Addressin Explained

Mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is a protein that in humans is encoded by the MADCAM1 gene.^{[1] [2] [3]} The protein encoded by this gene is an endothelial cell adhesion molecule that interacts preferentially with the leukocyte beta7 integrin LPAM-1 (alpha4 / beta7), L-selectin, and VLA-4 (alpha4 / beta1) on myeloid cells to direct leukocytes into mucosal and inflamed tissues. It is a member of the immunoglobulin superfamily and is similar to ICAM-1 and VCAM-1.^[1]

Nomenclature

Addressin is a lesser-used term to describe the group of adhesion molecules that are involved with lymphocyte homing, commonly found at high-endothelial venules (HEVs) where lymphocytes exit the blood and enter the lymph node.^{[4] [5]} Addressins are the ligands to the homing receptors of lymphocytes.^[6] The task of these ligands and their receptors is to determine which tissue the lymphocyte will enter next. They carry carbohydrates in order to be recognized by L-selectin.^[7] Addressins physically bind to mobile lymphocytes to guide them to the HEVs. Examples of molecules that are often referred to as addressins are CD34 and GlyCAM-1 on HEVs in peripheral lymph nodes, and MAdCAM-1 on endothelial cells in the intestine.

Function

In terms of migration, MAdCAM-1 is selectively expressed on mucosal endothelial cells, driving memory T-cell re-circulation through mucosal tissues. In contrast, and indeed the main difference between the two molecules, ICAM molecules are involved with naïve T-cell re-circulation. Whereas MAdCAM-1 is selectively expressed, ICAM is broadly expressed on inflamed endothelium.

Peripheral node addressins

Peripheral node addressins (PNAd) are carbohydrate residues that are lymphocyte homing receptor ligands that are expressed on the HEVs of peripheral lymph nodes.^[8] These proteins collectively bind to L-selectin to guide lymphocytes such as mature naïve B and T cells into the lymph node.^{[9] [10]} During the development of secondary lymphoid organs, PNAd expression is upregulated following the upregulation and subsequent downregulation of MAdCAM-1 on HEVs. PNAd expression, as well as the expression of MAdCAM-1, is dependent on lymphotoxin signaling in the HEVs of lymph nodes.

Clinical significance

In inflammatory bowel diseases, MAdCAM-1 can be overexpressed on the endothelial cells of intestinal mucosa and gut-associated lymphoid tissue, leading to excessive inflammation in the gut.^[11] A potential therapeutic target to manage these diseases could be the MAdCAM-1 molecules that are expressed on these cells and bring in lymphocytes. One example of a potential therapy is the fully human monoclonal antibody ontamalimab that targets and binds to MAdCAM-1, preventing it from interacting with the integrins on the surface of the lymphocytes.^[12]

