The role of the HLA-G gene and its expression in the genesis of recurrent miscarriage

Abstract

This review summarizes the results of modern foreign and domestic clinical studies that provide information on the importance of the main histocompatibility complex (HLA), in general, and the expression of non-classical HLA-G molecules on trophoblast cells, in particular, in the physiological course of early pregnancy. The HLA-G gene has central functions in the processing and presentation of antigen and inhibits the receptor of NK cells, which leads to a decrease in the immune response at the fetal-maternal interface and provides immune tolerance to the fetus from the maternal body. HLA-G expression is dependent on combinations of transcription factors, miRNAs, and environmental factors. Based on this, more than a hundred studies have been put into clarifying how HLA-G expression influences the development of pregnancy complications, such as recurrent pregnancy losses, in which immunological factors are believed to play a crucial role.

Keywords

HLA-G / pregnancy / miscarriage / recurrent pregnancy loss / reproductive loss

References

[1] Djurisic S, Hviid TV. HLA Class Ib molecules and immune cells in pregnancy and preeclampsia. Front Immunol. 2014;5:652. DOI: 10.3389/fimmu.2014.00652

[2] Djurisic S., Hviid T.V. HLA Class Ib molecules and immune cells in pregnancy and preeclampsia // Front. Immunol. 2014. Vol. 5. P. 652. DOI: 10.3389/fimmu.2014.00652

[3] Bakleicheva MO, Bespalova ON, Ivashchenko TE. Role of class I HLA (G, E, and C) expression in early reproductive losses. Obstetrics and Gynecology. 2020;(2):30−36. (In Russ.). DOI: 10.18565/aig.2020.2.30-36

[4] Баклейчева М.О., Беспалова О.Н., Иващенко Т.Э. Роль экспрессии HLA I класса (G, E и C) в ранних репродуктивных потерях // Акушерство и гинекология. 2020. № 2. С. 30−36. DOI: 10.18565/aig.2020.2.30-36

[5] Carosella ED, Ploussard G, LeMaoult J, Desgrandchamps F. A systematic review of immunotherapy in urologic cancer: Evolving roles for targeting of CTLA-PD-1/PD-L1, and HLA-G. Eur Urol. 2015;68(2):267−279. DOI: 10.1016/j.eururo.2015.02.032

[6] Carosella E.D., Ploussard G., LeMaoult J., Desgrandchamps F. A systematic review of immunotherapy in urologic cancer: Evolving roles for targeting of CTLA-PD-1/PD-L1, and HLA-G // Eur. Urol. 2015. Vol. 68. No. 2. P. 267−279. DOI: 10.1016/j.eururo.2015.02.032

[7] Szekeres-Bartho J, Markert UR, Varla-Leftherioti M. Immunology in reproduction. J Reprod Immunol. 2015;108:1. DOI: 10.1016/j.jri.2015.03.003

[8] Szekeres-Bartho J., Markert U.R., Varla-Leftherioti M. Immunology in reproduction // J. Reprod. Immunol. 2015. Vol. 108. P. 1. DOI: 10.1016/j.jri.2015.03.003

[9] de Wynter EA, Testa NG. Interest of cord blood stem cells. Biomed Pharmacother. 2001;55(4):195−200. DOI: 10.1016/s0753-3322(01)00049-x

[10] de Wynter E.A., Testa N.G. Interest of cord blood stem cells // Biomed. Pharmacother. 2001. Vol. 55. No. 4. P. 195−200. DOI: 10.1016/s0753-3322(01)00049-x

[11] Serova LD. Immunologicheskij HLA-status u zhenshhin s privychnym nevynashivaniem beremennosti: metodicheskie rekomendacii. Moscow, 1998. (In Russ.)

[12] Серова Л.Д. Иммунологический HLA-статус у женщин с привычным невынашиванием беременности: методические рекомендации. Москва, 1998.

[13] Steinbrook R. The cord-blood-bank controversies. N Engl J Med. 2004;351(22):2255−2257. DOI: 10.1056/NEJMp048283

[14] Steinbrook R. The cord-blood-bank controversies // N. Engl. J. Med. 2004. Vol. 351. No. 22. P. 2255−2257. DOI: 10.1056/NEJMp048283

[15] Ferreira LMR, Meissner TB, Tilburgs T, Strominger JL. HLA-G: At the interface of maternal-fetal tolerance. Trends Immunol. 2017;38:272–286. DOI: 10.1016/j.it.2017.01.009

[16] Ferreira L.M.R., Meissner T.B., Tilburgs T., Strominger J.L. HLA-G: At the interface of maternal-fetal tolerance // Trends Immunol. 2017. Vol. 38. P. 272–286. DOI: 10.1016/j.it.2017.01.009

