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Immunopathogenesis of Vanishing Bile Duct Syndromes
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
John M. Vierling, Marius Braun, Haimei Wang
Recent studies suggest that portal tract T cells have been sensitized to epithelial antigens in the gut. T cell lines derived from the common bile ducts of two patients with PSC exhibited oligoclonal TCRs that were identical to those in a second biopsy obtained more than a year later.139 The T cell lines proliferated when stimulated with enterocytes and were cytotoxic for enterocytes. T cells from PSC livers also preferentially expressed Vβ3 TCR regardless of disease stage, indicating activation by a limited number of antigens. These findings indicate that portal T cells might have been activated by antigen(s) expressed by enterocytes. Interestingly, mucosal addressin cell adhesion molecule (MadCAM-1), an adhesion molecule important for the homing of T cells to the gut, is aberrandy expressed by hepatic endothelial cells in UC and PSC.140 MadCAM-1 expression in sections of PSC liver biopsies mediated adhesion of gut-derived α4β7 integrin-positive T cells. Thus, aberrant expression of MadCAM-1 might explain preferential recruitment of enterocyte-sensitized, gut-derived mucosal T cells to the liver. TCR crossreactivity with antigens expressed by both enterocytes and BECs might instigate FOC by secreting fibrogenic cytokines.
Lymphocyte trafficking from inductive sites to effector sites
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Valerie Verhasselt, William Agace, Oliver Pabst, Andrew Stagg
It is now clear that CAM expression on HEVs in certain MALT structures differs from that of other HEVs, for example, those in skin-draining lymph nodes, and that selective CAM expression has an important impact on the mechanisms by which naive lymphocytes gain entry into these sites (Figure 16.5). The best example of this is the immunoglobulin (Ig) superfamily member MAdCAM-1, which in adults is constitutively expressed on HEVs in the gut-draining mesenteric lymph nodes and Peyer's patches but not on the HEVs of most extraintestinal lymph nodes. MAdCAM-1 can serve as a scaffold for sulfated glycans, thereby enabling the engagement of L-selectin, and can interact weakly with low-affinity α4β7 integrin. Both interactions contribute to lymphocyte rolling on MAdCAM-1+ venules. Subsequent to chemokine signaling, α4β7 integrin binds MAdCAM-1 with high affinity, resulting in lymphocyte arrest on these HEVs. Interactions of α4β7 integrin with MAdCAM-1 seem particularly important in mediating the entry of naive T lymphocytes into Peyer's patches, as demonstrated by the presence of hypocellular Peyer's patches in mice deficient for MAdCAM-1 or β7 integrins, whereas mice with a deletion in both L-selectin and β7 integrin display hypocellular gut-draining mesenteric lymph nodes. Thus, the constitutive expression of MAdCAM-1 and its binding to β7 integrins are required for the efficient homing of naive lymphocytes into the mesenteric lymph nodes and gut-associated lymphoid tissue (GALT) (see Figure 16.4).
Pathways of Cell Recruitment to Mucosal Surfaces
Published in Bruce S. Bochner, Adhesion Molecules in Allergic Disease, 2020
As deduced from cDNA cloning, murine MAdCAM-1 is a member of the immunoglobulin supergene family with three immunoglobulin domains (65). The two amino terminal domains are homologous to its closest relatives among Ig-like adhesion receptors, ICAM-1 and VCAM-1. The third (or membrane proximal) domain, although unrelated to adhesion receptors of this class, does in fact share homology with another mucosal-related Ig family member, namely IgA. In addition to the three immunoglobulin-like domains, MAdCAM-1 has a serine threonine-rich mucin-like domain between the second and third Ig loops. The unique combination of these structural elements has led us to propose that MAdCAM-1 may have the capacity to facilitate more than one function in cell adhesion cascades. Recent domain swapping experiments have shown that the two (ICAM-1 and VCAM-1-like) amino terminal Ig domains alone can facilitate MAdCAM-1/α4β7 interactions (109). Additionally, it has been shown that MAdCAM-1, when expressed in mesenteric lymph nodes, can present L-selectin binding carbohydrates associated with the peripheral node addressin epitope, MECA-79 (110). The addition of these carbohydrates is a likely modification of the mucin domain, due to its relationship to other selectin-binding mucin-like proteins such as GLYCAM-1, CD34, and PSGL-1 (111–113). This modified species of MAdCAM-1 is functional, as lymphocytes can roll on this substrate via L-selectin in laminar flow assays (110). L-selectin plays a role in the circulation of resting lymphocytes through the PPs, and it is likely that MAdCAM-1 is the predominant L-selectin ligand in these tissues (see below). Migration of memory/effector/T cells and gut-derived thoracic duct blasts is, however, predominately dominated by the α4β7/MAdCAM-1 pathway (41). It is therefore likely that the α4β7 interactions with MAdCAM-1 are more significant than selectin-mediated events with respct to homing to extra-lymphoid tissues (see below).
