Neutrophil granulocytes: participation in homeostatic and reparative processes. Part II

A supportive homeostatic function of neutrophilic granulocytes is accomplished in the physiology of diverse tissues and body systems. Neutrophils are found along the entire female reproductive tract (FRT), gradually declining in numbers from the upper parts towards the vagina. At the same time, both quantity and activity of FRT mucosal neutrophils are controlled by hormonal changes at different phases of menstrual cycle. Tissue neutrophils serve as an important source of broad-spectrum proteolytic enzymes such as matrix metalloproteinases and elastase necessary for extracellular matrix remodeling as well as vascular endothelial growth factor (VEGF) required for physiological FRT angiogenesis. During pregnancy, decidual neutrophils play a prominent role in vascular remodeling in pregnant uterus as well as development of maternal-fetal immune tolerance. The influx of neutrophils into the intestinal mucosa due to its trauma or infection not only ensures defense against pathogens, but also leads to increased proliferation of intestinal epithelial cells. Neutrophilic granulocytes elicit signals and events protective for the epithelium by marking them with a “hypoxic signature” to trigger transcription of the gene set responsible for production of mucins, mucin-modifying peptides, antimicrobial proteins, в-defensins, ultimately contributing to lesion healing and recovery of epithelial barrier function. “Inflammatory hypoxia” initiated by neutrophils and subsequent stabilization of the transcription factor hypoxia-induced factor (HIF) in intestinal epithelial cells trigger mechanisms of self-limited and resolved inflammation, which prevent excessive accumulation of neutrophils in the intestinal lumen and development of chronic inflammatory process. Neutrophilic granulocytes dominate in the oral cavity mucosa and comprise more than 95% of total leukocyte population recruited into the gingival sulcus and gingival fluid. Neutrophils maintain physiological amount and stability of symbiotic microflora composition in dental and gingival biofilms, counteracting pathogenic bacteria via phagocytosis, degranulation and extracellular trap formation, thereby ensuring healthy state in periodontal structures. Finally, similar to some other congenital disorders affecting neutrophil quantity and functions it was shown that in case of leukocyte adhesion deficiency type 1 (LAD-1) pathogenesis of periodontitis may not only be associated with a defect in their protective effector activity, but also with altered immunoregulatory function of tissue neutrophils

Neutrophil granulocytes: participation in homeostatic and reparative processes. Part I

After exiting from the bone marrow (BM) into the circulation, mature neutrophil granulocytes undergo a set of sequential phenotypic and physiological changes collectively called “aging” in the absence of inflammation, by constitutively sensing prime signals from commensal microbiota and acquiring higher functional alertness in case of activation upon tissue damage or pathogen invasion. Physiological aging of blood neutrophils and their subsequent return to the BM result in signals modulating size and function of the hematopoietic niche. Circadian physiological infiltration of BM by neutrophils contributes to maintaining baseline level of circulating hematopoietic progenitor cells capable of regeneration and immune surveillance. Apart from the BM, neutrophils actively enter other healthy tissues, probably exerting some effects on their baseline physiologic state. Using lung tissue, it has been shown that neutrophils can “govern” action of gene set regulating cell growth, migration, proliferation, differentiation, and carcinogenesis. Neutrophils participate in destruction of endometrial tissues during desquamation phase as well as subsequent repair and physiological angiogenesis during proliferative phase of the menstrual cycle; promote wall rupture of the preovulatory ovarian follicle and oocyte exit; contribute to degradation and resorption of the corpus luteum in pregnancy failure; play an important physiological role in vascular remodeling in pregnant uterus and developing maternal immune tolerance to semi-allogeneic fetus. Neutrophils actively migrating to the surface of intestinal epithelium during local infection and/or damage stimulate epithelial restitution and recovery of its barrier function. On the other hand, neutrophils recruited into the oral cavity regulate quantitative and qualitative composition of microbial communities in oral biofilms, and ensure healthy state of periodontal structures. Being a major player and regulator in healing of skin wounds at early stage, inflammation, neutrophils not only destroy potential pathogens, but also participate in cleansing wounds from cell debris, produce cytokines, enzymes, and growth factors affecting further stages in repair process. Both apoptosis and NETosis underlying neutrophil death greatly contribute to wound healing. However, dysregulation and imbalance in both apoptosis and NETosis may lead to unfavorable consequences as well as developing chronic non-healing wounds

