Heat shock proteins (hsps), in certain circumstances, could shape unique features of decidual dendritic cells (DCs) that play a key role in inducing immunity as well as maintaining tolerance. The aim ...of the study was to assess the binding of gp96 to Toll-like receptor (TLR) 4 and CD91 receptors on decidual CD1a
DCs present at the maternal-fetal interface in vitro as well as the influence of CD1a
DCs maturation status. Immunohistology and immunofluorescence of paraffin-embedded first-trimester decidua tissue sections of normal and pathological (missed abortion MA and blighted ovum BO) pregnancies were performed together with flow cytometry detection of antigens in CD1a
DCs after gp96 stimulation of decidual mononuclear cells. Gp96 efficiently bound CD91 and TLR4 receptors on decidual CD1a
DCs in a dose-dependent manner and increased the expression of CD83 and HLA-DR. The highest concentration of gp96 (1000 ng/mL) increased the percentage of Interferon-γ (INF-γ) and IL-15 expressing gp96
cells. Gp96 binds CD91 and TLR4 on decidual CD1a
DCs, which causes their maturation and significantly increases INF-γ and IL-15 in the context of Th1 cytokine/chemokine domination, which could support immune response harmful for ongoing pregnancy.
We investigated the polarisation of CD68+ macrophages and perforin and granulysin distributions in kidney lymphocyte subsets of children with IgA vasculitis nephritis (IgAVN). Pro-inflammatory ...macrophage (M)1 (CD68/iNOS) or regulatory M2 (CD68/arginase-1) polarisation; spatial arrangement of macrophages and lymphocytes; and perforin and granulysin distribution in CD3+ and CD56+ cells were visulaised using double-labelled immunofluorescence. In contrast to the tubules, iNOS+ cells were more abundant than the arginase-1+ cells in the glomeruli. CD68+ macrophage numbers fluctuated in the glomeruli and were mostly labelled with iNOS. CD68+/arginase-1+ cells are abundant in the tubules. CD56+ cells, enclosed by CD68+ cells, were more abundant in the glomeruli than in the tubuli, and co-expressed NKp44. The glomerular and interstitial/intratubular CD56+ cells express perforin and granulysin, respectively. The CD3+ cells did not express perforin, while a minority expressed granulysin. Innate immunity, represented by M1 macrophages and CD56+ cells rich in perforin and granulysin, plays a pivotal role in the acute phase of IgAVN.
Background:
We analysed clinical and biochemical parameters in predicting severe gastrointestinal (GI) manifestations in childhood IgA vasculitis (IgAV) and the risk of developing renal ...complications.
Methods:
A national multicentric retrospective study included children with IgAV reviewed in five Croatian University Centres for paediatric rheumatology in the period 2009–2019.
Results:
Out of 611 children, 281 (45.99%) had at least one GI manifestation, while 42 of 281 (14.95%) had the most severe GI manifestations. Using logistic regression several clinical risk factors for the severe GI manifestations were identified: generalized rash odds ratio (OR) 2.09 (95% confidence interval (CI) 1.09–4.01), rash extended on upper extremities (OR 2.77 (95% CI 1.43–5.34) or face OR 3.69 (95% CI 1.42–9.43) and nephritis (IgAVN) OR 4.35 (95% CI 2.23–8.50), as well as lower values of prothrombin time (OR 0.05 (95% CI 0.01–0.62), fibrinogen OR 0.45 (95% CI 0.29–0.70) and IgM OR 0.10 (95% I 0.03–0.35) among the laboratory parameters. Patients with severe GI involvement more frequently had relapse of the disease OR 2.14 (CI 1.04–4.39) and recurrent rash OR 2.61 (CI 1.27–5.38). Multivariate logistic regression found that the combination of age, GI symptoms at the beginning of IgAV and severity of GI symptoms were statistically significant predictors of IgAVN. Patients in whom IgAV has started with GI symptoms OR 6.60 (95% CI 1.67–26.06), older children OR 1.22 (95% CI 1.02–1.46) with severe GI form of IgAV (OR 5.90 (95% CI 1.12–31.15) were particularly high-risk for developing IgAVN.
Conclusion:
We detected a group of older children with the onset of GI symptoms before other IgAV symptoms and severe GI form of the IgAV, with significantly higher risk for acute and chronic complications of IgAV.
