Glycosylation Might Provide Endothelial Zip Codes for Organ-Specific Leukocyte Traffic into Inflammatory Sites

Abstract

Inflammatory diseases, such as acute kidney and heart allograft rejections or bronchial asthma, are characterized by a heavy infiltration of lymphocytes and monocytes, but not of granulocytes, leading finally to necrotic changes at the inflammatory site. [1][2][3][4] The recruitment of lymphocytes across the microvascular postcapillary endothelium 5-7 is a complex cascade, taking its origin from the initial tethering and rolling of leukocytes that are mediated by the members of the selectin family and their glycosylated ligands. These interactions are followed by a chemokine-mediated activation of integrins, leading to a firm adhesion of rolling leukocytes and, subsequently, to transendothelial migration into inflammatory sites. 8,9 The tethering and rolling phases of lymphocyte extravasation have been proposed to be initiated by L-selectin. This molecule recognizes endothelial ligands, such as CD34, podocalyxin, MAdCAM-1, and sgp200, provided that these ligands are decorated with ␣2,3-sialylated, ␣1,3-fucosylated, and sulfated lactosamines. 1,5-7,10 -12 These sulfated sialyl Lewis x (sLex) glycans are necessary for the L-selectin-mediated binding of lymphocytes to endothelium and are constantly expressed at least on the CD34 glycans of lymph node high endothelium. 13 Under normal conditions, the flat endothelium in parenchymal organs does not express properly glycosylated modifications of L-selectin ligands 14 and no extravasation occurs. However, the induction of sLex-or sulfo sLex-decorated L-selectin ligands onto the postcapillary microvascular endothelium occurs both in rodents and humans undergoing heart and kidney allograft rejection and also in the early specimens taken from bronchial asthma patients. [2][3][4]14 Moreover, the enzymatically synthesized multivalent sLex glycans can prevent the selectin-dependent lymphocyte adhesion to properly glycosylated endothelium ex vivo, pointing out a putative mean to inhibit the inflammatory reaction. 14,15 Here we expand these previous observations and analyze the endothelial sLex or sulfo sLex expression patterns in various inflammatory diseases. For this purpose, a large series of histological biopsies (Ͼ400) from patients with ulcerative colitis, psoriasis, thyroiditis, myocarditis, and vasculitis and their corresponding noninflamed tissues were collected. The endothelium of control noninflamed tissues did not express essentially any sLex or sulfo sLex epitopes whereas on the endothelium of inflamed organs they were prominently expressed. Most importantly, the up-regulated sLex or sulfo sLex expression patterns of inflamed tissues were clearly different between every organ analyzed, and when combined with

Keratin-8-deficient mice develop chronic spontaneous Th2 colitis amenable to antibiotic treatment

“…Abnormal expression of PNAd in inflamed tissues occurs in several chronic autoimmune diseases including IBD (Renkonen et al, 2002), as noted in the K8-/-inflamed colons. PNAd induction is probably dependent on chronicity of the colitis since it becomes more prominent in older mice.…”

“…5Ad and f as compared with c and e). Since high numbers of naive CD4+ T cells (L-selectin+ or CD62L+) were recovered from the inflamed colons of K8-null mice, and aberrant expression of PNAd in chronically inflamed tissues in human patients has been observed (Renkonen et al, 2002), we assessed the presence of PNAd+ venules in the colon. Unlike sections from K8+/+ mice where PNAd staining is absent, several PNAd+ venules were visible in K8-/-colons (Fig.…”

“…The mechanism by which naive T cells accumulate within chronically inflamed tissues is not fully understood but may involve aberrant PNAd expression. Such expression occurs in various tissues of patients with chronic autoimmune diseases including IBD (Renkonen et al, 2002), and T cells isolated from involved intestines of IBD patients (but not from healthy colons) interact with PNAd in vitro (Salmi et al, 1994;Salmi and Jalkanen, 2001). Whether similar events occur in animal models of IBD is not known.…”

Induction of peripheral lymph node addressin in human gastric mucosa infected byHelicobacter pylori

“…In previous studies, MECA-79 has been frequently used to characterize PNAd on HEV-like vessels. Although HECA-452 antibody was also used in one study, no structural basis for differential staining was inferred (28). By using HECA-452 and NCC-ST-439 antibodies in addition to MECA-79 antibody, we have obtained more detailed knowledge of the chemical nature of L-selectin ligands on HEV-like vessels induced by H. pylori infection.…”

“…The numbers of MECA-79 ϩ and HECA-452 ϩ vessels each were divided by the number of CD34 ϩ vessels, yielding the percentages of MECA-79 ϩ and HECA-452 ϩ vessels, respectively, as described in ref. 28.…”