ROLE OF CXCR3 CHEMOKINE RECEPTOR AND ITS LIGANDS IN CERTAIN DISEASES

Chemokines are a special family of cytokines whose main function is to control cell migration; they are key players in the innate and adaptive immune responses. Directed chemotaxis of specific leukocyte subpopulations is necessary not only to maintain homeostasis, but also in development of some immunopathological conditions such as cancer, inflammation, infection, allergies and autoimmune disorders. Chemokines are pleiotropic molecules that are involved in physiological and pathophysiological processes. For example, the CXCR3 chemokine receptor is expressed on various cells: activated T and B lymphocytes, natural killers, eosinophils and neutrophils, dendritic cells, fibroblasts, endothelial and epithelial cells. Hence, CXCR3 and its ligands have a wide range of functional activity. CXCR3 ligands are the IFNγ-induced chemokines: CXCL9, CXCL10, CXCL11, and platelet-derived chemokines: CXCL4, CXCL4L1. All the CXCR3 ligands share common angiostatic properties due to lack of the Glu-Leu-Arg (ELR) motif. IFNγ-induced ligands of the CXCR3 are proinflammatory chemokines, they mainly recruit activated T cells and exert an effect on T cell polarization. Due to wide spectrum of biological activity, the ligands of CXCR3 receptor are involved in pathogenesis of various disorders, such as inflammation, infection, cancer, allergies and autoimmune disorders. In this review, we discuss the role of CXCR3 ligands in immunopathogenesis of various diseases, including the results of our studies in chronic hepatitis C, rheumatoid arthritis and pulmonary tuberculosis. Moreover, we have also discussed the potential laboratory diagnostic applicability of the chemokines in various diseases. This review illustrates a universal role of IFNγ-induced chemokines as mediators of immune responses in various diseases. The studies of CXCR3 ligands, their isoforms and receptors, interactions between themselves and with their receptors can provide a significant contribution to our understanding of the chemokine network. Understanding the system of IFNγ-dependent chemokines may have clinical implications, both for diagnostic tasks, and for therapeutic purposes

ANALYSIS OF EXPRESSION OF ANGIOGENIC AND ANGIOSTATIC CHEMOKINES AND THEIR RECEPTORS IN SYNOVIAL TISSUE BY QUANTITATIVE REAL-TIME PCR

Abstract. Chemokines are generally believed to play an important role in immunopathogenesis of different joint diseases. Synovial fluid is the primary bio-material, along with peripheral blood, for evaluation of patients with joint pathology (rheumatoid arthritis, osteoarthritis, psoriatic arthritis, etc). However, analysis of synovial membranes is also of importance, since the main pathologic processes evolve at this site. Analysis of chemokines and their receptors in synovium may provide more complete information about immunopathogenesis of articular disease of different etiologies. We carried out optimization procedures for real-time reverse-transcription PCR analysis, in order to quantify specific mRNA expression of angiogenic and angiostatic chemokines and their receptors in synovium. All the stages, from sampling the biological material and until analysis of results are described in details. Normal ranges for mRNA expression rates are provided, as based on examination of subjects with previous traumatic joint injury, without any clinical signs of current systemic or local inflammation. We demonstrate that this method can be informative for comparing intra-articular expression of chemokines and their receptors between different clinical groups. It can also be used to investigate the role of chemokines in appropriate immunopathological events

COMPARISON OF THE DIAGNOSTIC INFORMATIVE VALUE OF DETERMINATION OF MRNA OF SOME HOMEOSTATIC AND PROINFLAMMATORY CYTOKINES IN THE SYNOVIAL MEMBRANE OF PATIENTS WITH RHEUMATOID ARTHRITIS

