Alternative titles; symbols
HGNC Approved Gene Symbol: ITGA4
Cytogenetic location: 2q31.3 Genomic coordinates (GRCh38): 2:181,457,205-181,538,940 (from NCBI)
The integrin family includes cell surface receptors for extracellular matrix components as well as receptors involved in various aspects of leukocyte adhesion. The integrins generally consist of alpha-beta heterodimeric transmembrane glycoproteins in which the alpha subunit is noncovalently associated with the beta subunit. Three major subfamilies of integrins have been defined, each containing a common beta subunit that can be associated with multiple alpha subunits. Two sets of integrins have been reported on lymphoid and myeloid cells. The first set, including LFA1 (see 153370/600065), Mac1 (120980), and p150,95 (151510), represents the molecules that are exclusively expressed on leukocytes. The second set, the VLA antigens, are not restricted to leukocytes because nearly all of the cell types, except granulocytes and red blood cells, express them. They consist of at least 6 different chains that can associate with the same beta-1 subunit. These complexes are mainly involved in cell-matrix adhesive interactions. Within the VLA family, VLA4 is atypical because it participates not only in extracellular matrix adhesion as receptor for fibronectin (135600) but also as cell-cell adhesion receptor.
Lu and Cyster (2002) studied the mechanisms that control localization of marginal zone B cells. They demonstrated that marginal zone B cells express elevated levels of the integrins LFA1 and alpha-4-beta-1 (see 135630), and that the marginal zone B cells bind to the ligands ICAM1 (147840) and VCAM1 (192225). These ligands are expressed within the marginal zone in a lymphotoxin-dependent manner. Combined inhibition of LFA1 and alpha-4-beta-1 causes a rapid and selective release of B cells from the marginal zone. Furthermore, lipopolysaccharide-triggered marginal zone B cell relocalization involves downregulation of integrin-mediated adhesion. Lu and Cyster (2002) concluded that their studies identified key requirements for marginal zone B cell localization and established a role for integrins in peripheral lymphoid tissue compartmentalization.
By examining the cation dependence of JAM2 (606870) adhesion to a T-cell line, Cunningham et al. (2002) identified a manganese-enhanced binding component indicative of integrin involvement. Using neutralizing integrin antibodies, they showed that the manganese-enhanced binding component was due to an interaction between JAM2 and ITGA4/ITGB1. However, the interaction was only enabled following prior adhesion of JAM2 to JAM3 (606871). Cunningham et al. (2002) determined that the engagement of all these ligands occurs through a nonacidic residue in an Ig-like fold of JAM2. An inhibitor of ITGA4, TBC772, attenuated the manganese-enhanced binding.
Miller et al. (2003) and Ghosh et al. (2003) reported clinical trials of natalizumab, a recombinant anticlonal antibody against alpha-4-integrins, for the treatment of multiple sclerosis (126200) and Crohn disease (see 266600), respectively. Miller et al. (2003) reported that a group of patients with multiple sclerosis who received monthly injections of natalizumab had significantly fewer new inflammatory central nervous system lesions than the placebo group (a reduction of approximately 90%) and had approximately half as many clinical relapses. Ghosh et al. (2003) reported that patients with Crohn disease also had a favorable response to natalizumab, with remission rates that were approximately twice as high in patients who received 2 injections of the antibody as in patients from the placebo group. The rate of adverse events did not differ significantly between the natalizumab and placebo groups in either trial. Von Andrian and Engelhardt (2003) stated that natalizumab probably has therapeutic effects because it blocks the ability of alpha-4/beta-1 and alpha-4/beta-7 to bind to their respective endothelial counter-receptors, VCAM1 and MADCAM1 (102670). In both disorders, lesions result from autoimmune responses involving activated lymphocytes and monocytes. Alpha-4-integrin is expressed on the surface of these cells and plays an integral part in their adhesion to the vascular endothelium and migration into the parenchyma.