Разнообразие субпопуляций регуляторных Т-клеток

Regulatory T-lymphocytes play a central role in the immunological tolerance system. To date, existence of many different subpopulations of regulatory T-cells have been described. However, a number of questions related to the function, differentiation, and homeostasis of these subpopulations in a body remain unclear. Interactions between the previously discovered pairs of helper and regulatory T-lymphocytes require further study. The main topic is identification and establishment of the functions of regulatory memory cells. Interstitial migration of activated regulatory T-lymphocytes is also a promising direction. In this review, we summarized the main findings in multiple subsets of regulatory T-lymphocytes, discussed unclear data that will require further studies, and  showed an application for regulatory T-lymphocytes in medicine.Регуляторные Т-лимфоциты являются центральными клетками системы иммунологической толерантности. В настоящее время описано существование множества различных субпопуляций регуляторных Т-клеток (Treg), однако большое количество вопросов, касающихся функционального назначения, путей дифференцировки и гомеостаза этих субпопуляций в организме, остаются неизученными. Продемонстрированные ранее пары хелперов и соответствующих им регуляторных Т-лимфоцитов требуют дальнейшего изучения их взаимодействий друг с другом. Актуальной темой является идентификация и установление функций клеток регуляторной памяти. Тканевая миграция активированных регуляторных Т-лимфоцитов также является перспективным направлением. В этом обзоре собраны и систематизированы данные о различных субпопуляциях регуляторных Т-лимфоцитов, выделены актуальные вопросы данной тематики, требующие дальнейшего изучения, а также затронуты пути развития области в клинической медицине

Роль нейтрофилов в патогенезе ишемического инсульта

Background. Immune responses and inflammation play an important role in the pathogenesis of ischemic stroke.Aim. To analyze the involvement of neutrophils in the pathogenesis of ischemic stroke.Results. Data on the contribution of neutrophil granulocytes to the development of local sterile inflammation and secondary brain injury in acute ischemic stroke were summarized. Mechanisms of neutrophil influence on thrombosis, neutrophil extracellular trap formation (NETosis), protease release, and direct interaction with platelets with subsequent formation of platelet-leukocyte aggregates were discussed. Available information on the effectiveness of reperfusion therapy and an association of changes in neutrophil activity with development of infectious complications of stroke were presented. In addition, research data were presented on the contribution of neutrophils to atherogenesis, which is one of the most important etiological factors in ischemic stroke. The review showed that the contribution of neutrophils to the pathogenesis of ischemic stroke is associated with implementation of their secretory, regulatory, and phagocytic functions, as well as with NETosis.Conclusion. It was shown that neutrophils are involved in the pathogenesis of ischemic stroke and modulate a response to treatment.Актуальность. Иммунные реакции и воспалительный процесс играют важную роль в патогенезе ишемического инсульта.Цель. На основании научных публикаций проанализировать вовлеченность нейтрофилов в патогенез ишемического инсульта.Результаты. Обобщены данные о вкладе нейтрофильных гранулоцитов в развитие локального асептического воспаления и вторичного повреждения мозга при остром инсульте. Обсуждены механизмы влияния нейтрофилов на процесс тромбообразования, образование нейтрофильных внеклеточных ловушек (нетоз), высвобождение протеаз и прямое взаимодействие с тромбоцитами с образованием лейкоцитарно-тромбоцитарных агрегатов. Приведены имеющиеся сведения об эффективности реперфузионной терапии, а также ассоциации изменений активности нейтрофилов с развитием инфекционных осложнений инсульта. Представлены данные исследований о вкладе нейтрофилов в атерогенез, являющийся одним из важнейших этиологических факторов ишемического инсульта. Показано, что участие нейтрофилов в патогенезе ишемического инсульта связано с реализацией их секреторных, регуляторных, фагоцитарных функций и с нетозом.Заключение. Установлено, что нейтрофилы принимают активное участие в патогенезе ишемического инсульта и модулируют ответ на лечение

Clinical immunological characteristics of the patients with chronic generalized parodontitis

