Russian Journal of BiotherapyRussian Journal of BiotherapyРоссийский биотерапевтический журнал1726-97841726-9792Publishing House ABV Press112810.17650/1726-9784-2018-17-4-64-70ORIGINAL REPORTSОРИГИНАЛЬНЫЕ СТАТЬИThe role of B-1 lymphocytes in antitumor immunity in patients with gastric cancerКлючевая роль популяций в1-лимфоцитов в иммунном ответе у больных раком желудкаhttps://orcid.org/0000-0003-4412-5019ChulkovaS. V.ЧулковаС. В.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478,

1 Ostrovitianov St., Moscow 117997

115478 Москва, Каширское шоссе, 24

117997 Москва, ул. Островитянова, 1

Светлана Васильевна Чулкова 

chulkova@mail.ruSholokhovaE. N.ШолоховаЕ. Н.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-7515-8182GrishchenkoN. V.ГрищенкоН. В.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

RyabchikovD. A.РябчиковД. А.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

GrivtsovaL. Y.ГривцоваЛ. Ю.
Russian Federation

10 Marshal Zhukov St., Obninsk, Kaluga region, 249031

249031 Калужская область,Обнинск, ул. Маршала Жукова, 10

BazinI. S.БазинИ. С.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0003-3966-128XTupitsynN. N.ТупицынН. Н.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «НМИЦ онкологии им. Н.Н. Блохина» Минздрава РоссииPirogov Russian National Research Medical UniversityФГБОУ ВО «РНИМУ им. Н.И. Пирогова» Минздрава РоссииA. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian FederationМРНЦ им. А.Ф. Цыба – филиал ФГБУ «НМИЦ радиологии» Минздрава России11122018174647010012019100120192018https://bioterapevt.abvpress.ru/jour/article/view/1128

Introduction. B1-lymphocytes are a subpopulation of B-cells, the proportion of which in the spleen accounts for 5 % of the total number of B-cells. B1-lymphocytes predominantly secrete IgM, which plays an important role in the induction of tumor cell apoptosis. Splenec tomy for the purpose of adequate lymph node dissection in gastric cancer causes marked and prolonged immunological disorders. It primarily affects the B1a-lymphocyte subpopulation, which provides a thymus-independent immune response.

Objective. To study the features of the B-cell component of immunity in patients with gastric cancer.

Materials and methods. The subpopulation composition of B-lymphocytes of peripheral blood of gastric cancer patients undergoing sur gical treatment using flow cytometry (Facs Can, Lysys II and FacsCanto II programs, Facs Diva program) was analyzed. Cells were stained simultaneously with three monoclonal antibodies labeled with different fluorochromes.

Results. The data obtained demonstrate a violation of the composition of B-cell subpopulations. In the group of patients with standard D2 lymph node dissection and splenectomy at the preoperative stage and three months after surgery, a significant correlation was found between the relative number of B lymphocytes (p = 0.018), CD5 + B lymphocytes (p = 0.012) and the number of CD19 + CD38 + cells (p = 0.035). In addition, after surgical treatment, the percentage of CD5 + B-lymphocytes increased significantly from 12.9 to 21.8 %, while the total number of CD19 + lymphocytes and CD19 + CD21 + cells decreased.

Conclusion. In patients of the experimental group, a decrease in antibody production, weakening of both general and antitumor immunity can be observed.

Введение. В1-лимфоциты – субпопуляция В-клеток, на долю которой в селезенке приходится 5 % от общего числа В-клеток. В1-лимфоциты секретируют преимущественно IgM, который играет важную роль в индукции апоптоза опухолевых клеток. Спленэктомия с целью адекватной лимфодиссекции при раке желудка вызывает выраженные и длительные иммунологические нарушения. Это в первую очередь затрагивает субпопуляцию В1а-лимфоцитов, которая обеспечивает тимуснезависимый иммунный ответ.

Цель исследования – изучить особенности В-клеточного звена иммунитета у больных раком желудка.

