Visfatin Plays a Significant Role in Alleviating Lipopolysaccharide-Induced Apoptosis and Autophagy Through PI3K/AKT Signaling Pathway During Acute Lung Injury in MiceAbstractVisfatin is involved in the body's inflammation and immune response. Inflammation could promote, while visfatin may directly or indirectly mitigate the effects of apoptosis and autophagy. Whether visfatin lessens the detrimental effects of lipopolysaccharide (LPS)-induced mouse acute lung injury (ALI) is poorly understood yet. Therefore, in the current study, the regulation mechanism of visfatin on apoptosis and autophagy was explored in Kunming mice by replicating LPS-induced inflammatory ALI model. Based on the mouse model of ALI, HE staining, TUNEL, transmission electron microscopy, immunohistochemical staining, real-time fluorescence quantitative PCR and western blot were used and the results showed that the alveolar septum was thinner than that of the LPS group, slight lung interstitial and alveolar exudation appeared, and a small number of inflammatory cell infiltration was found in the visfatin intervention group, indicating reduced tissue damage in lungs. After visfatin treatment, the expression of pro-apoptotic genes Bax, Bik, and p53 decreased and the expression of anti-apoptotic genes Bcl-2 and Bcl-xl increased, and expression of autophagy factors LC3 and Beclin1 decreased, indicating that visfatin inhibits apoptosis and reduces autophagy. The expression of PI3K and p-AKT was upregulated in the visfatin intervention group, the expression of AKT was downregulated, and the PI3K/AKT signaling pathway was activated. Hence, visfatin could activate the PI3K/AKT signaling pathway, reduce the apoptotic rate in alveolar epithelial cells and the level of autophagy in ALI by regulating the expression of autophagy factors, ultimately causing a protective effect on lung tissue. |
MicroRNAs: Potential Biomarkers and Targets of Therapy in Allergic Diseases?AbstractMicroRNAs (miRNAs) are small non-coding RNA molecules that are 18–22 nucleotides long and highly conserved throughout evolution. Currently, they are considered one of the fundamental regulatory mechanisms of genes expression. It has been demonstrated that miRNAs are involved in many biologic processes, such as signal transduction, cell proliferation and differentiation, apoptosis and stress responses. More recently, the role of miRNA has also been revealed in numerous immunological and inflammatory disorders, including allergic inflammation. Specific miRNA profiles were demonstrated in asthma, allergic rhinitis and atopic dermatitis. A core set of miRNAs involved in atopic diseases include upregulated miR-21, miR-223, miR-146a, miR-142-5p, miR-142-3p, miR-146b, miR-155 and downregulated let-7 family, miR-193b and miR-375. Most of the involved miRNAs increase secretion of Th2 cytokines (miR-1248, miR-146b), decrease secretion of Th1 cytokines (miR-513-5p, miR-625-5p) or promote differentiation of T cells towards Th2 (miR-21, miR-19a). In asthma miR-140-3p, miR-708 and miR-142-3p play a role in hyperplasia and hypertrophy of bronchial smooth muscle cells. Some single miRNAs or, more probably, their sets hold the promise for their use as biomarkers of atopic diseases. They are also promising target of future therapies. |
Conjugation of Meningococcal Lipooligosaccharides Through Their Non-Reducing Terminus Results in Improved Induction a Protective Immune ResponseAbstractThe present studies prove that conjugation of meningococcal lipooligosaccharides through their non-reducing terminus conserves their inner epitopes resulting in conjugates potent to induce a protective immune response. Four different oligosaccharides were obtained by specific degradations of the same L7 lipooligosaccharide (L7-LOS), and each was linked to tetanus toxoid by direct reductive amination. Two were truncated oligosaccharides with incomplete inner epitopes and were obtained by mild acid hydrolysis of lipooligosaccharide. The terminal galactose of one oligosaccharide was additionally enzymatically oxidized. These oligosaccharides were conjugated through a newly exposed terminal Kdo in reducing end or through oxidized galactose