Disease relevance of ITGA4

• These changes of integrin expression during tumour progression particularly, the data showing an increase of VLA-4, and a decrease of VLA-6 expression support the concept that integrins are a new additional set of prognostic markers which indicate predisposition to the development of metastases [1].
• LFA-1 and VLA-4 antagonists (antibodies, peptides, and small molecules) are being developed for controlling inflammation and autoimmune diseases [2].
• Mediastinal clear cell lymphoma of B-cell type differed from FCCL in its regular lack of VLA-3, -5, and -6 and in frequently lacking VLA-4 [3].
• Variable expression of CD49d antigen in B cell chronic lymphocytic leukemia is related to disease stages [4].
• VLA-4 affinity correlates with peripheral blood white cell count and DNA content in patients with precursor acute lymphoblastic leukemia (B-ALL). The data suggest that decreased VLA-4 activity results in increased circulating lymphoblasts [5].
• Although no individual agent mimics this effect of sepsis, we now report that following priming of human neutrophils with lipopolysaccharide or tumor necrosis factor alpha (TNF-alpha), addition of formyl-Met-Leu-Phe (fMLP) results in a "stimulated", sepsis-like, four- to fivefold rise in CD49d expression [6].

Psychiatry related information on ITGA4

• Critical period for a teratogenic VLA-4 antagonist: Developmental effects and comparison of embryo drug concentrations of teratogenic and non-teratogenic VLA-4 antagonists [7].

High impact information on ITGA4

• VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site [8].
• In addition, VLA-4 expression allowed K-562 cells to attach to the heparin II binding region (FN-40) of fibronectin [8].
• The VCAM-1/VLA-4 ligand-receptor pair may play a major role in the recruitment of mononuclear leukocytes to inflammatory sites in vivo [8].
• The structure of LPAM-1 is virtually identical to that of the human integrin receptor VLA-4 [9].
• Identification of a murine Peyer's patch--specific lymphocyte homing receptor as an integrin molecule with an alpha chain homologous to human VLA-4 alpha [9].
• VLA-4/VCAM-1 dependent cell adhesion is rapidly regulated by integrin conformational change without altering molecule expression (receptor density) [10]. VLA-4 conformational changes can be detected on live cells in real-time [11][12].

Chemical compound and disease context of ITGA4

• We also showed that CD49d receptor density on T cells obtained by bronchoalveolar lavage (BAL) of allergic patients before and 48 h after allergen challenge was significantly higher than that on T cells taken from BAL of normal subjects and from controls with other inflammatory lung diseases [13].
• Local, intrapulmonary blockade of CD49d by intranasal administration of CD49d mAb inhibited all signs of lung inflammation, IL-4 and IL-5 release, and hyperresponsiveness to methacholine [14].
• Pertussis toxin treatment implicates G(i) in an unknown pathway that connects shear, Ca(2+) elevation, VLA-4 affinity, and cell avidity [15].
• We studied the effect of intravenous methylprednisolone (MP) on the expression of the integrins, LFA-1 and VLA-4, on activated blood T-lymphocytes in 17 patients with relapses of clinically definite relapsing-remitting MS [16].
• We examined the effect of cysteine protease of Porphyromonas gingivalis (P. gingivalis) on cell adhesion molecules including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and very late antigen-4 (VLA-4) of human gingival epithelial cells [17].

Biological context of ITGA4

• ITGB1 was assigned to Chromosome (Chr) 19, ITGA4 to Chr 3, and ITGA5 to Chr 7 [18].
• We conclude that there is one VLA-4 binding site in the six Ig domains shared between VCAM-6D and VCAM-7D, and that the alternatively spliced domain 4 present in VCAM-7D provides a second VLA-4 binding site that is blocked by 4B9 but not the E1/6 mAb [19].
• This anti-VLA-4-induced cell adhesion is isotype and Fc independent [20].
• CC chemokines induced early activation and subsequent deactivation of VLA-4, whereas upregulation of VLA-5 avidity occurred later and persisted [21].
• Mn2+ and mAb TS2/16 inhibited CC chemokine-induced transendothelial migration, particularly chemotaxis across stimulated endothelium that involved VLA-4 and VCAM-1 [21].

Anatomical context of ITGA4

• We compared the inhibitory effects of anti-VCAM-1 and anti-VLA-4 mAbs on lymphoid cell adhesion to cultured human umbilical vein endothelial cells (HUVEC) [19].
• Studies with alpha-subunit (CD49)-specific mAbs indicated that the integrins VLA-4 and -5 mediated migration across FN-preincubated filters, and VLA-2, -4, -5, and -6 were involved in eosinophil migration through filters covered with HUVEC [22].
• The new finding that VLA-4/VCAM-1 mediates costimulation adds significance to observations that VCAM-1 is expressed on a unique set of potential antigen-presenting cells in vivo [23].
• Using a COS cell transient expression assay, we investigated whether VCAM-6D and VCAM-7D differ functionally in adhesion to the integrin VLA-4 (CD49d/CD29) on lymphoid cells [19].
• In Centers for Disease Control (CDC) stage A patients, whose monocytes' ability to phagocytose bacteria and generate reactive oxygen intermediates is often increased, the frequency of monocytes expressing CD49d, HLA-DP, HLA-DQ, and an activation epitope of CD11a/CD18 was increased and monocyte transendothelial migration was unimpaired [24].

