CXCR3/CXCL10 Expression in the Synovium of Children
CXCR3/CXCL10 Expression in the Synovium of Children
The accumulation of T cells in the synovial membrane is the crucial step in the pathophysiology of the inflammatory processes characterizing juvenile idiopathic arthritis (JIA). In this study, we evaluated the expression and the pathogenetic role in oligoarticular JIA of a CXC chemokine involved in the directional migration of activated T cells, i.e. IFNγ-inducible protein 10 (CXCL10) and its receptor, CXCR3. Immunochemistry with an antihuman CXCL10 showed that synovial macrophages, epithelial cells, and endothelial cells bear the chemokine. By flow cytometry and immunochemistry, it has been shown that CXCR3 is expressed at high density by virtually all T lymphocytes isolated from synovial fluid (SF) and infiltrating the synovial membrane. Particularly strongly stained CXCR3 T cells can be observed close to the luminal space and in the perivascular area. Furthermore, densitometric analysis has revealed that the mRNA levels for CXCR3 are significantly higher in JIA patients than in controls. T cells purified from SF exhibit a definite migratory capability in response to CXCL10. Furthermore, SF exerts significant chemotactic activity on the CXCR3 T-cell line, and this activity is inhibited by the addition of an anti-CXCL10 neutralizing antibody. Taken together, these data suggest that CXCR3/CXCL10 interactions are involved in the pathophysiology of JIA-associated inflammatory processes, regulating both the activation of T cells and their recruitment into the inflamed synovium.
The trafficking and accumulation of immunocompetent cells are essential components in the pathophysiology of the inflammatory processes. A number of recent data suggest that most of these events are regulated by chemokines, a superfamily of 8–10 kDa molecules that has been divided into four branches (C, CC, CXC, and CXXXC) according to variations in a shared cysteine. The current roster approaches more than 50 related proteins. Structural variations of chemokines have been associated with differences in their ability to regulate the trafficking of immune cells during inflammatory disorders. The biological activity of chemokines is mediated by seven-transmembrane-domain, G-protein-coupled receptors classified as C, CC, CXC, or CXXXC chemokine receptors according to the type of chemokine bound. Chemokine receptors are constitutively expressed on some cells, whereas they are inducible on others.
Three CXC chemokines (IP-10/CXCL10, Mig/CXCL9, and I-TAC/CXCL11) that are produced in response to IFNγ allow for the accumulation of activated lymphocytes by interacting with a specific receptor (CXCR3). Although the interactions of chemokine receptors are often characterized by considerable promiscuity, CXCR3 is selective in the recruitment of Th1 cells, B cells, and NK (natural killer) cells but not of nonlymphoid cells. Juvenile idiopathic arthritis (JIA) is characterized by chronic inflammation of the synovium in multiple joints. Early studies of the synovial membrane in JIA have shown the presence of a dense infiltrate of activated T cells clustered around activated dendritic cells, suggesting that lymphocyte recruitment is crucial in the pathogenesis of the disease. There is also strong evidence of an up-regulation of IFNγ expression in synovial tissue relative to that in peripheral blood of patients with JIA, indicating a Th1 type polarization of local inflammatory response. Taken together, these data suggest that lymphocyte-specific CXC chemokines could be involved in the mechanisms promoting the development of inflammatory events in JIA patients.
In this study, using immunohistochemical and molecular studies of tissue sections and flow cytometry evaluation of cells recovered from synovial fluid, we evaluated the role of CXCR3/CXCL10 interactions in the regulation of T-cell migration into the joints of patients with JIA. We have demonstrated the presence of IP-10/CXCL10 in the synovial tissue and its release into the synovial fluid, where it exerts chemotactic activity toward activated CXCR3 T cells. Taken together, our data suggest that the local production of CXCL10 is involved in the pathophysiology of JIA-associated inflammatory processes.
The accumulation of T cells in the synovial membrane is the crucial step in the pathophysiology of the inflammatory processes characterizing juvenile idiopathic arthritis (JIA). In this study, we evaluated the expression and the pathogenetic role in oligoarticular JIA of a CXC chemokine involved in the directional migration of activated T cells, i.e. IFNγ-inducible protein 10 (CXCL10) and its receptor, CXCR3. Immunochemistry with an antihuman CXCL10 showed that synovial macrophages, epithelial cells, and endothelial cells bear the chemokine. By flow cytometry and immunochemistry, it has been shown that CXCR3 is expressed at high density by virtually all T lymphocytes isolated from synovial fluid (SF) and infiltrating the synovial membrane. Particularly strongly stained CXCR3 T cells can be observed close to the luminal space and in the perivascular area. Furthermore, densitometric analysis has revealed that the mRNA levels for CXCR3 are significantly higher in JIA patients than in controls. T cells purified from SF exhibit a definite migratory capability in response to CXCL10. Furthermore, SF exerts significant chemotactic activity on the CXCR3 T-cell line, and this activity is inhibited by the addition of an anti-CXCL10 neutralizing antibody. Taken together, these data suggest that CXCR3/CXCL10 interactions are involved in the pathophysiology of JIA-associated inflammatory processes, regulating both the activation of T cells and their recruitment into the inflamed synovium.
The trafficking and accumulation of immunocompetent cells are essential components in the pathophysiology of the inflammatory processes. A number of recent data suggest that most of these events are regulated by chemokines, a superfamily of 8–10 kDa molecules that has been divided into four branches (C, CC, CXC, and CXXXC) according to variations in a shared cysteine. The current roster approaches more than 50 related proteins. Structural variations of chemokines have been associated with differences in their ability to regulate the trafficking of immune cells during inflammatory disorders. The biological activity of chemokines is mediated by seven-transmembrane-domain, G-protein-coupled receptors classified as C, CC, CXC, or CXXXC chemokine receptors according to the type of chemokine bound. Chemokine receptors are constitutively expressed on some cells, whereas they are inducible on others.
Three CXC chemokines (IP-10/CXCL10, Mig/CXCL9, and I-TAC/CXCL11) that are produced in response to IFNγ allow for the accumulation of activated lymphocytes by interacting with a specific receptor (CXCR3). Although the interactions of chemokine receptors are often characterized by considerable promiscuity, CXCR3 is selective in the recruitment of Th1 cells, B cells, and NK (natural killer) cells but not of nonlymphoid cells. Juvenile idiopathic arthritis (JIA) is characterized by chronic inflammation of the synovium in multiple joints. Early studies of the synovial membrane in JIA have shown the presence of a dense infiltrate of activated T cells clustered around activated dendritic cells, suggesting that lymphocyte recruitment is crucial in the pathogenesis of the disease. There is also strong evidence of an up-regulation of IFNγ expression in synovial tissue relative to that in peripheral blood of patients with JIA, indicating a Th1 type polarization of local inflammatory response. Taken together, these data suggest that lymphocyte-specific CXC chemokines could be involved in the mechanisms promoting the development of inflammatory events in JIA patients.
In this study, using immunohistochemical and molecular studies of tissue sections and flow cytometry evaluation of cells recovered from synovial fluid, we evaluated the role of CXCR3/CXCL10 interactions in the regulation of T-cell migration into the joints of patients with JIA. We have demonstrated the presence of IP-10/CXCL10 in the synovial tissue and its release into the synovial fluid, where it exerts chemotactic activity toward activated CXCR3 T cells. Taken together, our data suggest that the local production of CXCL10 is involved in the pathophysiology of JIA-associated inflammatory processes.
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