Материалы и методы. Проанализирован субпопуляционный состав В-лимфоцитов периферической крови больных раком желудка, подвергшихся хирургическому лечению методом проточной цитометрии (Facs Can, программа Lysys II и FacsCanto II, программа Facs Diva). Клетки окрашивались одномоментно тремя моноклональными антителами, меченными различны ми флуорохромами.

Результаты. Полученные данные демонстрируют нарушение состава субпопуляций В-клеток. В группе больных со стан дартной D2-лимфодиссекцией и спленэктомией на дооперационном этапе и спустя 3 мес после операции выявлена достовер ная корреляция между относительным количеством В-лимфоцитов (p = 0,018), CD5+В-лимфоцитов (p = 0,012) и количеством CD19+CD38+-клеток (p = 0,035). Кроме того, после хирургического лечения значительно возрос процент CD5+В-лимфоци тов – с 12,9 до 21,8 %, тогда как суммарное количество CD19+ лимфоцитов и CD19+СD21+ клеток снижалось.

Заключение. У больных опытной группы может наблюдаться снижение антителoпродукции, ослабление как общего, так и противоопухолевого иммунитета.B-lymphocytesthymus-independent antigenshumoral immunitygastric cancersplenectomyB-лимфоцитытимуснезависимые антигеныгуморальный иммунитетрак желудкаспленэктомия1. Tupitsyn N.N. The structure and function of the human immune system. 2nd ed. M.: Medicine, 2007. Pp. 46–65. 2. Abbas A.K., Lichtman A.H., Pober J.S. Cellular and molecular Immunology. W.B. Saunders company, 1996. Pp. 28–32.Tupitsyn N.N. The structure and function of the human immune system. 2nd ed. M.: Medicine, 2007. Pp. 46–65. 2. Abbas A.K., Lichtman A.H., Pober J.S. Cellular and molecular Immunology. W.B. Saunders company, 1996. Pp. 28–32.3. Koiko R., Sunshine D., Benjamin E. Immunology. M.: Academy, 2008. 362 р.Koiko R., Sunshine D., Benjamin E. Immunology. M.: Academy, 2008. 362 р.4. Vos Q., Lees A., Wu Z.-Q. et al. B-cell activation by T-cell-independent type 2 antigens as an integral part of the humoral immune response to pathogenic microorganisms. Immunological Reviews 2000;176:154–70. PMID: 11043775. DOI: 10.1034/j.1600-065X.2000.00607.x.Vos Q., Lees A., Wu Z.-Q. et al. B-cell activation by T-cell-independent type 2 antigens as an integral part of the humoral immune response to pathogenic microorganisms. Immunological Reviews 2000;176:154–70. PMID: 11043775. DOI: 10.1034/j.1600-065X.2000.00607.x.5. Chulkova S.V. Stilidi I.S., Glukhov V.G. et al. The spleen as a peripheral immunity organ. Vestnik RONC im. N.N. Blokhina RAMN 2014;25(1):21.Chulkova S.V. Stilidi I.S., Glukhov V.G. et al. The spleen as a peripheral immunity organ. Vestnik RONC im. N.N. Blokhina RAMN 2014;25(1):21.6. Rabons A., Roit A., Delvz P. Basics of Medical Immunology. M.: Mir, 2006. 320 р.Rabons A., Roit A., Delvz P. Basics of Medical Immunology. M.: Mir, 2006. 320 р.7. Liu Y.J. Sites of B lymphocyte selection, activation, and tolerance in spleen (review). J Exp Med 1997;186:625–9. PMID: 9312553. DOI: 10.1084/jem.186.5.625.Liu Y.J. Sites of B lymphocyte selection, activation, and tolerance in spleen (review). J Exp Med 1997;186:625–9. PMID: 9312553. DOI: 10.1084/jem.186.5.625.8. Mebius R., Kraal G. Structure and function of the spleen. Nature Rev Immunol 2005;5:606–16. DOI: 10.1038/nri1669.Mebius R., Kraal G. Structure and function of the spleen. Nature Rev Immunol 2005;5:606–16. DOI: 10.1038/nri1669.9. Roit A., Brostoff J., Mail D. Immunology. Per. from English. M.: Mir, 2000. 