Sulfated L-selectin ligands as a therapeutic target in chronic inflammation

doi:10.1016/j.it.2006.10.007

Trends in Immunology

Volume 27, Issue 12, December 2006, Pages 559-565

https://doi.org/10.1016/j.it.2006.10.007 Get rights and content

The homing of lymphocytes to peripheral lymph nodes is initiated by an adhesive interaction between L-selectin on lymphocytes and peripheral node addressin (PNAd), a set of sialomucins displayed on high endothelial venules (HEVs) of lymph nodes. The monoclonal antibody MECA-79 reacts with the PNAd sialomucins by recognizing an N-acetylglucosamine (GlcNAc)-6-sulfated oligosaccharide, which overlaps with sialyl 6-sulfo Lewis X, the L-selectin recognition determinant. Two HEV-expressed sulfotransferases, GlcNAc6ST-1 and GlcNAc6ST-2, are essential for the expression of the MECA-79 epitope and L-selectin ligand activity on lymph-node HEVs. PNAd, as defined by MECA-79 staining, is also expressed on activated blood vessels at several sites of chronic inflammation. Recent evidence indicates that the same two sulfotransferases underlie the formation of functional PNAd at these sites. Experiments in a sheep model of asthma demonstrate that a chronic inflammatory disease can be ameliorated by targeting PNAd.

Section snippets

PNAd and the sialyl 6-sulfo Lewis X determinant in lymphocyte homing

Investigations of lymphocyte recirculation resulted in the discovery of L-selectin as the ‘lymph node homing receptor’ involved in the interaction of lymphocytes with high endothelial venules (HEVs) of lymph nodes 1, 2. Further study revealed that L-selectin mediates the rolling interaction of lymphocytes with HEVs, the first step in a cascade of adhesive and signaling steps that culminate in the delivery of lymphocytes (naive T and B cells, and central memory T cells) into lymph nodes 3, 4.

Sulfotransferases involved in PNAd synthesis

Unsurprisingly, the enzymes involved in the critical post-translational modifications of PNAd have attracted a lot of interest from glycobiologists. With respect to fucosylation, sialylation, core-2 branching and the extension of the core-1 branch, considerable progress has been made in identifying the crucial enzymes, or at least prime candidates, for the biological activities 5, 16, 17. The importance of GlcNAc-6-sulfation to both sialyl 6-sulfo Lewis X and the MECA-79 epitope has motivated

PNAd induction during chronic inflammation

It has long been known that PNAd⁺ vessels are induced at many sites of chronic inflammation in animal models and humans [5]. In human diseases, the most completely documented examples include cutaneous sites of chronic inflammation, bronchial asthma, rheumatoid arthritis (RA), heart allografts, kidney allografts, thyroiditis, and, most recently, gastritis induced by Helicobacter pylori infection 40, 41, 42, 43, 44, 45. In some studies, positive MECA-79 staining has been directly confirmed to

Therapeutic effects of MECA-79

In a limited number of cases, short-term lymphocyte-homing assays have been employed to confirm that MECA-79 staining of vessels at inflammatory sites does, in fact, correspond to functional L-selectin ligands 54, 55. Thus, intravenous MECA-79 injection was found to block the short-term accumulation of adoptively transferred lymphocytes into the inflamed tissues exhibiting PNAd⁺ vessels. Unfortunately, only limited information has been available about the true pathophysiologic significance of

Acknowledgements

The work reviewed from our laboratory has been supported by NIH grants to S.D.R. (R01 GM57411, R01 GM23547 and P01 HL024136).

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Trends in Immunology

ReviewSulfated L-selectin ligands as a therapeutic target in chronic inflammation

Section snippets

PNAd and the sialyl 6-sulfo Lewis X determinant in lymphocyte homing

Sulfotransferases involved in PNAd synthesis

PNAd induction during chronic inflammation

Therapeutic effects of MECA-79

Acknowledgements

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Homing in on L-selectin

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Review
Sulfated L-selectin ligands as a therapeutic target in chronic inflammation