Immature monocyte-derived dendritic cells (DC) strongly express the endocytic mannose receptor (MR). Addition of a specific anti-MR mAb (clone PAM-1) for 24 h to cultures of immature DC induced ...phenotypical and functional maturation of the cells, assessed as up-regulation of costimulatory molecules and CD83, and chemotactic response to CCL19. A different isotype-matched anti-MR mAb (clone 19.2) had no significant effect. Engagement of MR with mAb PAM-1 induced the production of the anti-inflammatory cytokines IL-10, IL-1R antagonist, and of the nonsignaling IL-1R type II. In contrast IL-1beta, TNF, and IL-12 were not produced. PAM-1-treated DC were unable to polarize Th1 effector cells and did not secrete the chemokines CXCL10 and CCL19; in turn, they produced large amounts of CCL22 and CCL17, thus favoring the amplification of Th2 circuits. T cells cocultured with PAM-1-matured DC initially proliferated but later became anergic and behaved as suppressor/regulatory cells. Natural ligands binding to MR had differential effects. MUC III (a partially purified mucin), biglycan (a purified complex proteoglycan), and mannosylated lipoarabinomannan from Mycobacterium tuberculosis affected cytokine production with high IL-10, IL-1R antagonist, IL-1R type II, and inhibition of IL-12. In contrast, mannan, dextran, and thyroglobulin had no significant effect. In conclusion, the appropriate engagement of the MR by mAb PAM-1 and selected natural ligands elicit a secretory program in mono-derived DC characterized by a distinct profile of cytokines/chemokines with the ability to dampen inflammation and to inhibit the generation of Th1-polarized immune responses.
Abstract When medication management or percutaneous coronary intervention is not successful in patients with advanced ischemic heart disease, surgical revascularisation—predominantly coronary artery ...bypass grafting (CABG)—is considered the gold standard. However, CABG surgery can lead to ischemia/reperfusion injury, which is characterized by a strong inflammatory response. Interleukin (IL)-18, is a strong inflammatory mediator, that is released from cardiomyocytes and can be found in the systemic circulation of patients during and immediately after CABG surgery. The existing damage of endothelial glycocalyx in patients with ischemic heart disease is further impaired concurrently during the surgery due to the anaesthesia-surgical technique used and intravascular fluid loading. This results in the increased incidence of adverse events, including myocardial infarction. IL-18 leads to the activation of lymphocyte cytotoxicity via cytotoxic mediators (Fas ligand, Tumour necrosis factor (TNF)-related apoptosis-inducing ligand, perforin, and granulysin). We hypothesize that IL-18 is released locally in the heart and the systemic circulation in patients undergoing CABG surgery and may be correlated with the level of activity of circulating lymphocytes. In turn, this may lead to lymphocyte-mediated cytotoxicity directed toward damaged and activated endothelial cells. Shear stress glycocalyx, as well as damaged and activated endothelial cells then become the main the source of pro-inflammatory cytokines, chemokines, and adhesion molecules. These attract activated lymphocytes to adhere to the endothelium or enter the subintimal layer, increasing existing or initiating the formation of new plaques, which leads to the development of myocardial infarction during or shortly after surgery. To evaluate our hypothesis, we will measure the local concentration of IL-18 in the sinus coronarius and systemic circulation. These values will then be correlated with immunological and biochemical parameters, predominantly with the concentration of degradation products of glycocalyx and cytotoxic mediators in activated lymphocytes. If our hypothesis is correct, measuring the IL-18 concentration that is responsible for glycocalyx deterioration, may become a useful tool for predicting myocardial infarction occurrence in patients undergoing CABG surgery.
During pregnancy, a delicate balance of innate and adaptive immune responses at the maternal–fetal interface promotes survival of the semi‐allogeneic embryo and, at the same time, allows effective ...immunity to protect the mother from environmental pathogens. As in other tissues, antigen handling and processing in the decidualized endometrium constitutes a primary event in the onset of immune responses and is therefore likely to determine their stimulatory or tolerogenic nature. Maternal antigen‐presenting cells macrophages and dendritic cells (DCs) are scattered throughout the decidualized endometrium during all stages of pregnancy and appear to be important players in this feto‐maternal immune adjustment. This review focuses on the characterization of decidual macrophages and DCs, as well as their involvement in cell–cell interactions within the decidual leukocyte network, which are likely to influence uterine and placental homeostasis as well as the local maternal immune responses to the fetus during pregnancy.
During gestation, many different mechanisms act to render the maternal immune system tolerant to semi-allogeneic trophoblast cells of foetal origin, including those mediated via mucins that are ...expressed during the peri-implantation period in the uterus. Tumour- associated glycoprotein-72 (TAG-72) enhances the already established tolerogenic features of decidual dendritic cells with the inability to progress towards Th1 immune orientation due to lowered interferon (IFN)-γ and interleukin (IL)-15 expression. Mucine 1 (Muc 1) supports alternative activation of decidual macrophages, restricts the proliferation of decidual regulatory CD56+ bright natural killer (NK) cells, and downregulates their cytotoxic potential, including cytotoxic mediator protein expression. Removing TAG-72 and Muc 1 from the eutopic implantation site likely contributes to better control of trophoblast invasion by T cells and NK cells and appears to have important immunologic advantages for successful implantation, in addition to mechanical advantages. However, these processes may lead to uncontrolled trophoblast growth after implantation, inefficient defence against infection or tumours, and elimination of unwanted immunocompetent cells at the maternal-foetal interface. The use of mucins by tumour cells to affect the local microenvironment in order to avoid the host immune response and to promote local tumour growth, invasion, and metastasis confirms this postulation.