See also

• CD34
• GLYCAM1
• Integrin β7 - a constituent of α₄β₇

References

Further reading

• Ohara H, Isomoto H, Wen CY, Ejima C, Murata M, Miyazaki M, Takeshima F, Mizuta Y, Murata I, Koji T, Nagura H, Kohno S . 6 . Expression of mucosal addressin cell adhesion molecule 1 on vascular endothelium of gastric mucosa in patients with nodular gastritis . World Journal of Gastroenterology . 9 . 12 . 2701–5 . December 2003 . 14669317 . 4612036 . 10.3748/wjg.v9.i12.2701 . free .
• Ikeda S, Kudsk KA, Fukatsu K, Johnson CD, Le T, Reese S, Zarzaur BL . Enteral feeding preserves mucosal immunity despite in vivo MAdCAM-1 blockade of lymphocyte homing . Annals of Surgery . 237 . 5 . 677–85; discussion 685 . May 2003 . 12724634 . 1514523 . 10.1097/01.SLA.0000064364.40406.EA .
• Tan K, Casasnovas JM, Liu JH, Briskin MJ, Springer TA, Wang JH . The structure of immunoglobulin superfamily domains 1 and 2 of MAdCAM-1 reveals novel features important for integrin recognition . Structure . 6 . 6 . 793–801 . June 1998 . 9655832 . 10.1016/S0969-2126(98)00080-X . free .
• de Château M, Chen S, Salas A, Springer TA . Kinetic and mechanical basis of rolling through an integrin and novel Ca2+-dependent rolling and Mg2+-dependent firm adhesion modalities for the alpha 4 beta 7-MAdCAM-1 interaction . Biochemistry . 40 . 46 . 13972–9 . November 2001 . 11705388 . 10.1021/bi011582f .
• Miles A, Liaskou E, Eksteen B, Lalor PF, Adams DH . CCL25 and CCL28 promote alpha4 beta7-integrin-dependent adhesion of lymphocytes to MAdCAM-1 under shear flow . American Journal of Physiology. Gastrointestinal and Liver Physiology . 294 . 5 . G1257-67 . May 2008 . 18308860 . 10.1152/ajpgi.00266.2007 .
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S . 6 . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes . Genome Research . 16 . 1 . 55–65 . January 2006 . 16344560 . 1356129 . 10.1101/gr.4039406 .
• Grayson MH, Hotchkiss RS, Karl IE, Holtzman MJ, Chaplin DD . Intravital microscopy comparing T lymphocyte trafficking to the spleen and the mesenteric lymph node . American Journal of Physiology. Heart and Circulatory Physiology . 284 . 6 . H2213-26 . June 2003 . 12586641 . 10.1152/ajpheart.00999.2002 .
• Fujisaki S, Tomita R, Park YJ, Kimizuka K, Sugitoh K, Inoue M, Fukuzawa M . Semiquantative analysis of expression of mucosal addressin cell adhesion molecule-1 during small bowel graft rejection in rats . Transplantation Proceedings . 36 . 2 . 348–9 . March 2004 . 15050155 . 10.1016/j.transproceed.2003.12.010 .
• Nishimura T . Expression of potential lymphocyte trafficking mediator molecules in the mammary gland . Veterinary Research . 34 . 1 . 3–10 . 2003 . 12588680 . 10.1051/vetres:2002045 . free .
• Ogawa H, Binion DG, Heidemann J, Theriot M, Fisher PJ, Johnson NA, Otterson MF, Rafiee P . 6 . Mechanisms of MAdCAM-1 gene expression in human intestinal microvascular endothelial cells . American Journal of Physiology. Cell Physiology . 288 . 2 . C272-81 . February 2005 . 15483224 . 10.1152/ajpcell.00406.2003 .
• Ruiz-Velasco N, Guerrero-Esteo M, Briskin MJ, Teixidó J . The alpha(4) integrin subunit Tyr(187) has a key role in alpha(4)beta(7)-dependent cell adhesion . The Journal of Biological Chemistry . 275 . 10 . 7052–9 . March 2000 . 10702270 . 10.1074/jbc.275.10.7052 . free . 10261/169140 . free .
• Di Sabatino A, Rovedatti L, Rosado MM, Carsetti R, Corazza GR, MacDonald TT . Increased expression of mucosal addressin cell adhesion molecule 1 in the duodenum of patients with active celiac disease is associated with depletion of integrin alpha4beta7-positive T cells in blood . Human Pathology . 40 . 5 . 699–704 . May 2009 . 19157500 . 10.1016/j.humpath.2008.10.014 .
• Bowlus CL, Karlsen TH, Broomé U, Thorsby E, Vatn M, Schrumpf E, Lie BA, Boberg KM . 6 . Analysis of MAdCAM-1 and ICAM-1 polymorphisms in 365 Scandinavian patients with primary sclerosing cholangitis . Journal of Hepatology . 45 . 5 . 704–10 . November 2006 . 16750586 . 10.1016/j.jhep.2006.03.012 .
• Ambruzova Z, Mrazek F, Raida L, Stahelova A, Faber E, Indrak K, Petrek M . Possible impact of MADCAM1 gene single nucleotide polymorphisms to the outcome of allogeneic hematopoietic stem cell transplantation . Human Immunology . 70 . 6 . 457–60 . June 2009 . 19286444 . 10.1016/j.humimm.2009.03.008 .
• Arihiro S, Ohtani H, Suzuki M, Murata M, Ejima C, Oki M, Kinouchi Y, Fukushima K, Sasaki I, Nakamura S, Matsumoto T, Torii A, Toda G, Nagura H . 6 . Differential expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in ulcerative colitis and Crohn's disease . Pathology International . 52 . 5–6 . 367–74 . 2002 . 12100519 . 10.1046/j.1440-1827.2002.01365.x . 38219521 .
• Shroff HN, Schwender CF, Baxter AD, Brookfield F, Payne LJ, Cochran NA, Gallant DL, Briskin MJ . 6 . Novel modified tripeptide inhibitors of alpha 4 beta 7 mediated lymphoid cell adhesion to MAdCAM-1 . Bioorganic & Medicinal Chemistry Letters . 8 . 13 . 1601–6 . July 1998 . 9873398 . 10.1016/S0960-894X(98)00286-8 .
• Dando J, Wilkinson KW, Ortlepp S, King DJ, Brady RL . A reassessment of the MAdCAM-1 structure and its role in integrin recognition . Acta Crystallographica. Section D, Biological Crystallography . 58 . Pt 2 . 233–41 . February 2002 . 11807247 . 10.1107/S0907444901020522 . 2002AcCrD..58..233D .

