REGULATION OF PERIPHERAL B-LYMPHOCYTE DIFFERENTIATION IN RECURRENT MISCARRIAGE

The important role of immune disorders in recurrent miscarriage has been proven. Clarification of the character of B-lymphocyte differentiation and its regulation factors in women with threatened miscarriage and recurrent miscarriage in history is an urgent problem, since it will reveal the immune mechanisms of the pathogenesis of this pathology. Purpose: to establish the features of B-lymphocyte differentiation and factors of its regulation in women with a history of recurrent miscarriage and threatening spontaneous miscarriage at the time of examination.

Were examined pregnant women aged 18-40 years at a gestation period of 5-12 weeks. The main group consisted of 60 pregnant women with a threatening spontaneous miscarriage at the time of examination and a history of recurrent miscarriage. As a control, 35 pregnant women with uncomplicated pregnancy were examined. The comparison group consisted of 25 primary pregnant women with threatened spontaneous miscarriage at the time of examination. The material for the study was peripheral venous blood. Subpopulations of B-lymphocytes CD19⁺, CD19⁺ IgD⁺, CD20⁺IgM⁺, CD20⁺IgG⁺ were determined by flow cytometry; CD19⁺CD20^- CD38⁺, CD19⁺CD27^- , CD19⁺CD27⁺. Serum levels of BAFF and APRIL were assessed by enzyme-linked immunosorbent assay.

In the main group, an increase in the proportion of B-cells, CD20⁺IgM⁺-lymphocytes and memory cells was recorded in the peripheral blood, along with a decrease in the level of naive cells and plasma cells. In the comparison group, an increase in the proportion of immature IgM⁺B-cells, circulating memory cells, along with a decrease in naive B-lymphocytes, was registered. in the main group there was a pronounced decrease in the serum BAFF level compared with the control and comparison groups. Analysis of the APRIL content showed a pronounced downward trend in groups with threatened miscarriage relative to healthy pregnant women. Thus, threatening habitual and sporadic miscarriages were associated with a shift in the differentiation of B-lymphocytes towards immature forms and a lack of regulatory influence of BAFF and APRIL, which is reflected in the disruption of B-cell homeostasis and weakening of humoral effector mechanisms at the systemic level. The revealed changes may indicate a single mechanism for the development of a threatening spontaneous miscarriage, the severity of which increases with repeated loss of pregnancy. These changes can lead to an increase in effector cytotoxic mechanisms and an increase in proinflammatory cytokines, which can lead to the development of damaging reactions in the fetoplacental complex, which can be reflected in the clinical picture of the threat of termination of pregnancy. 

1. Agnaeva A.O., Bespalova O.N., Sokolov D.I., Selkov S.A., Kogan I.Yu. Role of natural killer cells in reproductive failure. Journal of Obstetrics and Women’s Diseases, 2017, Vol. 66, no. 3, pp. 143-156. (In Russ.)

2. Batrak N.V., Malyshkina A.I., Sotnikova N.Yu., Kroshkina N.V. The role of CD178+ mononuclear cells in the development of threatened late abortion in women with first-trimester threatened pregnancy interruption and a history of recurrent miscarriage. Obstetrics and Gynecology, 2020, no. 5. doi: 10.18565/aig.2020.5.70-77.

3. Baturina I.L., Markova V.A., Loginova Yu.V., Orner I.Yu., Zotova M.A., Nikonova T.I., Emel’yanov I.V., Koh E.V. Advanced analysis of B cells in patients with recurrent miscarriage. Russian Journal of Immunology, 2016, Vol. 10 (19), no. 3, pp. 219-220. (In Russ.)

4. Darmochwal-Kolarz D., Leszczynska-Gorzelak B., Rolinski J., Oleszczuk J. The immunophenotype of patients with recurrent pregnancy loss. Eur. J. Obstet. Gynecol. Reprod. Biol., 2002, Vol. 103, no. 1, pp. 53-57.

5. Fehres C.M., van Uden N.O., Yeremenko N.G., Fernandez L., Franco Salinas G., van Duivenvoorde L.M., Huard B., Morel J., Spits H., Hahne M., Baeten D.L.P. APRIL induces a novel subset of IgA+ regulatory B cells that suppress inflammation via expression of IL-10 and PD-L1. Front. Immunol., 2019, Vol. 14, no. 10, 1368. doi: 10.3389/fimmu.2019.01368.

6. Frolova M.V. The character of BAFF production and reception during pregnancy complicated intrauterine growthretardation. Russian Journal of Immunology, 2016, Vol. 10 (19), no. 2 (1), pp. 215-216. (In Russ.)

7. Gu J., Lei Y., Huang Y., Zhao Y., Li J., Huang T., Zhang J., Wang J., Deng X., Chen Z., Korteweg C., Deng R., Yan M., Xu Q., Dong S., Cai M., Luo L., Huang G., Wang Y., Li Q., Lin C., Su M., Yang C., Zhuang Z. Fab fragment glycosylated IgG may play a central role in placental immune evasion. Hum. Reprod., 2015, Vol. 30, no. 2, pp. 380-391.

8. Guo W.J., Qu X., Yang M.X. Expression of BAFF in the trophoblast and decidua of normal early pregnant women and patients with recurrent spontaneous miscarriage. Chin. Med. J., 2008, Vol. 121, no. 4, pp. 309-315.

9. Hu S., Wang R., Zhang M. BAFF promotes T cell activation through the BAFF-BAFF-R-PI3K-Akt signaling pathway. Biomed. Pharmacother., 2019, Vol. 114, 108796. doi: 10.1016/j.biopha.2019.108796.

10. Lima J., Cambridge,G., Vilas-Boas A., Martins C., Borrego L.M., Leandro M. Serum markers of B-cell activation in pregnancy during late gestation, delivery, and the postpartum period. Am. J. Reprod. Immunol., 2019, Vol. 81, no. 3, e13090. doi: 10.1111/aji.13090.

11. Lushova A.A., Zheremyan E.A., Astakhova E.A., Spiridonova A.B., Byazrova M.G., Filatov A.V. B-lymphocyte subsets: functions and molecular markers. Immunology, 2019, Vol. 40, no. 6, pp. 63-76. (In Russ.)

12. Matsuda Y., Haneda M., Kadomatsu K., Kobayashi T. A proliferation-inducing ligand sustains the proliferation of human naïve (CD27- ) B cells and mediates their differentiation into long-lived plasma cells in vitro via transmembrane activator and calcium modulator and cyclophilin ligand interactor and B-cell mature antigen. Cell. Immunol., 2015, Vol. 295, no. 2, pp. 127-136.

13. Samy E., Wax S., Huard B., Hess H., Schneider P. Targeting BAFF and APRIL in systemic lupus erythematosus and other antibody-associated diseases. Int. Rev. Immunol., 2017, Vol. 36, no. 1, pp. 3-19.

14. Xu J., Luo X., Qu S., Yang G., Shen N. B cell activation factor (BAFF) induces inflammation in the human fallopian tube leading to tubal pregnancy. BMC Pregnancy Childbirth, 2019, Vol. 19, no. 1, 169. doi: 10.1186/s12884-019-2324-5.