[17] Choudhury SR, Knapp LA. Human reproductive failure II: immunogenetic and interacting factors. Hum Reprod Update. 2001;7(2):135−160. DOI: 10.1093/humupd/7.2.135

[18] Choudhury S.R., Knapp L.A. Human reproductive failure II: immunogenetic and interacting factors // Hum. Reprod. Update. 2001. Vol. 7. No. 2. P. 135−160. DOI: 10.1093/humupd/7.2.135

[19] Lorentzen DF, Iwanaga KK, Meuer KJ, et al. A 25% error rate in serologic typing of HLA-B homozygotes. Tissue Antigens. 1997;50(4):359−365. DOI: 10.1111/j.1399-0039.1997.tb02888.x

[20] Lorentzen D.F., Iwanaga K.K., Meuer K.J. et al. A 25% error rate in serologic typing of HLA-B homozygotes // Tissue Antigens. 1997. Vol. 50. No. 4. P. 359−365. DOI: 10.1111/j.1399-0039.1997.tb02888.x

[21] Komlos L, Zamir R, Joshua H, Halbrecht I. Common HLA antigens in couples with repeated abortions. Clin Immunol Immunopathol. 1977;7(3):330−335. DOI: 10.1016/0090-1229(77)90066-6

[22] Komlos L., Zamir R., Joshua H., Halbrecht I. Common HLA antigens in couples with repeated abortions // Clin. Immunol. Immunopathol. 1977. Vol. 7. No. 3. P. 330−335. DOI: 10.1016/0090-1229(77)90066-6

[23] Christiansen OB, Ring M, Rosgaard A, et al. Association between HLA-DR1 and -DR3 antigens and unexplained repeated miscarriage. Hum Reprod Update. 1999;5(3):249−255. DOI: 10.1093/humupd/5.3.249

[24] Christiansen O.B., Ring M., Rosgaard A. et al. Association between HLA-DR1 and -DR3 antigens and unexplained repeated miscarriage // Hum. Reprod. Update. 1999. Vol. 5. No. 3. P. 249−255. DOI: 10.1093/humupd/5.3.249

[25] Dahl M, Klitkou L, Christiansen OB, et al. Human leukocyte antigen (HLA)-G during pregnancy part II: associations between maternal and fetal HLA-G genotypes and soluble HLA-G. Hum Immunol. 2015;76(4):260−271. DOI: 10.1016/j.humimm.2015.01.015

[26] Dahl M., Klitkou L., Christiansen O.B. et al. Human leukocyte antigen (HLA)-G during pregnancy part II: associations between maternal and fetal HLA-G genotypes and soluble HLA-G // Hum. Immunol. 2015. Vol. 76. No. 4. P. 260−271. DOI: 10.1016/j.humimm.2015.01.015

[27] Plaks V, Rinkenberger J, Dai J, et al. Matrix metalloproteinase-9 deficiency phenocopies features of preeclampsia and intrauterine growth restriction. Proc Natl Acad Sci USA. 2013;110(27):11109−11114. DOI: 10.1073/pnas.1309561110

[28] Plaks V., Rinkenberger J., Dai J. et al. Matrix metalloproteinase-9 deficiency phenocopies features of preeclampsia and intrauterine growth restriction // Proc. Natl. Acad. Sci. USA. 2013. Vol. 110. No. 27. P. 11109−11114. DOI: 10.1073/pnas.1309561110

[29] Zidi I, Rizzo R, Bouaziz A, et al. sHLA-G1 and HLA-G5 levels are decreased in Tunisian women with multiple abortion. Hum Immunol. 2016;77:342–345. DOI: 10.1016/j.humimm.2016.01.019

[30] Zidi I., Rizzo R., Bouaziz A. et al. sHLA-G1 and HLA-G5 levels are decreased in Tunisian women with multiple abortion // Hum. Immunol. 2016. Vol. 77. P. 342–345. DOI: 10.1016/j.humimm.2016.01.019

[31] Ikeno M, Suzuki N, Kamiya M, et al. LINE1 family member is negative regulator of HLA-G expression. Nucleic Acids Res. 2012;40(21):10742−10752. DOI: 10.1093/nar/gks874

[32] Ikeno M., Suzuki N., Kamiya M. et al. LINE1 family member is negative regulator of HLA-G expression // Nucleic Acids Res. 2012. Vol. 40. No. 21. P. 10742−10752. DOI: 10.1093/nar/gks874

[33] Bespalova O, Bakleicheva M, Ivashchenko T, et al. Expression of HLA-G and KIR2DL4 receptor in chorionic villous in missed abortion. Gynecol Endocrinol. 2020;36(Supp1):43−47. DOI: 10.1080/09513590.2020.1816716

[34] Bespalova O., Bakleicheva M., Ivashchenko T. et al. Expression of HLA-G and KIR2DL4 receptor in chorionic villous in missed abortion // Gynecol. Endocrinol. 2020. Vol. 36. No. 1 (Supl.). P. 43−47. DOI: 10.1080/09513590.2020.1816716

