Резюме. В настоящее время в литературе активно обсуждается неоднозначная роль распознаю-щих рецепторов врожденного иммунитета, в частности TLRs, в иммунопатогенезе бронхиальной астмы (БА).Цель нашей работы -исследование экспрессии ТLR2 и TLR4 на уровне клеток слизистой полости носа и лейкоцитов периферической крови (ЛПК) больных БА разной степени тяжести.В исследование были включены 40 детей с БА (3-12 лет) и 10 здоровых детей того же возраста. Методом ПЦР-РВ оценивали экспрессию генов TLR2 и TLR4 в соскобах со слизистой полости носа и в ЛПК; методом проточной цитометрии определяли процент моноцитов, лимфоцитов и гранулоци-тов, экспрессирующих TLR2 TLR4, и интенсивность их экспрессии; методом мультиплексного им-мунофлуоресцентного анализа оценивали уровень про-и противовоспалительных цитокинов (IL-1β, IL-1ra, IL-6, IL-8, IL-10, TNFα) в назальных смывах.В результате проведенного исследования выявлена гиперактивация факторов врожденного имму-нитета на уровне слизистой оболочки полости носа у больных с БА, проявляющаяся повышением экспрессии генов TLR2, TLR4 и выработки как провоспалительных, так и противовоспалительных цитокинов. Выявлена связь между уровнем цитокинов и степенью тяжести бронхиальной астмы. В периферической крови определено достоверное увеличение экспрессии TLR2 и TLR4 на циркули-рующих CD14 + моноцитах у детей с БА. Таким образом, показано увеличение экспрессии генов TLRs слизистой полости носа и повыше-ние поверхностной экспрессии TLR2 и TLR4 на циркулирующих моноцитах больных бронхиальной астмой по сравнению со здоровыми детьми. Выявленные изменения свидетельствуют о вовлечении системы TLRs в иммунопатогенез бронхиальной астмы. В дальнейшем TLRs могут быть использова-ны в качестве маркеров прогноза течения БА и возможных терапевтических мишеней.
Aging is one of the most complex biological phenomena that affects all human physiological systems, including the immune system. Immunosenescence is understood as structural and functional changes in both adaptive and innate immunity systems. The so-called inflammaging is among manifestations of immune aging. It is an age-related increase in inflammatory mediators and development of an inflammatory phenotype. An important role in development of inflammaging is assigned to chronic stimulation of immune system by exogenous and endogenous danger signals (pathogen-associated molecular pattern, PAMP and damage-associated molecular pattern, DAMP), which include viruses, microbiota of the gastrointestinal tract, free radicals, etc. PAMP and DAMP are recognized by the innate immunity system cells through the pattern recognition receptors (PRR), e.g., Toll-like receptors (TLR), RIG-I-like receptors (RLR), NODlike receptors (NLR), lectin receptors. Stimulation of PRR leads to activation of intracellular signaling and increased expression of pro-inflammatory factors. PAMPs are the most powerful activators of PRR and inflammation triggers; DAMPs can activate the same receptors and signaling pathways, causing the development of a sterile inflammatory response. The NF-kB signaling pathway is considered as a key signaling pathway for inflammaging. NLR stimulation also leads to formation of inflammasome. Its function is to transform the pro-inflammatory cytokines to a biologically active form, which is an important for the formation of a pro-inflammatory phenotype and development of inflammaging. This process is considered an important risk factor for morbidity and mortality among older people. Chronic inflammation underlies pathogenesis of many age-related diseases, such as osteoporosis, atherosclerosis, Alzheimer’s disease, Parkinson’s disease, type 2 diabetes. Various chronic diseases associated with age are directly related to PAMP and DAMP-induced TLR or NLRP3-mediated inflammatory response. Hence, these ligands and their receptors can be suggested as biomarkers and interventional targets for age-related disorders. Despite numerous studies in age-associated pathology, there are only few works on the contribution of innate immunity in healthy aging. It remains unclear whether the inflammatory phenotype is a manifestation of healthy aging, or it is associated with development of age-related pathology. Further study of the mechanisms of inflammatory aging will reveal biomarkers of healthy aging and potential targets for the treatment of age-associated diseases.