Notes and References

1. Web site: Entrez Gene: mucosal vascular addressin cell adhesion molecule 1.
2. Shyjan AM, Bertagnolli M, Kenney CJ, Briskin MJ . Human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) demonstrates structural and functional similarities to the alpha 4 beta 7-integrin binding domains of murine MAdCAM-1, but extreme divergence of mucin-like sequences . Journal of Immunology . 156 . 8 . 2851–7 . April 1996 . 10.4049/jimmunol.156.8.2851 . 8609404 . 24940438 . free .
3. Leung E, Berg RW, Langley R, Greene J, Raymond LA, Augustus M, Ni J, Carter KC, Spurr N, Choo KH, Krissansen GW . 6 . Genomic organization, chromosomal mapping, and analysis of the 5' promoter region of the human MAdCAM-1 gene . Immunogenetics . 46 . 2 . 111–9 . 1997 . 9162097 . 10.1007/s002510050249 . 9453114 .
4. Bevilacqua MP . Endothelial-leukocyte adhesion molecules . Annual Review of Immunology . 11 . 1 . 767–804 . 1993-04-01 . 8476577 . 10.1146/annurev.iy.11.040193.004003 .
5. Book: Punt J . Kuby immunology. 2019. Sharon A. Stranford, Patricia P. Jones, Judith A. Owen. 978-1-4641-8978-4. Eighth. New York. 1002672752.
6. http://www.emedicinehealth.com/script/main/srchcont_dict.asp?src=Addressin Addressin
7. Berg EL, Robinson MK, Warnock RA, Butcher EC . The human peripheral lymph node vascular addressin is a ligand for LECAM-1, the peripheral lymph node homing receptor . The Journal of Cell Biology . 114 . 2 . 343–9 . July 1991 . 1712790 . 10.1083/jcb.114.2.343 . 2289069 . free .
8. Picker LJ, Butcher EC . Physiological and molecular mechanisms of lymphocyte homing . Annual Review of Immunology . 10 . 1 . 561–91 . 1992-04-01 . 1590996 . 10.1146/annurev.iy.10.040192.003021 .
9. Lechleitner S, Kunstfeld R, Messeritsch-Fanta C, Wolff K, Petzelbauer P . Peripheral lymph node addressins are expressed on skin endothelial cells . The Journal of Investigative Dermatology . 113 . 3 . 410–4 . September 1999 . 10469342 . 10.1046/j.1523-1747.1999.00696.x . free .
10. Randall TD, Carragher DM, Rangel-Moreno J . Development of secondary lymphoid organs . Annual Review of Immunology . 26 . 1 . 627–50 . 2008-03-27 . 18370924 . 2590644 . 10.1146/annurev.immunol.26.021607.090257 .
11. Arihiro S, Ohtani H, Suzuki M, Murata M, Ejima C, Oki M, Kinouchi Y, Fukushima K, Sasaki I, Nakamura S, Matsumoto T, Torii A, Toda G, Nagura H . 6 . Differential expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in ulcerative colitis and Crohn's disease . Pathology International . 52 . 5–6 . 367–74 . 2002 . 12100519 . 10.1046/j.1440-1827.2002.01365.x . 38219521 .
12. Picardo S, Panaccione R . Anti-MADCAM therapy for ulcerative colitis . Expert Opinion on Biological Therapy . 20 . 4 . 437–442 . April 2020 . 31709847 . 10.1080/14712598.2020.1691520 . 207946274 .