[35] Akhter A, Das V, Naik S, et al. Upregulation of HLA-G in JEG-3 cells by dexamethasone and hydrocortisone. Arch Gynecol Obstet. 2012;285(1):7−14. DOI: 10.1007/s00404-011-1880-3

[36] Akhter A., Das V., Naik S. et al. Upregulation of HLA-G in JEG-3 cells by dexamethasone and hydrocortisone // Arch. Gynecol. Obstet. 2012. Vol. 285. No. 1. P. 7−14. DOI: 10.1007/s00404-011-1880-3

[37] Barrientos G, Toro A, Moschansky P, et al. Leptin promotes HLA-G expression on placental trophoblasts via the MEK/Erk and PI3K signaling pathways. Placenta. 2015;36(4):419−426. DOI: 10.1016/j.placenta.2015.01.006

[38] Barrientos G., Toro A., Moschansky P. et al. Leptin promotes HLA-G expression on placental trophoblasts via the MEK/Erk and PI3K signaling pathways // Placenta. 2015. Vol. 36. No. 4. P. 419−426. DOI: 10.1016/j.placenta.2015.01.006

[39] Gregori S, Amodio G, Quattrone F, Panina-Bordignon P. HLA-G Orchestrates the early interaction of human trophoblasts with the maternal niche. Front Immunol. 2015;6:128. DOI: 10.3389/fimmu.2015. 00128

[40] Gregori S., Amodio G., Quattrone F., Panina-Bordignon P. HLA-G Orchestrates the early interaction of human trophoblasts with the maternal niche // Front. Immunol. 2015. Vol. 6. P. 128. DOI: 10.3389/fimmu.2015.00128

[41] Wang X, Li B, Wang J, et al. Evidence that miR-133a causes recurrent spontaneous abortion by reducing HLA-G expression. Reprod Biomed Online. 2012;25(4):415−424. DOI: 10.1016/j.rbmo.2012.06.022

[42] Wang X., Li B., Wang J. et al. Evidence that miR-133a causes recurrent spontaneous abortion by reducing HLA-G expression // Reprod. Biomed. Online. 2012. Vol. 25. No. 4. P. 415−424. DOI: 10.1016/j.rbmo.2012.06.022

[43] Wu ZS, Wang CQ, Xiang R, et al. Loss of miR-133a expression associated with poor survival of breast cancer and restoration of miR-133a expression inhibited breast cancer cell growth and invasion. BMC Cancer. 2012;12:51. DOI: 10.1186/1471-2407-12-51

[44] Wu Z.S., Wang C.Q., Xiang R. et al. Loss of miR-133a expression associated with poor survival of breast cancer and restoration of miR-133a expression inhibited breast cancer cell growth and invasion // BMC Cancer. 2012. Vol. 12. P. 51. DOI: 10.1186/1471-2407-12-51

[45] Guo W, Fang L, Li B, et al. Decreased human leukocyte antigen-G expression by miR-133a contributes to impairment of proinvasion and proangiogenesis functions of decidual NK cells. Front Immunol. 2017;8:741. DOI: 10.3389/fimmu.2017.00741

[46] Guo W., Fang L., Li B. et al. Decreased human leukocyte antigen-G expression by miR-133a contributes to impairment of proinvasion and proangiogenesis functions of decidual NK cells // Front. Immunol. 2017. Vol. 8. P. 741. DOI: 10.3389/fimmu.2017.00741

[47] Rokhafrooz S, Ghadiri A, Ghandil P, et al. Association between HLA-G 14bp gene polymorphism and serum sHLA-G protein concentrations in preeclamptic patients and normal pregnant women. Immunol Invest. 2018;47:558–568. DOI: 10.1080/08820139.2018.1467925

[48] Rokhafrooz S., Ghadiri A., Ghandil P. et al. Association between HLA-G 14bp gene polymorphism and serum sHLA-G protein concentrations in preeclamptic patients and normal pregnant women // Immunol. Invest. 2018. Vol. 47. P. 558–568. DOI: 10.1080/08820139.2018.1467925

[49] Alenichev AS, Nasyhova JuA, Ivashhenko EJe, Baranov VS. Harakteristika geneticheskoj struktury populjacii Severo-Zapadnogo regiona RF po genu HLA-G. Jekologicheskaja genetika. 2014;12(2):74−80. (In Russ.)

[50] Аленичев А.С., Насыхова Ю.А., Иващенко Е.Э., Баранов В.С. Характеристика генетической структуры популяции Северо-Западного региона РФ по гену HLA-G // Экологическая генетика. 2014. Т. 12. № 2. С. 74−80.

RIGHTS & PERMISSIONS

Eсо-Vector