localized at non-reducing end of the core, respectively. The third was a full-length oligosaccharide obtained by O-deacylation of the L7-LOS and subsequent enzymatic removal of phosphate substituents from its lipid A moiety. The fourth one was also a full-length O-deacylated lipooligosaccharide, but treated with galactose oxidase. This allowed direct conjugation to tetanus toxoid through terminal 2-N-acyl-2-deoxy-d-glucopyranose or through oxidized galactose, respectively. Comparison of the immune performance of four conjugates in mice revealed, that while each was able to induce significant level of L7-LOS-specific IgG antibody, the conjugates made with the full-length saccharides were able to induce antibodies with increased bactericidal activity against homologous meningococci. Only full-length oligosaccharides were good inhibitors of the binding of L7-LOS to the bactericidal antiserum. Moreover, induction of the significant level of the L7-LOS-specific antibody by full-length lipooligosaccharide conjugated from non-reducing end, provided also the direct evidence that internal core epitopes are fully responsible for the immunorecognition and immunoreactivity. |
IgG from Non-atopic Individuals Induces In Vitro IFN-γ and IL-10 Production by Human Intra-thymic γδT Cells: A Comparison with Atopic IgG and IVIgAbstractMatured in the thymus, γδT cells can modulate the development of allergy in humans. The main γδT cell subsets have been described as interleukin (IL)-17A or interferon (IFN)-γ producers, but these cells can also produce other modulatory cytokines, such as IL-4 and IL-10. Here, we aimed to evaluate whether IgG can modulate the profile of cytokine production by γδT cells during their maturation in the thymus and after its migration to peripheral tissues. Thymic tissues were obtained from 12 infants, and peripheral blood mononuclear cells (PBMCs) were obtained from adults (both groups without an atopic background). IgG was purified from atopic and non-atopic volunteers. Thymocytes and PBMCs were cultured with purified atopic or non-atopic IgG, and intracellular cytokine production and phenotype were assessed. Mock and IVIg conditions were used as controls. IgG from non-atopic individuals induced IFN-γ and IL-10 production by thymic γδT cells, and no effect was observed on peripheral γδT cells. IL-17 production was inhibited by non-atopic IgG on thymic γδT cells and augmented by atopic IgG on peripheral γδT cells. Modulated thymic γδT cells did not produce IFN-γ and IL-10 simultaneously. We additionally evaluated the phenotype of intrathymic γδT cells and observed that IgG from all groups could induce CD25 expression and could not influence the CD28 expression of these cells. This report describes evidence revealing that IgG may influence the production of IFN-γ and IL-10 by intrathymic γδT cells depending on the donor atopic state. This observation is unprecedented and needs to be considered in further studies in the IgG immunotherapy field. |
Variant and Specific Forms of Autoimmune Cholestatic Liver DiseasesAbstractPrimary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the main autoimmune cholestatic liver diseases. IgG4-associated sclerosing cholangitis is another distinct immune-mediated cholestatic disorder of unknown aetiology that is frequently associated with autoimmune pancreatitis or other IgG4-related diseases. Although the majority of PBC and PSC patients have a typical presentation, there are common and uncommon important variants or specific subgroups that observed in everyday routine clinical practice. In this updated review, we summarize the published data giving also our own experience on the variants and specific groups of autoimmune cholestatic liver diseases. Actually, we give in detail the underlining difficulties and the rising dilemmas concerning the diagnosis and management of these special conditions in the clinical spectrum of autoimmune cholestatic liver diseases including the IgG4-associated sclerosing cholangitis highlighting also the uncertainties and the potential new eras of the research agenda. |
