mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-CCR-2181mimmun-2181Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESЛиганды хемокинового рецептора CXCR3 при саркоидозеCXCR3 chemokine receptor ligands in sarcoidosisЛазареваН. М.LazarevaN. M.

Лазарева Наталья Михайловна – старший лаборант кафедры иммунологии

197022, Санкт-Петербург, ул. Льва Толстого, 6-8

197022, St. Petersburg, L. Tolstoy str., 6-8

nmlazareva@gmail.comБарановаО. П.BaranovaO. P.

к.м.н., старший научный сотрудник научно-исследовательского института интерстициальных и орфанных заболеваний легких, доцент кафедры пульмонологии

Санкт-Петербург

 

PhD (Medicine), Senior Research Associate, Research Institute of Interstitial and Orphan Lung Diseases, Associate Professor, Department of Pulmonology

 

dr_baranova@mail.ruКудрявцевИ. В.KudryavtsevI. V.

к.б.н., заведующий лабораторией иммунорегуляции, отдел иммунологии ФГБНУ «Институт экспериментальной медицины»; доцент кафедры иммунологии

Санкт-Петербург

PhD (Biology), Head, Laboratory of Immunoregulation, Department of Immunology, nstitute of Experimental Medicine; Associate Professor, Department of Immunology

St. Petersburg

igorek1981@yandex.ruАрсентьеваН. А.ArsentievaN. A.

к.б.н., старший научный сотрудник лаборатории молекулярной иммунологии

Санкт-Петербург

 

PhD (Biology), Senior Research Associate, Laboratory of Molecular Immunology

St. Petersburg

arsentieva_n.a@bk.ruЛюбимоваН. Е.LiubimovaN. E.

к.б.н., научный сотрудник лаборатории молекулярной иммунологии

Санкт-Петербург

PhD (Biology), Research Associate, Laboratory of Molecular Immunology

St. Petersburg

natelu@mail.ruСесьТ. П.Ses’T. P.

д.б.н., профессор, профессор кафедры иммунологии

Санкт-Петербург

PhD, MD (Biology), Professor, Department of Immunology

St. Petersburg

sestp@mail.ruИльковичМ. М.IlkovichM. M.

д.м.н., профессор, директор научно-исследовательского института интерстициальных и орфанных заболеваний легких, заведующий кафедрой пульмонологии

Санкт-Петербург

PhD, MD (Medicine), Professor, Director, Research Institute of Interstitial and Orphan Lung Diseases, Head, Department of Pulmonology

St. Petersburg

mih.ilkovich@yandex.ruТотолянАрег А.TotolianAreg A.

д.м.н., профессор, академик РАН, директор; заведующий кафедрой иммунологии

Санкт-Петербург

PhD, MD (Medicine), Professor, Full Member, Russian Academy of Sceinces, Director; Head, Department of Immunology

St. Petersburg

totolian@spbraaci.ruФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения РФРоссияFirst St. Petersburg State I. Pavlov Medical UniversityRussian FederationФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения РФ; ФГБНУ «Институт экспериментальной медицины»РоссияFirst St. Petersburg State I. Pavlov Medical University; Institute of Experimental MedicineRussian FederationФБУН «Санкт-Петербургский научно-исследовательский институт эпидемиологии и микробиологии имени Пастера»РоссияSt. Petersburg Pasteur Research Institute of Epidemiology and MicrobiologyRussian FederationФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения РФ; ФБУН «Санкт-Петербургский научно-исследовательский институт эпидемиологии и микробиологии имени Пастера»Russian FederationFirst St. Petersburg State I. Pavlov Medical University; St. Petersburg Pasteur Research Institute of Epidemiology and MicrobiologyRussian Federation2021260220212317386Copyright © Лазарева Н.М., Баранова О.П., Кудрявцев И.В., Арсентьева Н.А., Любимова Н.Е., Сесь Т.П., Илькович М.М., Тотолян А.А., 20212021Лазарева Н.М., Баранова О.П., Кудрявцев И.В., Арсентьева Н.А., Любимова Н.Е., Сесь Т.П., Илькович М.М., Тотолян А.А.Lazareva N.M., Baranova O.P., Kudryavtsev I.V., Arsentieva N.A., Liubimova N.E., Ses’ T.P., Ilkovich M.M., Totolian A.A.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/2181

