Biomedical subjects

Bertus Eksteen

Publications and source records attributed to Bertus Eksteen.

7 recordsLinked to original sources

PubMed2006

Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells.

Normal intestinal mucosa contains abundant immunoglobulin A (IgA)-secreting cells, which are generated from B cells in gut-associated lymphoid tissues (GALT). We show that dendritic cells (DC) from GALT induce T cell-independent expression of IgA and gut-homing receptors on B cells. GALT-DC-derived retinoic acid (RA) alone conferred gut tropism but could not promote IgA secretion. However, RA potently synergized with GALT-DC-derived interleukin-6 (IL-6) or IL-5 to induce IgA secretion. Consequently, mice deficient in the RA precursor vitamin A lacked IgA-secreting cells in the small intestine. Thus, GALT-DC shape mucosal immunity by modulating B cell migration and effector activity through synergistically acting mediators.

Animals↗

PubMed2006

Epithelial inflammation is associated with CCL28 production and the recruitment of regulatory T cells expressing CCR10.

Mucosal tissues require constant immune surveillance to clear harmful pathogens while maintaining tolerance to self Ags. Regulatory T cells (Tregs) play a central role in this process and expression of alpha(E)beta(7) has been reported to define a subset of Tregs with tropism for inflamed tissues. However, the signals responsible for recruiting Tregs to epithelial surfaces are poorly understood. We have isolated a subset of CCR10-expressing CD25+CD4+Foxp3+ Tregs with potent anti-inflammatory properties from chronically inflamed human liver. The CCR10+ Tregs were detected around bile ducts that expressed increased levels of the CCR10 ligand CCL28. CCL28 was secreted by primary human cholangiocytes in vitro in response to LPS, IL-1beta, or bile acids. Exposure of CCR10+ Tregs to CCL28 in vitro stimulated migration and adhesion to mucosal addressin cell adhesion molecule-1 and VCAM-1. Liver-derived CCR10+ Tregs expressed low levels of CCR7 but high levels of CXCR3, a chemokine receptor associated with infiltration into inflamed tissue and contained a subset of alpha(E)beta7(+) cells. We propose that CXCR3 promotes the recruitment of Tregs to inflamed tissues and CCR10 allows them to respond to CCL28 secreted by epithelial cells resulting in the accumulation of CCR10+ Tregs at mucosal surfaces.

Bile Ducts↗

PubMed2006

Aberrant homing of mucosal T cells and extra-intestinal manifestations of inflammatory bowel disease.

Active inflammatory bowel disease (IBD) is often associated with simultaneous inflammation in the skin, eyes and joints. Inflammatory disease in the liver can also occur in patients with IBD but seems to be independent of inflammation in the bowel. In this Opinion article, we propose that the hepatic complications of IBD are mediated by long-lived mucosal T cells that are recruited to the liver in response to aberrantly expressed endothelial-cell adhesion molecules and chemokines that are normally restricted to the gut. Similar mechanisms might explain why certain diseases are associated with site-specific tissue distributions and might point to new therapeutic strategies that are based on modulating tissue-specific lymphocyte homing.

Cell Adhesion Molecules↗

PubMed2005

CXCR 3 activation promotes lymphocyte transendothelial migration across human hepatic endothelium under fluid flow.

T cells infiltrating the inflamed liver express high levels of CXCR 3 and show enhanced migration to CXCR 3 ligands in chemotactic assays. Moreover, CXCR 3 ligands are up-regulated on hepatic endothelium at sites of T-cell infiltration in chronic hepatitis, and their presence correlates with outcome of inflammatory liver disease. We used a flow-based adhesion assay with human hepatic endothelium to investigate the function of CXCR 3 on lymphocyte adhesion to and transmigration through hepatic endothelium under physiological conditions of blood flow. To more accurately model the function of in vivo activated CXCR 3(high) lymphocytes, we isolated T cells from human liver tissue and studied their behavior in flow-based adhesion assays. We demonstrate that CXCR 3 not only promoted the adhesion of effector T cells to endothelium from flow but also drove transendothelial migration. Moreover, these responses could be stimulated either by endogenous CXCR 3 ligands secreted by the endothelium or by exogenous CXCR 3 ligands derived from other cell types and presented by the endothelium. This study thus demonstrates that activation of CXCR 3 promotes lymphocyte adhesion and transendothelial migration under flow and that human hepatic endothelium can present functionally active chemokines secreted by other cell types within the liver.

Biliary Tract↗

PubMed2004

Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC), a chronic inflammatory liver disease characterized by progressive bile duct destruction, develops as an extra-intestinal complication of inflammatory bowel disease (IBD) (Chapman, R.W. 1991. Gut. 32:1433-1435). However, the liver and bowel inflammation are rarely concomitant, and PSC can develop in patients whose colons have been removed previously. We hypothesized that PSC is mediated by long-lived memory T cells originally activated in the gut, but able to mediate extra-intestinal inflammation in the absence of active IBD (Grant, A.J., P.F. Lalor, M. Salmi, S. Jalkanen, and D.H. Adams. 2002. Lancet. 359:150-157). In support of this, we show that liver-infiltrating lymphocytes in PSC include mucosal T cells recruited to the liver by aberrant expression of the gut-specific chemokine CCL25 that activates alpha4beta7 binding to mucosal addressin cell adhesion molecule 1 on the hepatic endothelium. This is the first demonstration in humans that T cells activated in the gut can be recruited to an extra-intestinal site of disease and provides a paradigm to explain the pathogenesis of extra-intestinal complications of IBD.

Cell Movement↗

PubMed2002

Gastroenterology.

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Attitude of Health Personnel↗

PubMedDate not supplied

Lymphocyte homing in the pathogenesis of extra-intestinal manifestations of inflammatory bowel disease.

Inflammatory bowel disease is associated with extra-intestinal manifestations which occur either at the same time as flares of bowel inflammation (skin and eye disease) or run a course that is independent to inflammation in the bowel (liver and some joint syndromes). It has been suggested that the skin and eye complications occur as a consequence of the recruitment of activated effector cells released from the gut into the circulation to extra-intestinal site where they cause acute damage. However, this does not explain how patients can develop primary sclerosing cholangitis many years after having their colon removed for colitis. We propose that long-lived populations of memory lymphocytes arise as a consequence of bowel inflammation and that these cells express homing receptors that direct their subsequent migration not only to the gut but also to the liver. These long-lived cells may recirculate to the liver for many years and, in the absence of a local activating stimulus, will not cause damage. However, if they are subsequently activated in the liver this will lead to the development of inflammation and tissue damage which promotes the recruitment of more mucosal lymphocytes resulting in persistent inflammation and disease. The recent findings that MAdCAM-1 and CCL25, previously thought to be restricted to the gut, are up-regulated in the liver during inflammatory liver diseases that complicate IBD support the concept that common mechanisms control lymphocyte recruitment to the inflamed liver and gut.

Cell Movement↗