vaccination. Further study of genes that regulate the development of immunity, along with immunological methods will make it possible to personalize the use of the existing vaccine against plague, and predict the immunogenicity and effectiveness of preventive drugs under development. 

1. Zverev V.V., Semenov B.F., Khaitov R.M., editors. [Vaccines and Vaccination: National Guidelines]. M.: “Geotar-Media”; 2011. 880 p.

2. Shchukovskaya T.N., Smol’kova E.A., Shmel’kova T.P., Klyueva S.N., Bugorkova S.A. [Induced production of IFNγ and IL-4 as an index of functional activity of Th1- and Th2-cells in persons vaccinated against plague]. Epidemiol. Vaktsinoprofilakt. 2011; 6(61): 78–83.

3. Barreiro L.B., Quintana-Murci L. From evolutionary genetics to human immunology: how selection shapes host defence genes. Nat. Rev. Genet. 2010; 11:17–30. DOI: 10.1038/nrg2698.

4. Cardozo D.M., Marangon A.V., Sell A.M., Visentainer L.J.E., de Souza C.A. HLA and Infectious Diseases. In: Yongzhi Xi, editor. HLA and Associated Important Diseases. InTech; 2014. Available from: https://www.intechopen.com/books/hla-and-associated-important-diseases/hla-and-infectious-diseases. DOI: 10.5772/57496.

5. Castiblanco J., Anaya J.M. Genetics and vaccines in the era of per- sonalized medicine. Curr. Genomics. 2015; 16(1):47–59. DOI: 10.2174/1389202916666141223220551.

6. Guis S., Pellissier J.F., Nicoli F., Reviron D., Mattei J.P., Gherardi R.K., Pelletier J., Kaplanski G., Figarella-Branger D., Roudier J. HLADRB1*01 and macrophagic myofasciitis. Arthritis Rheumatism. 2002; 46(9):2535–7. DOI: 10.1002/art.10465.

7. Matzaraki V., Kumar V., Wijmenga C., Zhernakova A. The MHC locus and genetic susceptibility to autoimmune and infectious iseases. Genome Biology. 2017; 18(1):76. DOI: 10.1186/s13059-017-1207-1.

8. Musson J.A., Ingram R., Durand G., Ascough St., Waters E.L., Hartley M.G., Robson T., Maillere B. Repertoire of HLA-DR1-Restricted CD4 T-Cell Responses to Capsular Caf1 Antigen of Yersinia pestis in Human Leukocyte Antigen Transgenic Mice. Infect. Immun. 2010; 78(10):4356–62. DOI:10.1128/IAI.00195-10.

9. Ovsyannikova I.G., Pankratz V.S., Vierkant R.A., Pajewski N.M., Quinn C.P., Kaslow R.A., Jacobson R.M., Poland G.A. Human leukocyte antigens and cellular immune responses to anthrax vaccine adsorbed. Infect. Immun. 2013; 81(7):2584–91. DOI: 10.1128/IAI.00269-13.

10. Ovsyannikova I.G., Poland G.A. Vaccinomics: current findings, challenges and novel approaches for vaccine development. AAPS J. 2011; 13(3):438–44. DOI: 10.1208/s12248-011-9281-x.

11. Poland G.A., Ovsyannikova I.G., Jacobson R.M., Smith D.I. Heterogeneity in vaccine immune response: the role of immunogenetics and the emerging field of vaccinomics. Clin. Pharmacol. Therap. 2007; 82(6):653–64. DOI: 10.1038/sj.clpt.6100415.

12. Reviron D., Foutrier C., Guis S., Mercier P., Roudier J. DRB1 alleles in polymyalgia rheumatica and rheumatoid arthritis in southern France. Eur. J. Immunogenet. 2001; 28(1):83–7.

13. Tan P.L., Jacobson R.M., Poland G.A., Jacobsen S.J., Pankratz V.S. Twin studies of immunogenicity-determining the genetic contribution to vaccine failure. Vaccine. 2001; 19(17–19): 2434–9. DOI: 10.1016/S0264410X(00)00468-0.

14. Trowsdale J., Knight J.C., Major histocompatibility complex genomics and human disease. Annu. Rev. Genomics Hum. Genet. 2013; 14:301–23. DOI: 10.1146/annurev-genom-091212-153455.

15. Zvi A., Rotem S., Zauberman A., Elia U., Aftalion M., Bar-Haim E., Mamroud E., Cohen O. Novel CTL epitopes identified through a Y. pestis proteome-wide analysis in the search for vaccine candidates against plague. Vaccine. 2017 Jun 9. pii: S0264-410X(17)30762-4. DOI: 10.1016/j. vaccine.2017.05.092. [Epub ahead of print].