581 p.Roit A., Brostoff J., Mail D. Immunology. Per. from English. M.: Mir, 2000. 581 p.10. Kruetzmann S., Rosado M.M., Weber H. et al. Human immuglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen. J Exp Med 2003;197(7):939–45. PMID: 12682112. DOI: 10.1084/jem.20022020.Kruetzmann S., Rosado M.M., Weber H. et al. Human immuglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen. J Exp Med 2003;197(7):939–45. PMID: 12682112. DOI: 10.1084/jem.20022020.11. Di Sabatino A., Rosado M., Ciccocioppo R. et al. Depletion of immunoglobulin M memory B cells is associated with splenic hypofunction in inflammatory bowel disease. Am J Gastroenterol 2005;100 (8):1788–95. PMID: 16086716. DOI: 10.1111/j.1572-0241.2005.41939.x.Di Sabatino A., Rosado M., Ciccocioppo R. et al. Depletion of immunoglobulin M memory B cells is associated with splenic hypofunction in inflammatory bowel disease. Am J Gastroenterol 2005;100 (8):1788–95. PMID: 16086716. DOI: 10.1111/j.1572-0241.2005.41939.x.12. Mikhaylenko A.A., Bazanov G.A., Pokrovsky V.I., Konenkov V.I. Prophylactic immunology. M.: Tver; Triad, 2004. 448 p.Mikhaylenko A.A., Bazanov G.A., Pokrovsky V.I., Konenkov V.I. Prophylactic immunology. M.: Tver; Triad, 2004. 448 p.13. Brandlein S., Lorenz J., Ruoff N. Human monoclonal IgM antibodies with apoptotic activity isolated from cancer patients. Hum Antibodies 2002;11(4):107–19. PMID: 12775891. DOI: 10.3233/HAB-2002-11401.Brandlein S., Lorenz J., Ruoff N. Human monoclonal IgM antibodies with apoptotic activity isolated from cancer patients. Hum Antibodies 2002;11(4):107–19. PMID: 12775891. DOI: 10.3233/HAB-2002-11401.14. Varambally S., Bar-Dayan Y., Bayry J. Natural human polyreactive IgM induce apoptosis of lymphoid cell lines and human peripheral blood mononuclear cells. Intern Immunology 2004;16(3):517–24. PMID: 14978025. DOI: 10.1093/intimm/dxh053.Varambally S., Bar-Dayan Y., Bayry J. Natural human polyreactive IgM induce apoptosis of lymphoid cell lines and human peripheral blood mononuclear cells. Intern Immunology 2004;16(3):517–24. PMID: 14978025. DOI: 10.1093/intimm/dxh053.15. Piao X., OzawaT., Hamana H. TRAILreceptor 1 IgM antibodies strongly induce apoptosis in human cancer cells in vitro and in vivo. Oncoimmunology 2016;5(5):e1131380. PMID: 27467950. DOI: 10.1080/2162402x.2015.1131380.Piao X., OzawaT., Hamana H. TRAILreceptor 1 IgM antibodies strongly induce apoptosis in human cancer cells in vitro and in vivo. Oncoimmunology 2016;5(5):e1131380. PMID: 27467950. DOI: 10.1080/2162402x.2015.1131380.16. Glukhov E.V., Chulkova C.V., Grivtsova L.Yu. et al. The role of splenectomy in cancer of the body and proximal stomach. Bulletin of the Russian Scientific Center for X-ray Radiology of the Ministry of Health of Russia 2018; 1. 17 p.Glukhov E.V., Chulkova C.V., Grivtsova L.Yu. et al. The role of splenectomy in cancer of the body and proximal stomach. Bulletin of the Russian Scientific Center for X-ray Radiology of the Ministry of Health of Russia 2018; 1. 