Abstract
BackgroundThe recruitment of lymphocytes to secondary lymphoid organs relies on interactions of circulating cells with high endothelial venules (HEV). HEV are exclusive to these organs under physiological conditions, but they can develop in chronically-inflamed tissues. The interaction of L-selectin on lymphocytes with sulfated glycoprotein ligands on HEV results in lymphocyte rolling, which represents the initial step in lymphocyte homing. HEV expression of GlcNAc6ST-2 (also known as HEC-GlcNAc6ST, GST-3, LSST or CHST4), an HEV-restricted sulfotransferase, is essential for the elaboration of L-selectin functional ligands as well as a critical epitope recognized by MECA-79 mAb.ResultsWe examined the expression of GlcNAc6ST-2 in relationship to the MECA-79 epitope in rheumatoid arthritis (RA) synovial vessels. Expression of GlcNAc6ST-2 was specific to RA synovial tissues as compared to osteoarthritis synovial tissues and localized to endothelial cells of HEV-like vessels and small flat-walled vessels. Double MECA-79 and GlcNAc6ST-2 staining showed colocalization of the MECA-79 epitope and GlcNAc6ST-2. We further found that both TNF-α and lymphotoxin-αβ induced GlcNAc6ST-2 mRNA and protein in cultured human umbilical vein endothelial cells.ConclusionThese observations demonstrate that GlcNAc6ST-2 is induced in RA vessels and provide potential cytokine pathways for its induction. GlcNAc6ST-2 is a novel marker of activated vessels within RA ectopic lymphoid aggregates. This enzyme represents a potential therapeutic target for RA.
Highlights
The recruitment of lymphocytes to secondary lymphoid organs relies on interactions of circulating cells with high endothelial venules (HEV)
The interaction of L-selectin on lymphocytes with sulfated glycoprotein ligands on HEV of lymph nodes results in lymphocyte rolling on endothelium which represents the initial step in lymphocyte homing [8]
MECA-79 blocks the attachment of lymphocytes to peripheral lymph node (PN) HEV in vitro and inhibits lymphocyte homing to PN in vivo [17]
Summary
The recruitment of lymphocytes to secondary lymphoid organs relies on interactions of circulating cells with high endothelial venules (HEV). The recruitment of cellular elements to secondary lymphoid organs relies on interactions between circulating leukocytes and the specialized endothelium of high endothelial venules (HEV), which are exclusive to these organs under physiological conditions. The interaction of L-selectin on lymphocytes with sulfated glycoprotein ligands on HEV of lymph nodes results in lymphocyte rolling on endothelium which represents the initial step in lymphocyte homing [8]. Expression of GlcNAc6ST-2 (commonly referred to as HEC-GlcNAc6ST or LSST), an HEV-localized sulfotransferase, is essential for the elaboration of functional ligands within lymph nodes, as well as the generation of the MECA-79 epitope [11,12,13]. MECA-79 blocks the attachment of lymphocytes to peripheral lymph node (PN) HEV in vitro and inhibits lymphocyte homing to PN in vivo [17]
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