mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2019-6-1015-1022mimmun-1871Research ArticleОБЗОРЫREVIEWSНеспецифическая составляющая вакцинации BCGA nonspecific component of BCG vaccinationhttps://orcid.org/0000-0001-6608-7557ЕремеевВ. В.YeremeevV. V.

Еремеев Владимир Витальевич — доктор медицинских наук, заместитель директора по научной работе ФГБНУЦНИИТ.

107564, Москва, Яузская аллея, 2, Teл.: 8 (499) 785-91-59

Vladimir V. Yeremeev - PhD, MD, DSci, Deputy Director.

107564, Moscow, Yauza all., 2, Phone: 7 (499) 785-91-59

yeremeev56@mail.ruhttps://orcid.org/0000-0001-6854-7932ШепельковаГ. С.ShepelkovaG. S.

Шепелькова Галина Сергеевна — кандидат биологических наук, старший научный сотрудник лаборатории клинической иммуногенетики и клеточных технологий ФГБНУ ЦНИИТ.

Galina S Shepelkova - PhD, Senior Staff Scientist Laboratory for Clinical Immunogenetics and Cell Technologies.

Moscow

shepelkovag@yahoo.comhttps://orcid.org/0000-0002-2494-9275ЭргешовА. Э.ErgeshovA. E.

Эргешов Атаджан Эргешович — доктор медицинских наук, профессор, директор ФГБНУ ЦНИИТ.

Atadzhan E. Ergeshov - MD, DSci, Professor, Director.

Moscow

cniit@ctri.ruФГБНУ Центральный научно-исследовательский институт туберкулезаРоссияFederal State Budgetary Scientific Institution “Central Tuberculosis Research Institute” (CTRI)Russian Federation20191001202021610151022Copyright © Еремеев В.В., Шепелькова Г.С., Эргешов А.Э., 20202020Еремеев В.В., Шепелькова Г.С., Эргешов А.Э.Yeremeev V.V., Shepelkova G.S., Ergeshov A.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/1871

Десятилетия исследования механизмов иммунологической защиты от возбудителя туберкулеза (ТБ), Mycobacterium tuberculosis, не позволяют сделать окончательный вывод об относительной значимости конкретных путей формирования протективной иммунологической памяти. Единственная на сегодняшний день разрешенная к применению противотуберкулезная вакцина BCG защищает детей от тяжелых форм туберкулезной инфекции. До сих пор непонятно, почему BCG не спасает от первичного инфицирования, реактивации ТБ и латентного носительства. В то же время продемонстрирована связь вакцинации BCG со сниженным риском немикобактериальных инфекций, аллергий, онкологических заболеваний и общей смертности. Подобные неспецифические эффекты вакцинации BCG опосредованы скорее клетками врожденной иммунной системы, а не специфическими Т-клетками памяти. Имеются данные, указывающие на адъювантный эффект вакцинации BCG в отношении гуморального иммунного ответа на разнообразные вакцины в детском возрасте. Данный обзор посвящен преимущественно анализу работ, направленных на изучение относительно недавно выявленного механизма генерации неспецифического эффекта вакцины BCG — развитие наведенного врожденного иммунитета. Наведенный врожденный иммунный ответ опосредован сигналами, поступающими в клетку через внутриклеточный связывающий бактериальный мурамилдипептид-ре-цептор NOD2, и эпигенетической модификацией макрофагов и выражается в усиленной в результате вакцинации BCG способности макрофагов секретировать такие цитокины, как TNFa и IL-6, в ответ на стимуляцию неродственными BCG микроорганизмами или лигандами TLR. Наведенный иммунитет заключается не только в перенастройке передачи иммунологических сигналов между клетками врожденной иммунной системы, но также в индукции глубоких изменений баланса метаболических путей, таких как гликолиз, окислительное фосфорилирование, метаболизм аминокислот и жирных кислот, и сопровождается увеличением способности клеток врожденной иммунной системы отвечать на вторичную стимуляцию. Понимание этих внутриклеточных процессов открывает новые возможности терапевтического вмешательства в регуляцию иммунных процессов, сопровождающих инфекционные и воспалительные заболевания. В целом углубленное изучение неспецифического компонента вакцинации BCG должно привести к формированию новых представлений о механизмах ее защитного действия, а также повлиять на дизайн новой противотуберкулезной вакцины. Полученные при этом знания способны стимулировать изменения глобальной политики вакцинации с целью оптимизации преимуществ вакцинации для снижения детской заболеваемости и смертности и уменьшения риска развития поствакцинальных осложнений.

Decades of research on the mechanisms of immunological protection against Mycobacterium tuberculosis, the causative agent of tuberculosis (ТВ), did not allow us to draw a final conclusion about the relative importance of specific pathways when forming protective immunological memory. The BCG vaccine, being the only so far approved tuberculosis vaccine protects children from severe forms of ТВ infection. It is still unclear why BCG does not save from primary infection, reactivation of ТВ and latent carrying. At the same time, the association between BCG vaccination and a reduced risk of non-mycobacterial infections, allergies, cancer and general mortality has been demonstrated. Such nonspecific effects of BCG are dependent mostly on the innate immune cells, rather than on specific memory Т cells. There is evidence of an adjuvant effect of BCG vaccination with respect to the humoral immune response to a variety of childhood vaccines. This review is focused mostly on the analysis of works aimed at studying the relatively recently identified mechanism for generating the non-specific effect of the BCG vaccine, i.e., development of induced natural immunity. This phenomenon is mediated by NOD2 signaling and epigenetic macrophage modification and, due to BCG vaccination, leads to enhanced capacity of macrophages to produce TNFa and IL-6 in response to stimulation by BCG-nonrelated microorganisms or TLR ligands. Induced immunity does not only reshape transmission of immunological signals between the cells of innate immune system, but also induces profound changes in the balance of metabolic pathways, such as glycolysis, oxidative phosphorylation, metabolism of amino acids and fatty acids, being accompanied by enhanced ability of innate immune cells to respond to the secondary stimulation. Realizing these intracellular processes opens up new opportunities for therapeutic intervention into the regulation of immune processes accompanying infectious and inflammatory diseases. In general, an in-depth study of the non-specific component of BCG vaccination should lead to emergence of new ideas about the mechanisms of its protective action, as well as affect development of a new ТВ vaccine. This knowledge can stimulate changes in global vaccination policy, aiming for optimization of vaccination benefits and reduction of childhood morbidity and mortality, as well as decrease of the post-vaccinal complications.

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The authors declare that there are no conflicts of interest present.