CC BY
7
II. DIAGNOSTIC AND TREATMENT
МРНТИ 76.29.29
Aubakirova A.T.
orcid.org/0000-0001-7585-2898
Abdilova G.B.
orcid.org/0000-0002-7587-412X
Kataeva K.
orcid.org/0000-0002-0840-6465
Tartipkyzy D.
orcid.org/0000-0003-5893-6992
Davenova N.A.
orcid.org/0000-0002-1421-0733
Nurgalieva A.N.
orcid.org/0000-0003-2849-3487
Dakenova G.B.
orcid.org/0000-0002-5725-6475
Keywords
sepsis, myeloid suppressor cells, T regulatory cells
PROGNOSTIC CLINICAL SIGNIFICANCE OF MYELOID SUPPRESSOR CELLS AND T REGULATORY CELLS IN SEPSIS (REVIEW)
Aubakirova A.T., Abdilova G.B., Kataeva K., Tartipkyzy D., Davenova N.A., Nurgalieva A.N., Dakenova G.B.
National Scientific Center of Surgery named after A.N. Syzganov, Almaty, Kazakhstan Abstract
Currently in developed countries there is an unsolved problem in medicine, this complication after surgery, in some cases leading to early death.
Modern medicine has made a great stride forward, but despite all the achievements, the problem of finding reliable criteria, concepts, definitions of sepsis remains relevant. Sepsis is potentially fatal in nature. The pronounced biological and clinical heterogeneity of patients with sepsis: age, premorbid background, drugs taken, different sources of infection create a high variability in the onset and course of the pathological process. New definitions of sepsis have refocused the focus on rethinking the clinical manifestations of this syndrome and have emphasized the importance of organ dysfunction as a key diagnostic feature. An unexplained organ failure in a patient should alert the physician to the possibility of sepsis. And the final result will depend on how quickly we can respond to changes, rationally and targeted therapy.
The reasons for the dysregulation of the body's response and delayed return to homeostasis in patients with sepsis are poorly understood. Growing interest is focused on a subpopulation of leukocytes called myeloid suppressor cells (MDSC). MDSC are involved in the regulation of the immune response in many pathological situations, the most studied of which is cancer. A number of comprehensive reviews have discussed MDSC in the context of cancer, autoimmunity, and infectious diseases. Interestingly, recent evidence suggests that MDSC are involved in the immune dysfunctions seen in sepsis.
Сепсис кезшде Т-реттеушi жасушалар мен миелоидты супрессорлык жасушалардьщ болжамдык клиникалык мэж (Эдебиет шолуы)
Аубакирова А.Т., Абдилова Г.Б., Катаева К., Тэртшкызы Д., Давенова Н.А., Нургалиева А.Н., Дакенова Г.Б.
«А.Н.Сьстанов атында?ы Улттык, ?ылыми хирургия орталь™» АК,, Алматы к,., Казахстан
Туйш сездер
сепсис, миелоидты супрессорлык жасушалар, Т-реттеушi жасушалар
Ацдатпа
K,a3Ípri танда дамы€ан елдерде медицинада wewÍMÍH таппа€ан мэселе бар, бул - ерте влiмге экелелн кейбр жа€дайларда€ы, хирургиялык араласудан кейiHri аскынулар.
Заманауи медицина каркынды шгершеу Yстiндe, дегенмен осыжетЫктердн барлырына карамастан, сепсис^н аныктамасын, урымдарын, накты влшемшарттарын iздeу мэселеа взектЫпн жоймай отыр. Сепсис вз табиеатынан ажал кууштыратын сыркат. Сепсис бар наукастардын айкын кврнет биологиялыкжэне клиникалык гeтepогeндiлiгi: жас, преморбидтк фон, кабылдайтын дэpi-дэpмeктep, жукпалы аурудын тypлi квздepi патологиялык процес^н басталуы мен а€ымынын жо€ары тYpлeнгiштiгiн калыптастырады.
Сепсислн жана аныктамалары бул кубылыстын клиникалык квpiнiстepiн кайта карауга назар аударылып, непзп диагностикалык белп ретнде органдык дисфункциянын маныздылы€ын атап вт. Наукаста€ы ^Yсiнiксiз органдык жeткiлiксiздiк сепсис^н даму мYмкiндiгiнe катысты дэpiгepдi аландатуы тшс. взгерстерге 6í3 каншалыкты жылдам эрекет ете алсак, со^ы нэтижеге эсер етелн терапияны да дурыс тагайындай аламыз.