Proportion of Cytotoxic Peripheral Blood Natural Killer Cells and T-Cell Large Granular Lymphocytes in Recurrent Miscarriage and Repeated Implantation Failure: Case–Control Study and Meta-analysisAbstractWe aimed to compare the proportion of peripheral blood natural killer (NK) cells (CD3–CD56+) and T-cell large granular lymphocytes (CD8+CD57+) during preconception in a homogenous group of women with unexplained well-defined recurrent miscarriage (RM) and repeated implantation failure (RIF) vs healthy controls in relation to pregnancy outcomes. This case–control study followed by a literature review and meta-analysis was conducted in three university hospitals. Patients and controls were consecutively recruited from December 2015 to October 2017. In total, 115 women were included in the study: 54 with RM, 41 with RIF and 20 healthy controls with ≥ 2 term births. Percentages of CD3–CD56+ and CD8+CD57+ cells and sub-populations of CD3–CD56+ cells did not differ between cases and controls. The results for women with subsequent miscarriage did not differ from those with live births. The meta-analysis of the literature showed higher NK-cell proportions in RM [mean difference 3.47 (95% CI 2.94–4.00); p < 0.001] and RIF [mean difference 1.64 (95% CI 0.82–2.45); p < 0.001] than controls. However, the heterogeneity between the different studies was high. The proportion of peripheral blood CD3–CD56+ and CD8+CD57+ cells in the preconception period does not reflect the risk of implantation failure or miscarriage and should not be recommended indicators for the management of RM and RIF. Further prospective large studies are needed to develop a reliable peripheral blood marker of immune deregulation. |
Adjuvant Allergen Fusion Proteins as Novel Tools for the Treatment of Type I AllergiesAbstractWhile acute allergic symptoms can be managed by emergency medication, to date, allergen-specific immunotherapy (SIT) with allergen extracts is the only available curative treatment option. However, the risk of anaphylactic reactions, long treatment duration, varying extract quality, and underrepresentation of certain allergens currently prevent many patients from successfully undergoing SIT. Novel strategies are needed to enhance efficacy, safety, and convenience of allergy treatment. Fusion proteins combining allergen and adjuvant into a single molecule can efficiently induce immune responses by targeting the allergen to the relevant immune cells in vivo. Simultaneous co-delivery of both antigen and adjuvant to the same cell in a fixed molecular ratio triggers the uptake and presentation of the conjugated allergen in the context of the adjuvant-induced immune cell activation. This review summarizes the published strategies to improve the treatment of type I allergies using fusion proteins consisting of allergen (peptides) and either (1) immune-activating bacterial (flagellin, MPLA, S-layer, cholera-, and tetanus toxin), (2) viral (PreS, VP-1, TAT), or (3) fungal (FIP-fve) components, (4) immune-activating DNA motifs, (5) forced delivery of allergens to the MHC-II loading pathway, and (6) killing of immune cells expressing allergen-specific IgE by fusion of the allergen to diphtheria toxin. |
Diverse Activity of IL-17 + Cells in Chronic Skin and Mucosa Graft-Versus-Host DiseaseAbstractExcessive inflammatory environment in a course of chronic graft-versus-host disease (cGvHD) is associated with T-cell trafficking into inflamed tissues. This study focused on the identification of IL-17-producing cells in the tissue biopsies of cGvHD patients. Forty-one biopsy specimens of cGvHD lesions of the skin (n = 27), gastrointestinal tract (n = 9) and oral mucosa (n = 5), examined in 24 patients, were morphologically defined according to the NIH criteria and analyzed for the presence of cellular infiltrations including: IL-17+, FOXP3+ and CCR6+ cells. IL-17+ cells were identified in 26/27 skin and in all gut and oral mucosa biopsies, being more frequent in mucosa lesions than in the skin (11/14 vs 14/26, respectively; NS: not significant). Double staining documented that CD138+/IL-17+ cells were commonly seen in the gut than in the skin (5/8 vs 3/11, respectively; NS). In the skin, cells expressing trafficking receptor CCR6+ were more frequent than IL-17+ cells compared to the mucosa (23/26 vs 2/13, respectively; p < 0.0001). CCR6 was present on a majority of IL-17+ cells in all examined skin biopsies but only in 6 out of 11 digestive tract biopsies (p = 0.0112). FOXP3+ cells were identified only in five patients (with mild lesions) at least in one biopsy. In this study group, results documented that local expansion of IL-17-producing cells in the digestive tract correlate with moderate and severe clinical symptoms of cGvHD, in contrast to the skin, where IL-17+ cells are rather scarcely present (p = 0.0301) and the course of cGvHD is slowly progressing with final organ deterioration. |
CTLA-4 Expression Inversely Correlates with Kidney Function and Serum Immunoglobulin Concentration in Patients with Primary GlomerulonephritidesAbstractMajor causes of chronic kidney disease are primary proliferative and nonproliferative glomerulonephritides (PGN and NPGN). However, the pathogenesis of PGN and NPGN is still not fully understood. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a T-cell membrane receptor that plays a key role in T-cell inhibition. Despite its role in autoimmunological diseases, little is known about the involvement of CTLA-4 in the pathogenesis of PGN and NPGN. The objective of this study was to determine the role of CTLA-4 in the pathogenesis of PGN and NPGN by evaluating the frequencies of T and B lymphocytes expressing CTLA-4 and the serum concentration of the sCTLA-4 isoform in patients with PGN and NPGN in relation to clinical parameters. The study included peripheral blood (PB) samples from 40 PGN and NPGN patients and 20 healthy age- and sex-matched volunteers (control group). The viable PB lymphocytes were labeled with fluorochrome-conjugated monoclonal anti-CTLA-4 antibodies and analyzed using flow cytometry. The serum concentration of sCTLA-4 was measured using ELISA. The frequencies and absolute counts of CD4+/CTLA-4+ T lymphocytes, CD8+/CTLA-4+ T lymphocytes and CD19+/CTLA-4+ B lymphocytes and the serum sCTLA-4 concentration were lower in PGN and NPGN patients that in the control group. Reduced sCTLA-4 expression was associated with a lower concentration of serum immunoglobulins. Our results indicate that deregulation of CTLA-4 expression may result in continuous activation of T cells and contribute to the pathogenesis of PGN and NPGN. |
Natural Killer and Natural Killer T Cells in Juvenile Systemic Lupus Erythematosus: Relation to Disease Activity and ProgressionAbstractThe contribution of innate immune cells, including natural killer (NK) and natural killer T (NKT) cells, in systemic lupus erythematosus (SLE) is still unclear. Herein, we examined the frequency of peripheral NK cells, CD56dimand CD56bright NK cells, and NKT cells in patients with juvenile SLE and their potential relations to SLE-related clinical and laboratory parameters. The study included 35 SLE children and 20 apparently healthy controls. After baseline clinical and lab work, SLE Disease Activity Index (SLEDAI-2K) and Pediatric Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (Ped-SDI) scores were assessed. The frequency of peripheral NK cells, CD56dim and CD56bright NK cells, and NKT cells was examined using flow cytometry. SLE patients showed significantly lower frequency of NK cells and NKT cells and higher frequency of CD56bright NK cells compared to controls. Disease activity, urea, and creatinine correlated negatively with NK, but positively with CD56bright NK cells. NK and NKT cells exhibited inverse correlation with the renal biopsy activity index; however, CD56bright NK cells showed direct correlations with both activity and chronicity indices. Regarding Ped-SDI, renal, neuropsychiatry disorders, and growth failure correlated inversely with NK but directly with CD56bright NK cells. NKT cell inversely correlated with renal damage and delayed puberty. In conclusion, low frequency of NK and NKT and expansion of CD56bright NK cells are marked in juvenile SLE, particularly with activity. These changes have direct effect on renal impairment and growth failure, reflecting their potential influence on disease progression. |
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