Резюме. Одной из важнейших теорий канцерогенеза является теория о полиэтиологичности опухолеобразования. Большое место в этой теории отводится роли воспалительного компонента, который реализуется посредством факторов врожденного иммунитета.К факторам врожденного иммунитета, участвующим в опухолеобразовании, относятся TLRs, хемокины и их рецепторы. Активация TLRs может приводить как к снижению прогрессии онкологического процесса, так и, наоборот, к усилению. Известно, что TLR3, TLR5, TLR7, TLR9 обладают наибольшим противоопухолевым эффектом через DCs-опосредованную активацию Тh1, активацию макрофагов М1-типа и ингибирование Treg. Стимуляция TLR4 и TLR2 обладает опухоль-активирующим эффектом, путем гиперактивации MyD88 и выработки IL-6 и TNFα, однако механизмы до конца не изучены. Помимо TLRs, большое влияние на развитие онкологического процесса оказывают хемокины и их рецепторы. Показано, что CCL2, CCL4, CCL17, CCL22 и CXCL12, выделяемые клетками микроокружения опухоли, активно влияют на хемотаксис опухолевых клеток. Также известно, что CXCR4 и CCR7, экспрессируемые опухолевыми клетками, активируются хемокинами, что ведет к метастазированию. Также показаны ассоциации некоторых полиморфизмов генов TLRs, хемокинов и их рецепторов с развитием опухолевого процесса. Таким образом, на основании литературных данных, можно сделать заключение о том, что TLR и хемокины имеют большое значение при онкогенезе. Дальнейшее изучение влияния факторов врожденного иммунитета на онкогенез имеет больше значение для обоснования новых подходов терапии рака, а также потенциал для создания вакцин против рака.Abstract. The theory of polyetiological tumorigenesis is one of the most important theories of carcinogenesis. A great place in this theory is given to the role of inflammatory component, which is implemented via the Svitich O.A., PhD, MD (Medicine), Corresponding Member,
Aim. The study of the mechanisms of atopic disease formation and a model of immunopathogenesis of the atopic diseases.Methods. Determination of surface lymphocytes receptors in peripheral blood of atopic bronchial asthma and atopic dermatitis patients with the help of monoclonal antibodies using the indirect immunofluorescence method. Expression of genes encoding TLR2, TLR4 and TLR9 receptors of airborne epithelial cells by real-time polymerase chain reaction, as well as determination of cytokine TSLP, IL-33, IL-4 and TGFβ (eBioscience) in airway flushes in atopic asthma patients and healthy people.Results. During the exacerbation of atopic diseases in peripheral blood lymphocytes, an intensive activation process develops with impaired lymphocytes activating apoptosis aimed at the formation of plasma cells capable of developing intensive IgE synthesis. To search for signals that could explain the mechanism of rearrangement of the B-cell part of the immune system during atopy, the epithelium cells of the airways were examined in a group of patients with atopic asthma and found an increase in gene expression coding for TLR2, TLR4, TLR9 in 6, 3 and 2.5 times respectively. Along with increased expression of TLRs genes in patients with bronchial asthma, an increased content of TSLP and IL-33 cytokines secreted by epithelial cells of the airways was detected. These cytokines have an immunoregulatory action - their nearby antigen presenting functions format the Th2 type of immune response, promote the production of cytokines (IL-4, IL-9, IL-13) and cause the development of an allergic type of inflammation.Conclusion. We suppose that the main link in pathogenesis is a disruption of the interaction of TLRs with the corresponding ligands caused by spontaneous dimerization of TLRs under the malonic dialdehyde influence. The intake of slowly metabolized dimers of TLRs into epithelial cells is a signal for genome activation, which leads to the synthesis of allergic cytokines IL-33 and TSLP. Thus, the main immunopathogenesis pathway of atopic diseases is the pathological functional interaction between epithelial cells and peripheral blood B-lymphocytes.
The problem of studying cardiovascular diseases (CVD) for a long time remains extremely important, and, therefore, there are many works that offer new ways to diagnose and treat this group of diseases. Great opportunities are provided by the study of molecular interactions for a more accurate understanding of the pathogenesis of cardiovascular pathology. Many studies have recently been devoted to finding potential markers of CVD risk with the aim of more accurate and early diagnosis. In this review we analyze the latest literature data dedicated to the role of heat shock protein 70 (HSP70) in cardiovascular pathology. HSP70 take part in such processes as arterial hypertension, coronary heart disease, and atherosclerosis. In atherogenesis, serum heat shock proteins 70 play a major role. It has been proven that in patients with a high concentration of heat shock protein molecules circulating in the blood, increased values of the carotid intima-media complex were observed. The important role of antibodies to circulating HSP70 is noted. Found an association of high levels of these antibodies with atherosclerosis in patients with arterial hypertension in history, with myocardial infarction. Low levels of anti-HSP70 antibodies are observed in patients with acute coronary syndrome. This proves the complexity of the mechanism and the dual role of antibodies against serum heat shock proteins 70. Thus, antibodies against heat shock proteins 70 can be assessed as a protective marker, and as a predictor, which requires further study, and the HSP70 molecules themselves can somehow to participate in the development of cardiovascular pathologies. Much attention is paid to the role of the inflammatory process and the mechanisms of innate immunity in CVD. As it is currently believed that Danger-associated molecular patterns (DAMPs) are involved in the pathogenesis of these pathologies in the context of a “hazard/damage” model. According to this model, the triggering factor is stress, leading to the release of DAMPs and their binding to innate immunity receptors - Toll-like receptors (TLRs). Activation of TLRs triggers the signaling cascade in the cell leading to the synthesis of pro-inflammatory cytokines. This contributes to the development of inflammation, which can provoke the emergence of new pathological processes in the body and worsen the course of existing diseases. The identification of new potential markers and knowledge of the molecular mechanisms of the pathogenesis of CVD can play an important role in the development of a new individual approach to the prevention of cardiovascular diseases.