Миелоидты супрессорлык жасушалар (МС) деп аталатын лeйкоциттepдiн субпопуляциясына Yлкeн кызыгушылык туындап отыр. МС квптеген патологиялыкжардайлардары иммундыкжауаптын peттeлуiнe катысады, олардын iшiндe ке^нен зepттeлгeнi - кaтepлi idк. МС-ны жан-жакты шолуларда кaтepлi idк, аутоиммунитет жэне жукпалы аурулардын контешнде талкыланады. Кызыты, со^ы деректер бойынша МС сепсис кезнде бакыланатын иммундык дисфункциялар€а катысады деген болжам бар.
Прогностическое клиническое значение миелоидных супрессорных клеток и Т регуляторных клеток при сепсисе (Обзор литературы)
Аубакирова А.Т., Абдилова Г.Б., Катаева К., Тэртшкызы Д., Давенова Н.А., Нургалиева А.Н., Дакенова Г.Б.
АО «Национальный научный центр хирургии им. А.Н.Сызганова», г. Алматы, Казахстан
Аннотация
В настоящее время в развитых странах существует не решенная проблема в медицине, эта осложнения после хирургического вмешательство, в некоторых случаях приводящей к ранней смерти.
Современная медицина далеко шагнула вперед, но, несмотря на все достижения, проблема поиска достоверных критериев, понятий, определений сепсиса остается актуальной. Сепсис потенциально смертелен по своей природе. Выраженная биологическая и клиническая гетерогенность пациентов с сепсисом: возраст, преморбид-ный фон, принимаемые препараты, разные источники инфекции создают высокую вариабельность начала и течения патологического процесса. Новые определения сепсиса перенастроили фокус на переосмысление клинических проявлений этого синдрома и подчеркнули важность органной дисфункции как ключевого диагностического признака. Необъяснимая органная недостаточность у пациента должна насторожить врача в отношении возможности развития сепсиса. И от того, насколько быстро мы сможем среагировать на изменения, рационально и адресно назначить терапию, будет зависеть конечный результат.
Причины нарушения регуляции ответной реакции организма и задержки возврата к гомеостазу у пациентов с сепсисом мало исследованы. Растущий интерес сфокусирован на субпопуляции лейкоцитов, называемой миело-идными клетками-супрессорами (МС)
Ключевые слова
сепсис, миелоидные супрессорные клетки, Т регуляторные клетки
The mortality rate from sepsis is five to six million deaths out of 30 million cases per year worldwide, while in Kazakhstan over the past 5 years about 500 people have died from sepsis.
The incidence of sepsis is increasing due to an aging population, the burden of chronic disease, an increase in the number of immunocompromised patients and microbial resistance to antimicrobial drugs. The World Health Assembly and the World Health Organization made sepsis a global health priority by adopting a resolution on improving the prevention, diagnosis and treatment of sepsis in 2017 [1, 2].
The reasons for the dysregulation of the body's response and delayed return to homeostasis in patients with sepsis are poorly understood. Growing interest is focused on a subpopulation of leukocytes called myeloid suppressor cells (MDSC). MDSC are involved in the regulation of the immune response in many pathological situations, the most studied of which is cancer. A number of comprehensive reviews have discussed MDSC in the context of cancer, autoimmunity, and infectious diseases. Interestingly, recent evidence suggests that MDSC are involved in the immune dysfunctions seen in sepsis [3, 4].
Sepsis is characterized by an early exacerbation of antimicrobial defense mechanis MDSC, the so-called hyperinflammatory "cytokine storm," mediating tissue damage, organ dysfunction, and early mortality, as well as a concomitant shift towards resolving inflammation and tissue repair. Sepsis-
induced immunoparalysis (or immunosuppression) promotes the development of secondary infections and long-term immune deficiency, which leads to late mortality.
In the Republic of Kazakhstan and the CIS countries, molecular immunological studies on MDSC and T regulatory cells in sepsis have not been carried out until now [5, 6].
A scientific studies review carried out in the world gives the scientific significance of sepsis in clinical trials on MS and T-regulatory cells aimed at identifying the immunosuppression of myeloid cells, which will increase the effectiveness and safety of sepsis treatment.
Clinical trials that have tested adjunctive therapy to alleviate inflammation-related dysfunctions in sepsis have not been conclusive. This can be attributed to several reasons, among which there is a great heterogeneity of sepsis. It is now widely believed that the restoration of immunity with the help of immunostimulants may be more effective than anti-inflammatory therapy. In any case, personalized drugs should be used to determine on an individual level whether they should target inflammatory cytokines, immunoparalysis, or metabolism. From this point of view, significant efforts are directed towards identifying genetic, molecular and cellular biomarkers to stratify patients for clinical research and treatment based on clinical condition and disease stage [7-9].