Whereas naive T cells migrate only to secondary lymphoid organs, activation by antigen confers to T cells the ability to home to nonlymphoid sites. Activated effector/memory T cells migrate preferentially to tissues that are connected to the secondary lymphoid organs where antigen was first encountered. Thus, oral antigens induce effector/memory cells that express essential receptors for intestinal homing, namely the integrin alpha-4-beta-7 (see 147559) and CCR9 (604738), the receptor for the gut-associated chemokine TECK/CCL25 (602565). Mora et al. (2003) showed that this imprinting of gut tropism is mediated by dendritic cells from Peyer patches. Stimulation of CD8 (see 186910)-expressing T cells by dendritic cells from Peyer patches, peripheral lymph nodes, and spleen induced equivalent activation markers and effector activity in T cells, but only Peyer patch dendritic cells induced high levels of alpha-4-beta-7, responsiveness to TECK, and the ability to home to the small intestine. Mora et al. (2003) concluded that their findings established that Peyer patch dendritic cells imprint gut-homing specificity on T cells, and thus license effector/memory cells to access anatomic sites most likely to contain their cognate antigen.
Bone marrow minimal residual disease causes relapse after chemotherapy in patients with acute myelogenous leukemia. Matsunaga et al. (2003) postulated that the drug resistance is induced by the attachment of VLA4 on leukemic cells to fibronectin on bone marrow stromal cells. Matsunaga et al. (2003) found that VLA4-positive cells acquired resistance to anoikis (loss of anchorage) or drug-induced apoptosis through the phosphatidylinositol-3-kinase (see 601232)/AKT (164730)/Bcl2 (151430) signaling pathway, which is activated by the interaction of VLA4 and fibronectin. This resistance was negated by VLA4-specific antibodies. In a mouse model of minimal residual disease, Matsunaga et al. (2003) achieved a 100% survival rate by combining VLA4-specific antibodies and cytosine arabinoside, whereas cytosine arabinoside alone prolonged survival only slightly. In addition, overall survival at 5 years was 100% for 10 VLA4-negative patients and 44.4% for 15 VLA4-positive patients. Thus, Matsunaga et al. (2003) concluded that the interaction between VLA4 on leukemic cells and fibronectin on stromal cells may be crucial in bone marrow minimal residual disease and AML prognosis.
Garmy-Susini et al. (2005) demonstrated that integrin alpha-4-beta-1 and its ligand VCAM1 are expressed by proliferating but not quiescent endothelial cells and mural cells, respectively. Antagonists of this integrin-ligand pair blocked the adhesion of mural cells to proliferating endothelia in vitro and in vivo, thereby inducing apoptosis of endothelial cells and pericytes and inhibiting neovascularization. Garmy-Susini et al. (2005) concluded that integrin alpha-4-beta-1 and VCAM1 facilitate a critical cell-cell adhesion event required for survival of endothelial and mural cells during vascularization.
Jaspers et al. (1991) mapped the alpha-4 subunit of the VLA4 receptor (CD49D) to chromosome 2 by polymerase chain reaction (PCR) probing of a panel of human-mouse hybrid cell lines and refined the assignment to 2q31-q32 by nonisotopic in situ hybridization; see also Zhang et al. (1991). ITGA4 was also mapped to 2q31-q32 by Fernandez-Ruiz et al. (1992) by fluorescence in situ hybridization.