The problem of the early diagnosis of rheumatoid arthritis (RA) remains relevant, which is associated with the limited potential of available biomarkers and the heterogeneity of the disease. Chemokines and cytokines produced by the synovial membrane of the patients play a leading role in the pathogenesis of the disease, suggesting that they may be used as promising biomarkers.Objective: to comparatively investigate the relative mRNA expression of the homeostatic chemokines: stromal cellderived factor 1 (SDF-1/CXCL12), B-cell-attracting chemokine-1 (BCA-1/CXCL13), their receptors CXCR4 and CXCR5, the proinflammatory chemokines: macrophage chemotactic protein-1 (MCP-1/CCL2), T cell expressed and secreted chemokine on activation (CCL5/RANTES), interleukin-8 (IL-8) (IL-8/CXCL8), IL-17, and vascular endothelial growth factor (VEGF) in the synovial membrane biopsy specimens from patients with RA or osteoarthritis (OA) and from healthy individuals and to estimate the diagnostic informative value of these biomarkers.Subjects and methods. The expression of mRNA was estimated using a real-time polymerase chain reaction assay. The RA group included 28 patients, their median age was 47 [35; 54] years; disease duration – 8 [4; 12] years; DAS28 – 4.9 [3.9; 5.5]; 16 and 14 patients were seropositive for rheumatoid factor and anti-cyclic citrulinated peptide antibodies, respectively. The OA group comprised 22 patients whose median age was 70.5 [61; 74] years. Fifteen clinically healthy individuals with a median age of 45 [28; 64] years were also examined.Results and discussion. The RA group was noted to have significantly higher RANTES, IL-8, IL-17, VEGF, BCA-1, and CXCR5 mRNA levels than the OA group and healthy individuals. In the patients with OA, the level of the homeostatic chemokines BCA-1 and SDF-1, which had B-cell chemoattractant activities, was higher than that in the control group, which may suggest that they are implicated in the pathogenesis of the disease. The determination of RANTES mRNA expression was most informative in diagnosing RA: the area under the curve (AUC), 0.91 [95% confidence interval (CI), 0.84–0.99]; diagnostic sensitivity, 72.97% (95% CI, 55.88–86.21), diagnostic specificity, 96.15% (95% CI, 80.36–99.90); positive likelihood ratio (LR+), 18.95; negative likelihood ratio (LR-), 0.28 at a diagnostic threshold of 0.0350, so was CBC1 mRNA. The AUC for BCA-1 was 0.78 (95% CI, 0.66–0.89); diagnostic sensitivity, 56.25% (95% CI, 37.66–73.64), diagnostic specificity, 92.59% (95% CI, 75.71–99.09); LR+, 7.59; LR-, 0.47 at a diagnostic threshold of 0.0184

ANGIOGENIC AND ANGIOSTATIC CHEMOKINES LEVEL IN NORMAL SYNOVIAL FLUID

Chemokines are believed to play an important role in immunopathogenesis of different joint diseases. One of important problems in studies of synovial fluid is determination of normal level of chemokines from control patients. In our study we determined concentrations of number of chemokines in relatively normal synovial fluid from subjects with background traumatic joint injury without systemic or local inflammation at the moment of study. Results for several CC- and CXC-chemokines are shown for the first time. Therefore, our data can be further used in analysis of synovial fluid chemokine profile in studies of joint disease of different etiology

LEVELS OF ANGIOGENESIS-REGULATORY CHEMOKINES IN THE SYNOVIAL FLUID OF PATIENTS WITH RHEUMATOID ARTHRITIS

The role of chemokines in the immunopathogenesis of rheumatoid arthritis (RA) has been actively investigated in recent years. Angiogenic and angiostatic chemokines are important mediators of angiogenesis in the development and extent of pannus. Peripheral blood and synovial fluid (SF) is a major biomaterial in clinical and immunological studies. At the same time, it is the SF test that may yield the most informative results since that gives an idea of the processes that occur locally within a joint. Objective: to perform a comparative analysis of the levels of a number of CXC, CC, and CX3C chemokines in the SF of patients with RA, osteoarthritis (OA), and joint injuries. Subjects and methods. The multiplex analysis using xMAP technology (Luminex, USA) was used to analyze levels of CXC, CC, and CX3C chemokines in SF and serum of patients with RA (n = 20), OA (n = 9) and controls (n = 9). Results and discussion. The SF levels of CCL24/eotaxin-2, as well as those of the angiostatic chemokines CXCL9/MIG, CXCL10/IP10, CXCL11/ITAC, and CXCL13/BCA-1 were higher in the RA group than in the control and OA groups. There was a direct correlation between SF levels of CCL5/RANTES and DAS28, as well as patient global disease activity assessment on visual analogue scale, and that between the level of CCL2/MCP-1 in the SF and that of anticyclic citrullinated peptide (anti-CCP) antibodies in the serum. The SF concentrations of CXCL5/ENA78 and CXCL7/NAP-2 were shown to depend on the presence of serum anti-CCP. Serum CXCL13/BCA-1 levels were higher in RA than those in OA, as that of CXCL7/NAP-2 than in the control group

The European Virus Archive: a new resource for virology research

The European Virus Archive (EVA) was conceived as a direct response to the need for a coordinated and readily accessible collection of viruses that could be made available to academia, public health organisations and industry, initially within Europe, but ultimately throughout the world. Although scientists worldwide have accumulated virus collections since the early twentieth century, the quality of the collections and the viruses collected may vary according to the personal interests and agenda of the scientists. Moreover, when laboratories are re-organised or closed, collections are no longer maintained and gradually cease to exist. The tragedy of 9/11 and other disruptive activities have also meant that some previously available biological reagents are no longer openly exchanged between countries. In 2008, funding under the FP7-EU infrastructure programme enabled the initiation of the EVA. Within three years, it has developed from a consortium of nine European laboratories to encompass associated partners in Africa, Russia, China, Turkey, Germany and Italy. There is every reason to believe that EVA will continue to expand and ultimately exist as a globally networked, quality-controlled non-profit archive for the benefit of science. Organizations or individuals who would like to be considered as contributors are invited to contact the EVA coordinator, Jean-Louis Romette, at [email protected]