Citation Veljkovic Vujaklija D, Gulic T, Sucic S, Nagata K, Ogawa K, Laskarin G, Saito S, Haller H, Rukavina D. First trimester pregnancy decidual natural killer cells contain and spontaneously ...release high quantities of granulysin. Am J Reprod Immunol 2011; 66: 363–372
Problem Granulysin (GNLY) is a novel cytolytic protein lytic against a variety of tumor cells and microbes. The role of GNLY during pregnancy has not been extensively explored. The aim of this study is to examine GNLY expression and distribution in the first trimester pregnancy peripheral blood (PB) and decidua, the ability of decidual and PB natural killer (NK) cells to secrete GNLY spontaneously, and the role of antigen‐presenting cells (APC) in the regulation of GNLY expression in decidual NK cells.
Method of study GNLY expression was analyzed using cell permeabilization method, flow cytometry, and immunohistochemistry. GNLY secretion by purified NK cells was detected by ELISA method.
Results GNLY is abundantly expressed at the maternal–fetal interface in the first trimester pregnancy. Decidual T lymphocytes express significantly higher levels of GNLY (58%) then PB T lymphocytes (11%). Over 85% of decidual CD56+ cells express GNLY and when cultured spontaneously release high quantities of GNLY. Decidual APC participate in the control of GNLY expression in CD56+ cells.
Conclusion Abundant expression of GNLY in the decidual immunocompetent cells and the capacity of decidual CD56+ cells to spontaneously secrete high quantities of GNLY point to important protective and immunomodulatory role that this molecule could play at the maternal–fetal interface.
Citation Laskarin G, Redzovic A, Vukelic P, Veljkovic D, Gulic T, Haller H, Rukavina D. Phenotype of NK cells and cytotoxic/apoptotic mediators expression in ectopic pregnancy. Am J Reprod Immunol ...2010
Problem The expression of cytotoxic/apoptotic mediators and the phenotype characteristics of uterine NK cells (uNK) in tubal ectopic pregnancy (EP) were investigated.
Method of study Samples of uterine decidua and tubal mucosa as well as peripheral blood (PB) of the same women with EP were used for phenotype characterization of NK cells and detection of cytotoxic/apoptotic mediators and IL‐15.
Results In tubal mucosa, perforin, FasL, granulysin and IL‐15 were almost completely absent, but they were present in normal and EP uterine deciduas. TRAIL was present on trophoblast and tubal mucosa, contrary to its lack in normal and EP uterine decidua. CD16−CD56dim NK cells, mostly CD94− and NKG2A−, predominate in tubal mucosa, whereas CD16−CD56bright NK cells, predominantly CD94+ and NKG2A+ prevail in EP uterine decidua. NK cells at the EP implantation site express lower percentages of perforin and granulysin, but they express a higher percentage of TRAIL than do EP uterine decidual and PB NK cells. Lower percentage of TNF‐α‐expressing and IL‐4‐expressing NK cells were found at the implantation site compared to EP uterine decidua.
Conclusions Authentic uNK cell population seems to be insufficient to restrict trophoblast invasion because of low expression of cytotoxic/apoptotic mediators.
The endothelial glycocalyx (EGC) is a layer of proteoglycans (associated with glycosaminoglycans) and glycoproteins, which adsorbs plasma proteins on the luminal surface of endothelial cells. Its ...main function is to participate in separating the circulating blood from the inner layers of the vessels and the surrounding tissues. Physiologically, the EGC stimulates mechanotransduction, the endothelial charge, thrombocyte adhesion, leukocyte tissue recruitment, and molecule extravasation. Hence, severe impairment of the EGC has been implicated in various pathological conditions, including sepsis, diabetes, chronic kidney disease, inflammatory disorders, hypernatremia, hypervolemia, atherosclerosis, and ischemia/reperfusion injury. Moreover, alterations in EGC have been associated with altered responses to therapeutic interventions in conditions such as cardiovascular diseases. Investigation into the function of the glycocalyx has expanded knowledge about vascular disorders and indicated the need to consider new approaches in the treatment of severe endothelial dysfunction. This review aims to present the current understanding of the molecular mechanisms underlying cardiovascular diseases and to elucidate the impact of heart surgery on EGC dysfunction.
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