The reasons for the dysregulation of the body's response and delayed return to homeostasis in pa-
tients with sepsis are poorly understood. Growing interest is focused on a subpopulation of leukocytes called myeloid suppressor cells (MDSC). MDSC are involved in the regulation of the immune response in many pathological situations, the most studied of which is cancer. A number of comprehensive reviews discuss MDSCs in the context of cancer, au-toimmunity, and infectious diseases. Interestingly, recent evidence suggests that MDSC are involved in the immune dysfunctions seen in sepsis [10-12].
MDSCs are immature myeloid cells that proliferate in chronic and acute inflammatory conditions. The prerequisites for the discovery of MDSC date back more than a century, when tumor progression was associated with extramedullary hematopoiesis and neutrophilia. In the mid-1960s, Lappat and Cawein reported that subcutaneously transplanted A-280 tumor cells generate factors involved in a leukocytosis response that supports tumor growth. Subsequently, leukocytosis was involved in the multiplication of cells of myeloid origin with immu-nosuppressive activity. These cells express reduced levels of common markers for mature myeloid and lymphoid cells and have been termed natural suppressor cells, null cells, immature myeloid cells, or myeloid suppressor cells. In 2007, the term "myeloid suppressor cells" was adopted as an umbrella term to minimize confusion in the literature [11, 12, 13].
MDSC are primarily determined by their immunosuppressive functions. In sepsis, MDSC can be predicted to play a dual role depending on the progression of the disease. On the one hand, MDSC may be beneficial by limiting hyperinflammation in the early stages of sepsis, hence protecting against early organ dysfunction. On the other hand, MDSC can be harmful, enhancing long-term immunosuppression. As discussed later, these two aspects were highlighted in experimental models, while all clinical studies indicated a deleterious role for MDSC [13, 14].
Minimal phenotypic characteristics of MDSC have been suggested, but there is no definite consistent phenotyping scheme. Two main subpopulations of MDSC are usually considered: polymorphonuclear MDSC (PMN-MDSC, formerly called granulocytic-MDSC) and monocytic MDSC (M-MD-SC), so called because of their morphological and phenotypic homology with PMN and monocytes. In humans, PMN-MDSC is CD11b + CD14- CD33 + (CD15 + or CD66 +) cells and M-MDSC CD11b
References
1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. (2016) 315:801-10. 10.1001/jama.2016.0287
+ CD14 + HLA-DRlow / - CD15- cells. PMN-MDSC phenotypically overlap with mature neutrophils, but, unlike PMN, MDSC is deposited in the PMN fraction in Ficoll gradients after whole blood density separation. The identification of PMN-MDSC by density gradient is further limited by the growth of not only low density neutrophils, but also high density CD62Ldim neutrophils, which suppress T cells in the blood of healthy people infused with endotoxin. Additional markers for the differentiation of MDSC from monocytes or granulocytes have been proposed, for example, high expression of the oxidized LDL-1 receptor of the lectin type (LOX-1) PMN-MDSC compared to granulocytes in whole blood. Other subsets of MDSC have been described, including early stage MDSC and eo-sinophilic MDSC. In addition, tumor-associated macrophages (TAMDSC), which, unlike their name, indicate the presence of inflammatory conditions in cancer, can be considered as one of the members making up the MDSC spectrum. Lastly, MDSCs are known very malleable. They can differentiate into osteoclasts and non-suppressing mature myeloid cells, while M-MDSC can differentiate into TAM and PMN-MDSC. In general, to this day, MDSC identification based on cell surface phenotyping usually ends up in a mixed population eventually containing other types of myeloid cells, which does not take into account the characteristic immunosuppressive function of MDSC [15 -18].
Hematopoietic stem cells differentiate into common myeloid progenitors, resulting in the formation of immature myeloid cells. The inflammatory environment observed in sepsis stimulates the release of immature myeloid cells from the bone marrow into the bloodstream and enhances immu-nosuppressive functions. The identification of mediators and molecular mechanis MDSC underlying the expansion and immunosuppressive functions of MDSC may indicate original therapeutic targets for various diseases [17, 18].
Conclusion
Thus, according to the literature data, it can be seen that myeloid suppressor cells and T regulatory cells study has prognostic value. The level of these cells can be an indicative and prognostic laboratory marker for reducing mortality of patients from sepsis after and before surgery.
2. Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. (2013) 41:116774. 10.1097/CCM.0b013e31827c09f8]
3. Goldmann O, Beineke A, Medina E. Identification of
a novel subset of myeloid-derived suppressor cells during chronic staphylococcal infection that resembles immature eosinophils. J Infect Dis. (2017) 216:1444-51. 10.1093/infdis/jix494
4. Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res. (2017) 5:3-8. 10.1158/2326-6066.CIR-16-0297
5. Roussel M, Ferrell PB, Jr., Greenplate AR, Lhomme F, Le Gallou S, Diggins KE. et al. Mass cytometry deep phenotyping of human mononuclear phagocytes and myeloid-derived suppressor cells from human blood and bone marrow. J Leukoc Biol. (2017) 102:437-47. 10.1189/jlb.5MA1116-457R
6. Bah I, Kumbhare A, Nguyen L, MDSCCall CE, El Gazzar M. IL-10 induces an immune repressor pathway in sepsis by promoting S100A9 nuclear localization and MDSC development. Cell Immunol. (2018) 332:328. 10.1016/j.cellimm.2018.07.003
7. Bayik D, Tross D, Klinman DM. Factors influencing the differentiation of human monocytic myeloid-derived suppressor cells into inflammatory macrophages. Front Immunol. (2018) 9:608. 10.3389/fimmu.2018.00608
8. Dai J, Kumbhare A, WilliaMDSC DA, Youssef D, Yao ZQ, MDSCCall CE, et al. Nfia deletion in myeloid cells blocks expansion of myeloid-derived suppressor cells during sepsis. Innate Immun. (2018) 24:54-65. 10.1177/1753425917742956
9. Darcy CJ, Minigo G, Piera KA, Davis JS, MDSCNeil YR, Chen Y, et al. Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients. Crit Care (2014) 18:R163. 10.1186/cc14003
10. Kulkarni U, Herrmenau C, Win SJ, Bauer M, Kamradt T. IL-7 treatment augments and prolongs sepsis-induced expansion of IL-10-producing B lymphocytes and myeloid-derived suppressor cells. PLoS ONE. (2018) 13:e0192304. 10.1371/journal.pone.0192304
11. MDSCClure C, MDSCPeak MB, Youssef D, Yao ZQ, MDSCCall CE, El Gazzar M. Stat3 and C/EBPbeta
synergize to induce miR-21 and miR-181b expression during sepsis. Immunol Cell Biol. (2017) 95:42-55. 10.1038/icb.2016.63
12. Newson J, Motwani MP, Kendall AC, Nicolaou A, Muccioli GG, Alhouayek M, et al. Inflammatory resolution triggers a prolonged phase of immune suppression through COX-1/mPGES-1-derived prostaglandin E2. Cell Rep. (2017) 20:3162-75. 10.1016/j. celrep.2017.08.098
13. Stoll H, Ost M, Singh A, Mehling R, Neri D, Schafer I, et al. . Staphylococcal enterotoxins dose-depend-ently modulate the generation of myeloid-derived suppressor cells. Front Cell Infect Microbiol. (2018) 8:321. 10.3389/fcimb.2018.00321
14. Rieber N, Singh A, Oz H, Carevic M, Bouzani M, Amich J, et al. Pathogenic fungi regulate immunity by inducing neutrophilic myeloid-derived suppressor cells. Cell Host Microbe. (2015) 17:507-14. 10.1016/j.chom.2015.02.007
15. Wang J, Shirota Y, Bayik D, Shirota H, Tross D, Gulley JL, et al. . Effect of TLR agonists on the differentiation and function of human monocytic myeloid-derived suppressor cells. J Immunol. (2015) 194:4215-21. 10.4049/jimmunol.1402004
16. MDSCClure C, Ali E, Youssef D, Yao ZQ, MDSCCall CE, El Gazzar M. NFI-A disrupts myeloid cell differentiation and maturation in septic mice. J Leu-koc Biol. (2016) 99:201-11. 10.1189/jlb.4A0415-171 RR
17. MDSCPeak MB, Youssef D, WilliaMDSC DA, Pritchett C, Yao ZQ, MDSCCall CE, et al. Myeloid cell-specific knockout of NFI-A improves sepsis survival. Infect Immun. (2017) 85:17. 10.1128/IAI.00066-17
18. MDSCPeak MB, Youssef D, WilliaMDSC DA, Pritchett CL, Yao ZQ, MDSCCall CE, et al. Frontline science: myeloid cell-specific deletion of Cebpb decreases sepsis-induced immunosuppression in mice. J Leu-kocBiol. (2017) 102:191-200. 10.1189/jlb.4HI1216-537R