Саркоидоз – это полисистемное воспалительное заболевание неизвестной этиологии, относящееся по своим морфологическим особенностям к группе гранулематозов, гетерогенное по клиническим проявлениям и исходам. Клетки иммунной системы, в частности Т-хелперы (Тh), по хемокиновым градиентам привлекаются в легочную ткань и/или другие органы и играют важную роль в формировании гранулем. Из периферической крови в ткани Тh мигрируют благодаря наличию на их поверхности хемокинового рецептора CXCR3, взаимодействующего с такими лигандами, как CXCL9/MIG, CXCL10/IP-10, CXCL11/I-TAC. Целью исследования явилось определение уровней хемокинов CXCL9/MIG, CXCL10/IP-10, CXCL11/I-TAC в периферической крови больных саркоидозом в зависимости от особенностей клинического течения заболевания до назначения иммуносупрессивной терапии. Были исследованы образцы плазмы крови больных саркоидозом (n = 52). У 37% (19/52) отмечалось острое, а у 63% (33/52) – хроническое течение заболевания. Контролем служили образцы периферической крови, полученные от 22 практически здоровых добровольцев. Концентрации хемокинов (пг/мл) определялись методом мультиплексного анализа по технологии xMAP (Luminex), тест-системы Milliplex MAP (Millipore, США). У обследованных больных обнаружено достоверно повышенное содержание хемокинов относительно здоровых лиц: CXCL9 – 4013,00 пг/мл против 1142,00 пг/ мл, p < 0,001; CXCL10 – 565,90 пг/мл против 196,60 пг/мл, p < 0,001; CXCL11 – 230,20 пг/мл против 121,10 пг/мл, p = 0,018. Концентрации CXCL9 и CXCL10 достоверно повышены как в образцах крови больных острым, так и хроническим саркоидозом относительно условно здоровых добровольцев, при p < 0,001. Уровень хемокина CXCL11 был достоверно повышен только у больных с хроническим саркоидозом, по сравнению с группой здоровых: 251,50 пг/мл и 121,10 пг/ мл, при p = 0,044, причем уровень этого хемокина коррелировал с активностью ангиотензин-превращающего фермента (АПФ) (r = 0,374; p = 0,042). Как известно, уровень АПФ при саркоидозе служит клинико-лабораторным показателем активности заболевания. При остром течении саркоидоза уровень хемокина CXCL11 не был достоверно выше, чем у здоровых лиц, в то же время концентрация хемокина CXCL9 была достоверно повышенной и коррелировала с активностью АПФ (r = 0,762; p = 0,037). Установлено, что по мере появления признаков фиброзирования легочной ткани уровень хемокина CXCL9 снижается: у больных с признаками фиброзирования показатель составил 1839,88 пг/мл против 4375,52 пг/мл – у больных без признаков фиброза, р = 0,035. При системных проявлениях саркоидоза определялся достоверно более высокий уровень CXCL9: у больных с системными прояв-лениями – 6036,84 пг/мл против 1927,44 пг/мл у больных без признаков системности, р = 0,018. Анализ клинико-лабораторной значимости уровней хемокинов в плазме крови обследованных больных саркоидозом выявил параметры их чувствительности и специфичности. У больных с острым течением саркоидоза они составили: для CXCL9 – 84% и 95%, CXCL10 – 84% и 95%, CXCL11 – 74% и 59%; при хроническом: CXCL9 – 82% и 72%, CXCL10 – 91% и 77%, CXCL11 – 79% и 55% соответственно. Таким образом, определение хемокинов CXCL9, CXCL10 и CXCL11 при саркоидозе вносит вклад в понимание их роли в развитии заболевания – привлечении Т-хелперов из периферической крови в легочную ткань и формировании гранулем. Клинико-иммунологические сопоставления уровня CXCL9 в периферической крови больных и особенностей течения саркоидоза указывают на роль этого диагностического параметра для оценки активности, признаков фиброзирования легочной ткани и системности заболевания.