Promising phase II biologics for future Crohn’s disease therapy
Published in Expert Opinion on Investigational Drugs, 2023
Pauline Wils, Silvio Danese, Laurent Peyrin-Biroulet
The α4ß7 integrin present on lymphocytes interacts with the mucosal vascular addressin cell adhesion molecule (MAdCAM-1). MAdCAM-1 is expressed on the vascular endothelium under the intestinal lamina propria and intestinal lymphoid tissues, allowing their migration into the gut and causing inflammation [34–36]. Interestingly MAdCAM-1 is not expressed in the central nervous system [36]. MAdCAM-1 expression is upregulated in CD patients and has been shown to play a role in chronic inflammation of the intestinal mucosa in IBD patients [35]. Anti-adhesion therapies that target α4 integrins (vedolizumab and natalizumab) are approved for CD treatment, blocking T-cell recruitment to the intestinal tissues. Natalizumab targets both α4ß7 and α1ß7 integrins and consequently blocks also the recruitment of leukocytes across the blood-brain barrier [18].
α4β7 integrin inhibitors: a patent review
Published in Expert Opinion on Therapeutic Patents, 2018
Hao Li, Shi-Ying Huang, Fang-Hong Shi, Zhi-Chun Gu, Shun-Guo Zhang, Ji-Fu Wei
In the intestinal tracts of patients with UC or CD, the extent of α4β7+ cellular infiltration and MAdCAM-1+ endothelial cells is increased [10,11]. Homing of T lymphocytes to the gut is the major event in the pathogenesis of T cell related to chronic intestinal inflammation [12]. α4β7 integrin are expressed on T cells, B cells, and natural killer cells. A higher level of α4β7 integrin are observed on intestinal-homing T and B cells than on naïve T and B cells [13]. MAdCAM-1 is an endothelial cell receptor and a ligand for α4β7 integrin, which is primarily expressed in high endothelial venules (HEVs) in the small intestine, the colon, and the Peyer’s paths [14]. A conformational change of α4β7 integrin on leucocytes enables α4β7 integrin binding to MAdCAM-1 with high affinity. The engagement of α4β7 integrin and MAdCAM-1 slows leucocyte movement along the endothelial surface. These activated T cells then circulate to the intestinal lamina propria, carrying out effector functions, such as inflammatory response [15]. Inhibitors of α4β7 integrin bind to monomers or heterodimers of α4β7 integrin and block the interaction of α4β7 integrin with MAdCAM-1, resulting in the accumulation of T-cells in the HEVs (Figure 2).
Anti-integrin drugs in clinical trials for inflammatory bowel disease (IBD): insights into promising agents
Published in Expert Opinion on Investigational Drugs, 2021
Virginia Solitano, Tommaso Lorenzo Parigi, Elisa Ragaini, Silvio Danese
Ontamalimab (PF-00547659, PF-547659; SHP-647) is a fully human monoclonal IgG2 antibody that binds the MAdCAM-1, which is constitutively expressed on the endothelium of venules of intestinal lamina propria of the gut and gut-associated lymphoid tissue [37,38]. Importantly, MAdCAM1 is selective for α4β7 leukocytes and does not bind to the α4β1 integrin that, in turn, binds to the ubiquitous VCAM-1 [39]. Mucosal biopsies of patients with active CD or UC showed increased expression of MAdCAM-1 and in animal model blockade of MAdCAM-1 decreased leukocyte recruitment and inflammation [38,40]. In addition, MAdCAM-1 is not constitutively expressed in the central nervous system, a reassuring characteristic in light of previous cases of PML following treatment with natalizumab [41].