ANALYSIS OF ASSOCIATIONS BETWEEN PROMOTER ALLELES OF TNFA, IL2. IL4 AND IL10, AND PARAMETERS OF IMMUNE SYSTEM IN HIV-INFECTED PATIENTS

Abstract. Establishment of basic processes leading to differences in immune response at genetic level occurs in the course of studying associations between certain polymorphic alleles, as well as evaluation of correlations between the haplotypes of cytokine genes, and specific protein production in vitro. The features of association between main parameters of humoral and cellular immunity, as well as levels of pro-inflammatory (TNFA и IL2) and anti-inflammatory (IL4 и IL10) cytokines with allelic variants of promoter regions of the mentioned genes were analyzed in HIV-infected patients, as compared with healthy Russian population of Caucasoid origin. In present work, we have performed genotyping, along with evaluation of humoral and cellular immunity, in 127 HIV-infected patients, and 52 donors served as a control group. To determine spontaneous and ConA-stimulated cytokine production in some patients, ELISA technique was used for assays with conditioned media from mononuclear cells. From the data obtained one may be inferred, that 308А TNFA, -330Т IL2, -592А IL10 alleles are more characteristic to the HIV-infected patients with decreased cellular pro-inflammatory component of immunity, and increased activity of B-cell immunity, in comparison with persons carrying other gene variants. In general, it should be stressed that the mentioned genes variants may determine general susceptibility for more severe course of disease, exerting some pleiotropic action upon some pathogenetically important parameters of HIV.

1. Иммунодефицитные состояния / под ред. проф. Смирнова В.С., Фрейдлин И.С. - СПб: Фолиант, 2000. - С.411-447.

2. Кетлинский С.А., Симбирцев А.С., Воробьев А.А. Эндогенные иммуномодуляторы. - СПб: Гиппократ, 1992.- 256 с.

3. Смольникова М.В., Прокофьев В.Ф., Сизякина Л.П., Шемшура А.Б., Ольховский И.А., Коненков В.И. Аллельные варианты генов IL-4, IL-10 и TNFα при ВИЧ инфекции // Цитокины и воспаление. - 2002. - T.1. - N1. - C.35-39.

4. Ярилин А.А. Система цитокинов и принципы ее функционирования в норме и при патологии // Иммунология. - 1997. - N5. - С. 7-14.

5. Ameisen J.C., Capron A. Cell dysfunction and depletion in AIDS: the programmed cell death hypothesis // Immunol. Today.- 1991.- V.12(4).- P.102-105.

6. Bidwell J., Keen L., Gallageher G., Kimberly R., Huizinga T., McDermott M.F., Oksenberg J., McNicholl J., Pociot F., Hardt C., D’Alfonso S. Cytokine gene polymorphism in human disease: on-line databases // Genes Immun. - 1999. - V.1. - P. 3-19.

7. Butera S.T. Cytokine involvement in viral permissiveness and the progression of HIV disease // J. Cell Biochem. - 1994. - N53. - P. 336-342.

8. Digeon M., Laver M., Riza J., Bach J.F. Detection of circulating immune complexes in human sera by simplified assays with polyethylene glycol // J. Immunol. Methods. - 1977. – V.16. - P. 165-183.

9. Foli A., Saville M.W., Baseler M.W., Yarchoan R. Effects of the Th1 and Th2 stimulatory cytokines interleukin-12 and interleukin-4 on human immunodeficiency virus replication // Blood. -1995. - V.85(8). - P.2114-2123.

10. Gandhi R., Chen B., Straus S., Dale J.K., Lenardo M.J., Baltimore D. HIV-1 directly kills CD4 T cells by a Fas-independent mechanism // J. Exp. Med.- 1998. - V.187(7). - P.1113-1122.

11. Hutchinson I.V., Pravica V., Hajeer A., Sinnott P.J. Identification of high and low responders to allografts // Rev Immunogenetics. –1999.-V.1.-P.323-333.

12. Koss K., Satsangi J., Fanning G.C., Welsh K.I., Jewell D.P. Cytokine (TNFα, LT-α and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies // Gen. Immun. - 2000. - V.1. - P. 185-190.

13. Luxton R.W., Thompson E.J. Affinity distributions of antigen-specific IgG in patients with multiple sclerosis and in patients with viral encephalitis // J. Immunol. Methods. – 1990. – V.131(2). - P. 277-282.

14. Marsh D.G., Neely J.D., Breazeale D.R., Ghosh B., Freidhoff L.R., Ehrlich-Kautzky E., Schou C., Krishnaswamy G., Beaty T.H. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentration // Science. – 1994. – V. 264. – P. 1152-1156.

15. Naif H., Ho-Shon M., Chang J., Cunningham A.L. Molecular mechanisms of IL-4 effect on HIV expression in promonocytic cell linesand primary human monocytes // J. Leukoc. Biol. – 1994. - V.56(3) - P.335-339.

16. Pociot F., Wilson A.G., Nerup J., Duff G.W. No independent association between a TNF-α promoter region polymorphism and insulin-dependent diabetes mellitus // Eur. J. Immunol . - 1993. – V.23. - P. 3043-3049.

17. Pravica V., Asderakis A., Perrey C., Hajeer A., Sinnott P.J., Hutchinson I.V. In vitro production of IFN-γ correlates with CA repeat polymorphism in the human IFN-γ gene // Eur. J. of Immunogenetics. – 1999. - V.26. - P.1-3.

18. Reynard M.P., Turner D., Navarrete C.V. Allele frequencies of polymorphisms of the tumour necrosis factor-α, interleukin-10, interferon-γ and interleukin-2 genes in a North European Caucasoid group from the UK // Eur. J. Immunogenetics. - 2000. - V.27. - P. 241-249.

19. Sennikov S.V., Krysov S.V., Injelevskaya T.V., Silkov A.N., Grishina L.V., Kozlov V.A. Quantitative analysis of human immunoregulatory cytokines by electrochemiluminescence method // J. Immunol. Methods. – 2003. – V.275(1-2). – P.81-88.

20. Shin H.D., Winkler C., Stephens J.C., Bream J., Young H., Goedert J.J., O’Brien T.R., Vlahov D., Buchbinder S., Giorgi J., Rinaldo C., Donfield S., Willoughby A., O’Brien S.J., Smith M.W. Genetic restriction of HIV-1 pathogenesis to AIDS by promoter alleles of IL10 // PNAS. - 2000. -V.97(26). - P. 14467-14472.

21. Smolnikova M.V., Konenkov V.I. Association of IL2, TNFA, IL4 and IL10 promoter gene polymorphisms with rate of the HIV-infection progression // Russian. J. Immunology. - 2002. - V. 7(4). - P. 349-356.