Associations of ITGA4 with chemical compounds

• Binding of small molecule ligands to VLA-4 binding pocket induces exposure of specific epitopes (Ligand Induced Binding SItes, LIBS). This conformationnal flexibility can be used for a discovery of novel integrin antagonists [25] [26].
• Tyrosine phosphorylation of several stromal cell proteins was stimulated within 5 to 10 min of contact with either CD49d-expressing or CD49d-deficient RAMOS [27].
• Abs to the beta(1) integrins, CD49d and CD49e, as well as to P-selectin and P-selectin glycoprotein ligand 1, inhibited basophil rolling and adhesion [28].
• CD49d expression and function on allergen-stimulated T cells from blood and airway [13].
• Both CD29 and CD49d clustering significantly inhibited anti-IgE-induced histamine release from the human basophil [29].
• We observed that stimulated neutrophil CD49d expression was decreased by activation of A(2A) adenosine receptors (A(2A)AR) with the selective agonist 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylicacid methyl ester (ATL146e; EC(50)=6.4 nM) [6].

Physical interactions of ITGA4

• The VCAM-1 sequence G65NEH also appears to be involved in binding VLA-4 [30].
• K562 lacked VLA-4 and a low binding affinity of the VLA-5 on these cells resulted in an absence of binding to the bone-marrow stroma [31].
• Thus, extravasation of activated T cells initiated by CD44 binding to HA depends upon VLA-4-mediated firm adhesion, which may explain the frequent association of these adhesion receptors with diverse chronic inflammatory processes [32].
• These results underline that the FN-binding activity of VLA-4 is dependent on processes affecting cellular activation as described for other members of the integrin family [33].
• We postulate that the mode of action of IFN-beta therapy in MS may involve the induction of an increase in sVCAM. sVCAM could bind VLA-4 on T-cells and intercept their adhesion to the blood brain barrier (BBB) [34].

Co-localisations of ITGA4

• However, when conjugates are formed in the presence of anti-alpha 4 antibodies, VLA-4 colocalizes with the CD3-zeta chain at the center of the synapse [35].

Regulatory relationships of ITGA4

• VLA-4 dependent cell adhesion is regulated by G-protein coupled receptors. Activation of Gαi- coupled receptors (CXCR4 or formyl peptide receptor) results in up-regulation of VLA-4 affinity for the ligand and stimulates cell adhesion. Activation of Gαs-coupled receptors (β2-adrenergic receptor or histamine receptor H2) leads to affinity down-regulation and promote cell de-adhesion [36]
• The CD18- and VLA-4-independent migration across HSF was completely inhibited by mAb to alpha5 of VLA-5 [37].
• VLA-4 on Jurkat cells is of constitutively high avidity and interfered with migration across barriers expressing VCAM-1 [21].
• The mAb to VLA-4 not only blocked the capacity of immobilized fibronectin to enhance anti-CD3-induced T cell proliferation but also directly costimulated T cell responses [38].
• VLA-4-dependent and -independent pathways in cell contact-induced proinflammatory cytokine production by synovial nurse-like cells from rheumatoid arthritis patients [39].
• Moreover, in vivo short-term homing experiments in a model dependent on CD44 and HA demonstrate that superantigen-activated T cells require VLA-4, but not LFA-1, for entry into an inflamed peritoneal site [32].

Other interactions of ITGA4

• This binding was blocked by mAbs to the VLA alpha-subunits alpha 6 (CD49f), or alpha 5 (CD49e) and alpha 4 (CD49d), respectively [40].
• An alternative leukocyte homotypic adhesion mechanism, LFA-1/ICAM-1-independent, triggered through the human VLA-4 integrin [20].
• Additive inhibition of adherence to unstimulated human umbilical vein endothelium (HUVE) was observed when monocytes were pretreated with both MoAb to CD49d and MoAb to CD18, the common beta-chain of the leukocyte beta 2 integrin receptors [41].
• These data further demonstrate that CDE maturing in the continued presence of IL-5 adhere to HUVEC predominantly through VLA-4 ligation [42].
• Adherence of monocytes to HUVE stimulated by recombinant human tumor necrosis factor-alpha was not reduced by MoAbs to CD18, CD49d, or ELAM-1 when used singly, but combinations of these MoAbs produced significant inhibition [41].

Analytical, diagnostic and therapeutic context of ITGA4

• Immunoprecipitation studies reveal that mAb 8A2 recognizes beta 1-subunit (CD29) of integrin receptors [40].
• Epitope mapping of this integrin on the human B-cell line Ramos, performed with a wide panel of anti-VLA-4 mAb by both cross-competitive cell binding and protease sensitivity assays, revealed the existence of three topographically distinct epitopes on the alpha 4 chain, referred to as epitopes A-C [43].
• Blockade of LFA-1 and VLA-4 interactions with their ligands is a potential target for immunosuppression [2].
• Adhesion molecules on peripheral blood-derived CD34+ cells: effects of cryopreservation and short-term ex vivo incubation with serum and cytokines [44].
• The most significant finding was a significant decrease of ICAM-1 expression on monocytes and CD49d on monocytes and lymphocytes as well as an increase of L-selectin expression on monocytes after treatment with DSCG, without any associated effect on CD11a and CD18 [45].

References