Cunningham, S. A., Rodriguez, J. M., Arrate, M. P., Tran, T. M., Brock, T. A. JAM2 interacts with alpha-4/beta-1: facilitation by JAM3. J. Biol. Chem. 277: 27589-27592, 2002. [PubMed: 12070135] [Full Text: https://doi.org/10.1074/jbc.C200331200]
Fernandez-Ruiz, E., Pardo-Manuel de Villena, F., Rubio, M. A., Corbi, A. L., Rodriguez de Cordoba, S., Sanchez-Madrid, F. Mapping of the human VLA-alpha-4 gene to chromosome 2q31-q32. Europ. J. Immun. 22: 587-590, 1992. [PubMed: 1537388] [Full Text: https://doi.org/10.1002/eji.1830220243]
Garmy-Susini, B., Jin, H., Zhu, Y., Sung, R.-J., Hwang, R., Varner, J. Integrin alpha-4-beta-1--VCAM-1--mediated adhesion between endothelial and mural cells is required for blood vessel maturation. J. Clin. Invest. 115: 1542-1551, 2005. [PubMed: 15902308] [Full Text: https://doi.org/10.1172/JCI23445]
Ghosh, S., Goldin, E., Gordon, F. H., Malchow, H. A., Rask-Madsen, J., Rutgeerts, P., Vyhnalek, P., Zadorova, Z., Palmer, T., Donoghue, S. Natalizumab for active Crohn's disease. New Eng. J. Med. 348: 24-32, 2003. [PubMed: 12510039] [Full Text: https://doi.org/10.1056/NEJMoa020732]
Jaspers, M., Zhang, Z., Marynen, P., Vekemans, S., Aly, M. S., Cuppens, H., Hillicker, C., Cassiman, J.-J. Localization of the genes encoding the alpha-2 and alpha-4 subunits of the human VLA-receptors to chromosome 5q23-31 and 2q31-32 respectively. (Abstract) Cytogenet. Cell Genet. 58: 1870 only, 1991.
Lu, T. T., Cyster, J. G. Integrin-mediated long-term B cell retention in the splenic marginal zone. Science 297: 409-412, 2002. [PubMed: 12130787] [Full Text: https://doi.org/10.1126/science.1071632]
Matsunaga, T., Takemoto, N., Sato, T., Takimoto, R., Tanaka, I., Fujimi, A., Akiyama, T., Kuroda, H., Kawano, Y., Kobune, M., Kato, J., Hirayama, Y., Sakamaki, S., Kohda, K., Miyake, K., Niitsu, Y. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nature Med. 9: 1158-1165, 2003. Note: Erratum: Nature Med. 11: 578 only, 2005. [PubMed: 12897778] [Full Text: https://doi.org/10.1038/nm909]
Miller, D. H., Khan, O. A., Sheremata, W. A., Blumhardt, L. D., Rice, G. P. A., Libonati, M. A., Willmer-Hulme, A. J., Dalton, C. M., Miszkiel, K. A., O'Connor, P. W. A controlled trial of natalizumab for relapsing multiple sclerosis. New Eng. J. Med. 348: 15-23, 2003. [PubMed: 12510038] [Full Text: https://doi.org/10.1056/NEJMoa020696]
Mora, J. R., Bono, M. R., Manjunath, N., Weninger, W., Cavanagh, L. L., Rosemblatt, M., von Andrian, U. H. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424: 88-93, 2003. [PubMed: 12840763] [Full Text: https://doi.org/10.1038/nature01726]
Rosemblatt, M., Vuillet-Gaugler, M. H., Leroy, C., Coulombel, L. Coexpression of two fibronectin receptors, VLA-4 and VLA-5, by immature human erythroblastic precursor cells. J. Clin. Invest. 87: 6-11, 1991. [PubMed: 1824634] [Full Text: https://doi.org/10.1172/JCI115002]
von Andrian, U. H., Engelhardt, B. Alpha-4 integrins as therapeutic targets in autoimmune disease. (Editorial) New Eng. J. Med. 348: 68-72, 2003. [PubMed: 12510047] [Full Text: https://doi.org/10.1056/NEJMe020157]
Zhang, Z., Vekemans, S., Aly, M. S., Jaspers, M., Marynen, P., Cassiman, J.-J. The gene for the alpha-4 subunit of the VLA-4 integrin maps to chromosome 2q31-32. Blood 78: 2396-2399, 1991. [PubMed: 1932750]