Addressin

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

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]

## Contents

* 1 Nomenclature
* 2 Function
* 3 Peripheral node addressins
* 4 Clinical significance
* 5 See also
* 6 References
* 7 Further reading
* 8 External links

## 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.[4] 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.[5]

## 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.[7][9][10] During the development of secondary lymphoid organs, PNAd expression is upregulated following the upregulation and subsequent downregulation of MAdCAM-1 on HEVs.[10] PNAd expression, as well as the expression of MAdCAM-1, is dependent on lymphotoxin signaling in the HEVs of lymph nodes.[10]

## 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

1. ↑ 1.0 1.1 "Entrez Gene: mucosal vascular addressin cell adhesion molecule 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8174.
2. ↑ "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. doi:10.4049/jimmunol.156.8.2851. PMID 8609404.
3. ↑ "Genomic organization, chromosomal mapping, and analysis of the 5' promoter region of the human MAdCAM-1 gene". Immunogenetics 46 (2): 111–9. 1997. doi:10.1007/s002510050249. PMID 9162097.
4. ↑ 4.0 4.1 "Endothelial-leukocyte adhesion molecules". Annual Review of Immunology 11 (1): 767–804. 1993-04-01. doi:10.1146/annurev.iy.11.040193.004003. PMID 8476577.
5. ↑ 5.0 5.1 Kuby immunology. Sharon A. Stranford, Patricia P. Jones, Judith A. Owen (Eighth ed.). New York. 2019. ISBN 978-1-4641-8978-4. OCLC 1002672752.
6. ↑ Addressin at eMedicine Dictionary
7. ↑ 7.0 7.1 "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. doi:10.1083/jcb.114.2.343. PMID 1712790.
8. ↑ "Physiological and molecular mechanisms of lymphocyte homing". Annual Review of Immunology 10 (1): 561–91. 1992-04-01. doi:10.1146/annurev.iy.10.040192.003021. PMID 1590996.
9. ↑ "Peripheral lymph node addressins are expressed on skin endothelial cells". The Journal of Investigative Dermatology 113 (3): 410–4. September 1999. doi:10.1046/j.1523-1747.1999.00696.x. PMID 10469342.
10. ↑ 10.0 10.1 10.2 "Development of secondary lymphoid organs". Annual Review of Immunology 26 (1): 627–50. 2008-03-27. doi:10.1146/annurev.immunol.26.021607.090257. PMID 18370924.
11. ↑ "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. doi:10.1046/j.1440-1827.2002.01365.x. PMID 12100519.
12. ↑ "Anti-MADCAM therapy for ulcerative colitis". Expert Opinion on Biological Therapy 20 (4): 437–442. April 2020. doi:10.1080/14712598.2020.1691520. PMID 31709847.

## Further reading

* "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. doi:10.3748/wjg.v9.i12.2701. PMID 14669317.
* "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. doi:10.1097/01.SLA.0000064364.40406.EA. PMID 12724634.
* "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. doi:10.1016/S0969-2126(98)00080-X. PMID 9655832.
* "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. doi:10.1021/bi011582f. PMID 11705388.
* "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. doi:10.1152/ajpgi.00266.2007. PMID 18308860.
* "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research 16 (1): 55–65. January 2006. doi:10.1101/gr.4039406. PMID 16344560.
* "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. doi:10.1152/ajpheart.00999.2002. PMID 12586641.
* "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. doi:10.1016/j.transproceed.2003.12.010. PMID 15050155.
* "Expression of potential lymphocyte trafficking mediator molecules in the mammary gland". Veterinary Research 34 (1): 3–10. 2003. doi:10.1051/vetres:2002045. PMID 12588680.
* "Mechanisms of MAdCAM-1 gene expression in human intestinal microvascular endothelial cells". American Journal of Physiology. Cell Physiology 288 (2): C272-81. February 2005. doi:10.1152/ajpcell.00406.2003. PMID 15483224.
* "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. doi:10.1074/jbc.275.10.7052. PMID 10702270.
* "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. doi:10.1016/j.humpath.2008.10.014. PMID 19157500.
* "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. doi:10.1016/j.jhep.2006.03.012. PMID 16750586.
* "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. doi:10.1016/j.humimm.2009.03.008. PMID 19286444.
* "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. doi:10.1046/j.1440-1827.2002.01365.x. PMID 12100519.
* "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. doi:10.1016/S0960-894X(98)00286-8. PMID 9873398.
* "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. doi:10.1107/S0907444901020522. PMID 11807247. Bibcode: 2002AcCrD..58..233D. http://journals.iucr.org/d/issues/2002/02/00/ad0159/ad0159.pdf.

## External links

* vascular+addressins at the US National Library of Medicine Medical Subject Headings (MeSH)
* Human MADCAM1 genome location and MADCAM1 gene details page in the UCSC Genome Browser.
* Overview of all the structural information available in the PDB for UniProt: Q13477 (Mucosal addressin cell adhesion molecule 1) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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PDB gallery

* 1bqs: THE CRYSTAL STRUCTURE OF MUCOSAL ADDRESSIN CELL ADHESION MOLECULE-1 (MADCAM-1)

* 1gsm: A REASSESSMENT OF THE MADCAM-1 STRUCTURE AND ITS ROLE IN INTEGRIN RECOGNITION.

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