Sarcoidosis is a polysystemic inflammatory disease of unknown etiology, morphologically related to the group of granulomatosis, with heterogeneous clinical manifestations and outcomes. Immune cells, in particular T helper cells, are attracted to lung tissue and/or other organs by chemokine gradients and play an important role in the granuloma formation. T helper cells migrate from peripheral blood to the tissues due to expression of CXCR3 chemokine receptor on their surface. It interacts, e.g., with CXCL9/MIG, CXCL10/IP- 10, and CXCL11/I-TAC. Our study was aimed for determining the levels of CXCL9/MIG, CXCL10/IP-10, CXCL11/I-TAC chemokines in peripheral blood of the patients with sarcoidosis, depending on the features of their clinical course before administration of immunosuppressive therapy. We studied peripheral blood plasma samples of the patients with sarcoidosis (n = 52). In 37% (19/52), they exhibited acute clinical manifestations, and 63% (33/52) had chronic sarcoidosis. The control group included peripheral blood samples from healthy volunteers (n = 22). The chemokine concentrations (pg/ml) were determined by multiplex analysis using xMAP technology (Luminex), and Milliplex MAP test system (Millipore, USA). In the patients with sarcoidosis, significantly higher levels of chemokines were shown relative to healthy volunteers: CXCL9, 4013.00 pg/ml vs 1142.00 pg/ml (p < 0.001); CXCL10, 565.90 pg/ml vs 196.60 pg/ml (p < 0.001); CXCL11, 230.20 pg/ml vs 121.10 pg/ml (p = 0.018). Plasma concentrations of CXCL9 and CXCL10 were significantly increased both in blood samples from patients with acute and chronic sarcoidosis compared to healthy volunteers, p < 0.001. The level of CXCL11 chemokine was significantly increased only in the patients with chronic sarcoidosis, compared to the healthy volunteers: respectively, 251.50 pg/ml and 121.10 pg/ml (p = 0.044). The levels of this chemokine correlated with the activity of angiotensin-converting enzyme (ACE), with r = 0.374; p = 0.042. The ACE level in sarcoidosis is considered a clinical and laboratory index of the disease activity. In acute sarcoidosis, the level of CXCL11 chemokine was not significantly higher than in healthy individuals, whereas the CXCL9 chemokine content was significantly increased and correlated with ACE activity (r = 0.762; p = 0.037). The level of CXCL9 chemokine was significantly decreased in patients with signs of fibrosis as compared with fibrosis-free patients (1839.88 pg/ml vs 4375.52 pg/ml, p = 0.035). Significantly higher levels of CXCL9 were detected in cases of systemic sarcoidosis, i.e. 6036.84 pg/ml, as compared with 1927.44 pg/ml in the patients without these signs (p = 0.018). Evaluation of clinical and laboratory diagnostic characteristics for plasma chemokine levels in sarcoidosis patients allowed to assess their sensitivity and specificity. The respective values were as follows: in acute sarcoidosis: for CXCL9, 84% and 95%; for CXCL10, 84% and 95%; for CXCL11, 74% and 59%. In chronic sarcoidosis, the respective values for CXCL9 were 82% and 72%; for CXCL10, 91% and 77%; for CXCL11, 79% and 55%, respectively. Thus, the determination of plasma CXCL9, CXCL10, and CXCL11 chemokines in sarcoidosis allows of understanding their role in development of the disease, e.g., recruitment of T helper cells from peripheral blood to the lung tissue, and granuloma formation. Clinical and immunological comparisons of CXCL9 levels in the peripheral blood of patients and characteristics of the clinical course of sarcoidosis indicate to the role of this diagnostic parameter for assessing the disease activity, signs of lung fibrosis, and systemic manifestations in this disease.

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