17 p.17. Brady M.S., Rogatko A., Dent L.L., Shiu M.H. Effect of splenectomy on morbidity and survival following curative gastrectomy for carcinoma. Arch Surg 1991;126(3):359–64. PMID: 1998479. DOI: 10.1001/archsurg.1991.01410270105017.Brady M.S., Rogatko A., Dent L.L., Shiu M.H. Effect of splenectomy on morbidity and survival following curative gastrectomy for carcinoma. Arch Surg 1991;126(3):359–64. PMID: 1998479. DOI: 10.1001/archsurg.1991.01410270105017.18. Csendes A., Burdiles P., Rojas J. et al. A prospective randomized study comparing D2 total gastrectomy versus D2 total gastrectomy plus splenectomy in 187 patients with gastric carcinoma. Surgery 2002;131(4):401–7. PMID: 11935130. DOI: 10.1016/S0003-3944 (02)00835-0.Csendes A., Burdiles P., Rojas J. et al. A prospective randomized study comparing D2 total gastrectomy versus D2 total gastrectomy plus splenectomy in 187 patients with gastric carcinoma. Surgery 2002;131(4):401–7. PMID: 11935130. DOI: 10.1016/S0003-3944 (02)00835-0.19. Fatouros M., Roukos D.H., Lorenz M. et al. Impact of spleen preservation in patients with gastric cancer. Anticancer Res 2005;25(4):3023–30. PMID: 16080561.Fatouros M., Roukos D.H., Lorenz M. et al. Impact of spleen preservation in patients with gastric cancer. Anticancer Res 2005;25(4):3023–30. PMID: 16080561.20. Griffith J.P., Sue-Ling H.M., Martin I. et al. Preservation of the spleen improves survival after radical surgery for gastric cancer. Gut 1995;36(5):684–90. PMID: 7797117. DOI: 10.1136/gut.36.5.684.Griffith J.P., Sue-Ling H.M., Martin I. et al. Preservation of the spleen improves survival after radical surgery for gastric cancer. Gut 1995;36(5):684–90. PMID: 7797117. DOI: 10.1136/gut.36.5.684.21. Okuno K., Tanaka A., Shigeoka H. et al. Suppression of T-cell function in gastric cancer patients after total gastrectomy with splenectomy: implications of splenic autotransplantation. Gastric Cancer 1999;2(1):20–5. PMID: 11957066. DOI: 10.1007/s101200050016.Okuno K., Tanaka A., Shigeoka H. et al. Suppression of T-cell function in gastric cancer patients after total gastrectomy with splenectomy: implications of splenic autotransplantation. Gastric Cancer 1999;2(1):20–5. PMID: 11957066. DOI: 10.1007/s101200050016.22. Vorobev A.A., Kiselevsky M.V., Titov K.S. et al. The concept of adoptive immunotherapy in patients with gastric cancer after radical surgical treatment. Bulletin of RAMS 2003;6:16–9.Vorobev A.A., Kiselevsky M.V., Titov K.S. et al. The concept of adoptive immunotherapy in patients with gastric cancer after radical surgical treatment. Bulletin of RAMS 2003;6:16–9.23. Pavlova I.E., Bubnova L.N. Dynamics of indicators of cellular and humoral immunity in patients undergoing splenectomy in the late postoperative period by trauma. Medline Express 2007;3–4:26–31.Pavlova I.E., Bubnova L.N. Dynamics of indicators of cellular and humoral immunity in patients undergoing splenectomy in the late postoperative period by trauma. Medline Express 2007;3–4:26–31.24. Tuguz A.R., Gromova E.G., Anisimova N.Yu. et al. Production of INF-alpha neutrophils, mononuclear cells and splenocytes of cancer patients with postoperative complications. Herald intensive care 2003;3:48–50.Tuguz A.R., Gromova E.G., Anisimova