Clinical immunological study of 99 patients with CHGP and 25 clinically healthy persons with intact paradont was carried out. A number ot disorders of cellular and humoral immunity and functional neutrophils activity of peripheral blood is revealed among the patients with chronic generalized parodontitis. The intensity of immune disorders depends on the severity of parodontitis. The interrelation of inflammatory destructive processes in parodontium tissues and disorders in cellular and humoral immunity chains as well as functional neutrophils activity is proved by the correlation relationship.Проведено клинико-иммунологическое обследование 99 пациентов с ХГП и 25 клинически здоровых лиц с интактным пародонтом. У пациентов с ХГП выявлены нарушения ряда показателей клеточного и гуморального иммунитета, функциональной активности нейтрофилов периф ерической крови. Выраженность нарушений иммунитета зависела от степени тяжести пародонтита. Взаимозависимость воспалительно-деструктивных процессов в тканях пародонта и нарушений в клеточном и гуморальном звеньях иммунитета, функциональной активности нейтрофилов подтверждена корреляционной связью

Clinical and immunological features of chronic odontogenic maxillary sinusitis, depending on the length of the flow

The study involved 29 patients with an established diagnosis of chronic odontogenic maxillary sinusitis, oro-antral fistula: an assessment of clinical and immunological parameters and identified a number of features, depending on the duration of the disease.Обследовано 29 пациентов с установленным диагнозом хронический одонтогенный верхнечелюстной синусит, оро-антральное соустье: проведена оценка клинико-иммунологических показателей и выявлены ряд особенностей, в зависимости от длительности заболевания

Relationships between serum HMGB1 concentration and subpopulation composition of circulating monocytes in patients with subclinical atherosclerosis

Chronic non-infectious inflammation of low intensity is the most important mechanism of development and progression in atherosclerosis. Under the conditions of persistent non-resolving inflammation observed in the vascular wall and atherosclerotic plaque (ASB), permanent tissue damage occurs, thus leading to increased formation of endogenous danger-associated molecular patterns (DAMPs). The non-histone chromosomal protein HMGB1 may be regarded as a prototypical DAMPs. HMGB1 acts as a DAMP if entering the extracellular space, causing inflammation by its binding to pattern-recognizing receptors (TLR2, TLR4, RAGE, CD36, etc.). A number of clinical studies have revealed higher HMGB1 levels in the blood of patients with coronary heart disease and atherosclerotic disease of the lower limb arteries, as well as its interrelations with the burden of coronary artery atherosclerosis. Currently, the mechanisms of HMGB1-mediated atherosclerosis progression are studied only fragmentary. The aim of our study was to investigate relationships between the serum HMGB1 level and subsets of circulating monocyte subpopulations in patients with subclinical atherosclerosis.The study enrolled patients aged 40-64 years with subclinical atherosclerosis of peripheral arteries. Serum HMGB1 concentration was determined using enzyme immunoassay kits (Human HMGB1/HMG-1 ELISA Kit, NBP2-62766, Novus Biologicals, USA). The serum HMGB1 threshold was 18.75 pg/ml, whereas the measurement range was 31.25 to 2000 pg/ml. Phenotyping of the blood monocyte subpopulations was performed by flow cytometry using Navios 6/2 device (Beckman Coulter, USA).An increase in serum HMGB1 concentration was associated with decreased number of classical M2 monocytes, and an increase in intermediate and M1 monocytes. Moreover, an increase in HMGB1 concentration was associated with higher numbers of classical, intermediate, and non-classical monocytes expressing CD36 and TLR2. Increased HMGB1 concentration (from Q1 to Q4) correlated with higher numbers of classical (p = 0.001) and intermediate monocytes (p = 0.006) but not with non-classical phenotypes (p = 0.147). Upon increase of HMGB1 concentration (Q1 to Q4), we have found an increase in the number of classical (p < 0.0001), intermediate (p < 0.0001), and non-classical (p < 0.0001), CD36-expressing monocytes. An increased number of intermediate (p = 0.022; p1, 4 = 0.034) and non-classical, TLR2-expressing monocytes was also revealed (p = 0.002; p1, 4 = 0.035). By mean of correlation analysis, IL-1β concentrations showed direct correlation with the number of M1 monocytes (r = 0.268; p = 0.035) and inverse relation with the number of M2 monocytes (r = -0.376; p = 0.003).Increased serum HMGB1 concentration in patients with subclinical atherosclerosis was associated with decreased numbers of classical and M2 monocytes, as well as higher numbers of intermediate and M1 monocytes, like as with increased contents of intermediate and non-classical monocytes expressing CD36 and TLR2. IL-1β levels directly correlated with HMGB1 concentration and the number of Mi-monocytes