Резюме. Цель: исследование экспрессии генов TLR2, TLR4 и HBD-1 в эпителиальных клетках сли-зистой уретры у женщин с хроническим бактериальным циститом и у здоровых женщин. Материалы и методы: Из образцов слизистой уретры была выделена РНК, далее проводили ОТ-ПЦР. Результаты: У женщин с хроническим бактериальным циститом было выявлено увеличение экспрессии генов TLR2 в 6,9 раз, TLR4 в 2,6 раз, а также снижение экспрессии гена HBD1 в 13,6 раз в сравнении со здоровыми женщинами. Спустя 6 месяцев после комбинированной терапии с применением аутологичного комплек-са иммунопептидов у больных циститом наблюдалась нормализация показателей уровня экспрессии ге-нов TLR2, TLR4 и HBD1 до аналогичных в группе здоровых женщин. Заключение: У больных хрониче-ским циститом был выявлен дисбаланс в экспрессии генов врожденного иммунитета на уровне слизистой уретры, способствующий более высокой подверженности заболеваниям мочевыводящих путей. Ключевые слова: врожденный иммунитет, слизистая оболочка, инфекции мочевыводящих путей, Toll-подобные рецепторы, дефенсины STUDIES OF INNATE IMMUNITY PARAMETERS (TLR2, TLR4 AND HBD1) OF URETHERAL MUCOUS EPITHELIUM IN CHRONIC BACTERIAL CYSTITIS
Psoriasis is a chronic auto-inflammatory, genetically determined dermatosis, being multifactorial by origin, characterized by hyperproliferation of epidermis, affected keratinocyte differentiation and inflammatory reaction in dermis. The disease is characterized by a tendency to spread over the area of lesion, and involvement of articular tissue in the pathological process, which significantly affects the living standards of patients and causes their disability. There are many provoking factors that contribute to occurrence of psoriasis, or progression of existing psoriatic process in individuals with a genetic predisposition. These factors include adverse climatic conditions, skin trauma, exposure to ultraviolet light, burns, infections, etc.This review describes the role of innate immunity in pathogenesis of psoriasis, and describes in detail the mechanisms involved into induction of inflammation of PAMPs and DAMPs. In psoriasis, positively charged catelicidin is considered one of the most important DAMPs, which can form a complex with negatively charged cell polyanions-LL-37/auto-RNA and LL-37/auto-DNA. The interaction of PAMP/DAMP ligands with specific PRR receptors leads to signal activation of effector components of immune system, i.e., assembly of inflammasome complex, caspase activation, synthesis of inflammatory cytokines and processing of their immature forms. The review focuses on the role of TLRs under the conditions of physiological norm, which recognize danger signals and provide protection from pathogens and their timely elimination, and in development of pathological process. Activation of TLRs induces the production of pro-inflammatory cytokines, interferons and antimicrobial peptides, chemokines that support the development of psoriatic inflammation.In addition to TLRs, the mechanisms of involvement of inflammasomes in the development of psoriasis, which provides processing of mature forms of IL-1β and IL-18, are described in detail. Mature forms of these cytokines mediate the development of inflammation in psoriatic focus. In addition, processing of these cytokines by caspases using the positive feedback mechanism provides an additional signal to activate transcriptional activity of their genes and contributes to perpetuated inflammation.The review presents data confirming participation of inflammasomes in the pathogenesis of psoriasis. Much attention is paid to description of pharmacological inhibitors of inflammasomes, which in the future may be the drugs of choice for treatment of inflammatory diseases. The study of molecular mechanisms of the innate immune system will reveal new approaches to prognosis and development of targeted therapy for psoriasis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.