N.Yu. et al. Production of INF-alpha neutrophils, mononuclear cells and splenocytes of cancer patients with postoperative complications. Herald intensive care 2003;3:48–50.25. Grivtsova L.Yu., Glukhov E.V., Chulkova S.V. et al. Role of splenectomy in peculiarities of peripheral blood B cell sub populations in patients with gastric cancer. J Immunology 2014;5:279–86.Grivtsova L.Yu., Glukhov E.V., Chulkova S.V. et al. Role of splenectomy in peculiarities of peripheral blood B cell sub populations in patients with gastric cancer. J Immunology 2014;5:279–86.26. Hardy R.R., Hayakawa K. B-cell development pathways. Ann Rev Immunol 2001;19:595–621. PMID: 11244048. DOI: 10.1146/annurev.immunol.19.1.595.Hardy R.R., Hayakawa K. B-cell development pathways. Ann Rev Immunol 2001;19:595–621. PMID: 11244048. DOI: 10.1146/annurev.immunol.19.1.595.27. Hayakawa K., Hardy R.R., Parks D.R., Herzenberg L.A. The “Ly-1 B” cell subpopulation in normal immunodefective, and autoimmune mice. J Exp Med 1983;157:202–18. PMID: 6600267. DOI: 10.1084/jem.157.1.202.Hayakawa K., Hardy R.R., Parks D.R., Herzenberg L.A. The “Ly-1 B” cell subpopulation in normal immunodefective, and autoimmune mice. J Exp Med 1983;157:202–18. PMID: 6600267. DOI: 10.1084/jem.157.1.202.28. Martin F., Kearney J.F. B-cell subsets and the mature preimmune repertoire. Marginal zone and B1 B-cells as part of a “natural immune memory”. Immunol Rev 2000;175:70–9. PMID: 10933592. DOI: 10.1111/j.1600-065x.2000.imr017515.x.Martin F., Kearney J.F. B-cell subsets and the mature preimmune repertoire. Marginal zone and B1 B-cells as part of a “natural immune memory”. Immunol Rev 2000;175:70–9. PMID: 10933592. DOI: 10.1111/j.1600-065x.2000.imr017515.x.29. Berland R., Wortis H.H. Origins and functions of B-1 cells with notes on the role of CD5. Annu Rev Immunol 2002;20:253–300. PMID: 11861604. DOI: 10.1155/2013/827254.Berland R., Wortis H.H. Origins and functions of B-1 cells with notes on the role of CD5. Annu Rev Immunol 2002;20:253–300. PMID: 11861604. DOI: 10.1155/2013/827254.30. Montecino-Rodriguez E., Leathers H., Dorshkind K. Identification of a B-1 B cell-specified progenitor. Nat Immunol 2006;7:293–301. PMID: 16429139. DOI: 10.1038/ni1301.Montecino-Rodriguez E., Leathers H., Dorshkind K. Identification of a B-1 B cell-specified progenitor. Nat Immunol 2006;7:293–301. PMID: 16429139. DOI: 10.1038/ni1301.31. Dorshkind K., Montecino-Rodriguez E. Fetal B-cell lymphopoiesis and the emergence of B-1-cell potential. Nat Rev Immunol 2007;7:213–9. PMID: 17318232. DOI: 10.1371/journal.pntd.0001173.Dorshkind K., Montecino-Rodriguez E. Fetal B-cell lymphopoiesis and the emergence of B-1-cell potential. Nat Rev Immunol 2007;7:213–9. PMID: 17318232. DOI: 10.1371/journal.pntd.0001173.32. LeBien T. W., Tedder T.F. B lymphocytes: how they develop and function. Blood 2008;112:1570–80. PMID: 18725575. DOI: 10.1182/blood-2008-02-078071.LeBien T. W., Tedder T.F. B lymphocytes: how they develop and function. Blood 2008;112:1570–80. PMID: 18725575. DOI: 10.1182/blood-2008-02-078071.33. Burmester G.-R., Pecutto A. Visual immunology. M.: Binom. 3rd ed. 2014. 320 p.Burmester G.-R., Pecutto A. Visual immunology. M.: Binom. 3rd ed. 2014. 320 p.