CXCR3 is a G protein-coupled, seven-transmembrane receptor that binds and is activated by the three IFN-gamma-inducible chemokines of the CXC family named CXCL9, CXCL10, and CXCL11. These chemokines are not constitutively expressed but are up-regulated in a proinflammatory cytokine milieu. Consequently, their major function is to selectively recruit immune cells at inflammation sites, but they also play a role in angiogenesis mechanisms. In the last few years, strong experimental and clinical evidence has been obtained supporting the idea that the CXCR3 pathway is involved in the development of autoimmune diseases, especially by creating local amplification loops of inflammation in target organs, thereby inducing worsening of clinical manifestations. This article briefly reviews what we know today about the nature and functions of CXCR3, with special emphasis on its involvement in two main rheumatic systemic autoimmune diseases, namely rheumatoid arthritis and systemic lupus erythematosus.
Humoral responses are central to the development of chronic autoimmune diseases such as systemic lupus erythematosus. Indeed, autoantibody deposition is responsible for tissue damage, the kidneys being one of the main target organs. As the source of pathogenic antibodies, plasma cells are therefore critical players in this harmful scenario, both at systemic and local levels. The aim of the present study was to analyze plasma cells in NZB/W lupus mice and to get a better understanding of the mechanisms underlying their involvement in the renal inflammation process. Using various techniques (i.e. flow cytometry, quantitative PCR, ELISpot), we identified and extensively characterized three plasma cell intermediates, according to their B220/CD138/MHCII expression levels. Each of these cell subsets displays specific proliferation and antibody secretion capacities. Moreover, we evidenced that the inflammation-related CXCR3 chemokine receptor is uniquely expressed by CD138highMHCII+ plasma cells, which encompass both short- and long-lived cells and mostly produce IgG (auto)antibodies. Expression of CXCR3 allows efficient chemotactic responsiveness of these cells to cognate chemokines, which production is up-regulated in the kidneys of diseased NZB/W mice. Finally, using fluorescence and electron microscopy, we demonstrated the presence of CD138+CXCR3+IgG+ cells in inflammatory areas in the kidneys, where they are very likely involved in the injury process. Thus, early differentiated CD138highMHCII+ rather than terminally differentiated CD138highMHCIIlow plasma cells may be involved in the renal inflammatory injury in lupus, due to CXCR3 expression and IgG secretion.
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