Disease relevance of Itgal

• Blocking LFA-1 in vivo significantly delayed lethal injury following adoptive transfer of D4 cells into HA-Tg mice as assessed by weight loss and histology [1].
• By quantitative immunofluorescence flow cytometry, the EL-4 T lymphoma and P388D1 macrophage-like lines were estimated to express 10(5) LFA-1 and 1.6 x 10(5) Mac-1 molecules/cell, respectively [2].
• Rapid development of murine AIDS is dependent of signals provided by CD54 and CD11a [3].
• LFA-1-deficient mice exhibit leukocytosis but do not develop spontaneous infections, in contrast to CD18-deficient mice [4].
• Overall, our results suggest that the increased severity of Lyme carditis in CD18 hypomorph mice is caused by deficiency in CD11a or CD11c, possibly via different mechanisms [5].

Psychiatry related information on Itgal

• The present study demonstrated that a short-term administration of mAbs against leukocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) at critical periods resulted in complete protection of autoimmune diabetes in non-obese diabetic (NOD) mice [6].

High impact information on Itgal

• Several antibodies to more abundant cell-surface determinants (T200, Ly15, H-2Db) do not inhibit this interaction [7].
• Here we show a crucial role for host MHC class I-dependent NK cell reactivity for allograft tolerance in mice induced through either costimulation blockade using CD154-specific antibody therapy or by targeting LFA-1 (also known as CD11a) [8].
• The lymphocyte function-associated 1 (LFA-1) and macrophage 1 (Mac-1) glycoproteins mediate differing types of adhesion reactions on these cells [9].
• Sequence homology of the LFA-1 and Mac-1 leukocyte adhesion glycoproteins and unexpected relation to leukocyte interferon [9].
• LFA-1 but not Lyt-2 is associated with killing activity of cytotoxic T lymphocyte hybridomas [10].

Chemical compound and disease context of Itgal

• CD18 hypomorph mice expressing reduced levels of the common beta2 integrin chain develop aggravated Lyme carditis, compared to that developed by wild-type (WT) mice, upon infection with the spirochete Borrelia burgdorferi [5].
• The genetic deficiency of leukocyte surface glycoprotein Mac-1, LFA-1, p150,95 in humans is associated with defective antibody-dependent cellular cytotoxicity in vitro and defective protection against herpes simplex virus infection in vivo [11].
• Utilizing a T lymphoma cell line, EL-4, it was found that [35S] sulfate, [3H]glucosamine, [3H]mannose, and [3H]fucose were incorporated into both the alpha- and beta-chains of LFA-1 [12].
• Pertussis toxin inhibition of T-cell hybridoma invasion is reversed by manganese-induced activation of LFA-1 [13].
• The effect of a blocking-antibody specific for lymphocyte function-associated antigen-1 (LFA-1) was studied in an atopic-like dermatitis model, which was induced by the repeated application of picrylchloride in NC/Nga mice [14].

Biological context of Itgal

• Mapping of antigenic and functional epitopes on the alpha- and beta-subunits of two related mouse glycoproteins involved in cell interactions, LFA-1 and Mac-1 [15].
• Ly-15.2 and LFA-1 show identical tissue distributions, being present on all thymocytes, lymphocytes, and neutrophils, and flow cytofluorometric analysis indicated identical cell surface expression of these molecules [16].
• These results indicate that LFA-1/ICAM-1 interactions facilitate murine thymic development and suggest that cell adhesion molecules mediate important events in T cell differentiation [17].
• These results suggest that the CD54/CD11a signal transduction pathway is a critical determinant of MAIDS development, and the lack of an immune response against viral Ag is enough to suppress BM5def replication and to prevent MAIDS [3].
• These results suggest that the presence of high levels of LFA-1 on T cells is absolutely necessary for their epidermotropic migration, but its up-regulation is neither necessary nor sufficient to trigger the epidermotropic migration [18].

Anatomical context of Itgal

• A search for similarities to previously sequenced proteins reveals a further unexpected homology between LFA-1 and leukocyte (alpha) interferons [9].
• LFA-1 participates in T-lymphocyte and natural killer-cell adhesion to target cells, whereas the Mac-1 antigen is identical to the complement receptor type 3, which mediates adhesion of monocytes and granulocytes to C3bi-sensitized particles [9].
• The in vivo blocking of VCAM-1 and VLA-4 inhibited antigen-induced CD4+ and CD8+ T cell infiltration into the trachea more potently than that of ICAM-1 and LFA-1 [19].
• For the first time, we show that LFA-1 makes a contribution to neutrophil rolling by stabilizing the transient attachment or tethering phase of rolling [20].
• Mouse Mac-1, a complement receptor-associated surface structure on macrophages, and LFA-1, a function-associated structure on lymphocytes, comprise a novel family of leukocyte differentiation antigens participating in adhesive cell interactions [15].

Associations of Itgal with chemical compounds

• Low levels of alpha4beta1 integrin can be detected on neutrophils from LFA-1(+/+) and (-/-) mice [20].
• Residence time of adoptively transferred Indium 111 (111In)-labeled D4 cells in lungs of normal and HA-Tg mice as analyzed by dual modality imaging revealed a significantly shorter transit time of 4 hours for the D4 cells upon in vivo blockade of LFA-1 [1].
• The presence of manganese dramatically enhanced the binding to ICAM-1 of LFA-1 lacking the alpha cytoplasmic domain or both cytoplasmic domains, whereas it had relatively little effect on wild-type LFA-1 or the mutant lacking the beta cytoplasmic domain [21].
• However, LFA703 did not decrease the expression of LFA-1 on circulating leukocytes [22].
• Furthermore, constitutive LFA-1 and VLA-4 expression on T-cells was not affected by PGE1 [23].

Physical interactions of Itgal

• We have investigated the role of the cytoplasmic domains of LFA-1 in binding to ICAM-1 and in postadhesion events [21].
• LFA-1 binding site in ICAM-3 contains a conserved motif and non-contiguous amino acids [24].
• LFA-1 binding to ICAM-I provides a costimulatory signal for CD8(+) T cell activation that results in increased IL-2 mRNA levels and protein production to support proliferation [25].
• These experiments provide direct physical evidence that ligation of the CD3 complex specifically increases the proximity of LFA-1 and microfilaments, which may be relevant to T cell mediated adherence reactions [26].
• Major histocompatibility complex-restricted antigen receptor on T cells. VIII. Role of the LFA-1 molecule [27].

Co-localisations of Itgal

• ADAP also colocalized with LFA-1 at the immunological synapse [28].

Regulatory relationships of Itgal

• Control of leukocyte rolling velocity in TNF-alpha-induced inflammation by LFA-1 and Mac-1 [29].
• Blocking studies revealed that anti-CD3 induced T cell proliferation and T cell-LC cluster formation was inhibited by both anti-LFA-1 and anti-ICAM-1 mAb suggesting that ICAM-1 expressed on LC must bind to LFA-1 on T cells to facilitate proliferative responses of T cells to anti-CD3 mAb [30].
• We conclude that LFA-1 participates in LPS-induced lethal shock/liver injury by regulating IL-10 secretion from macrophages and that IL-10 plays a decisive role in resistance to shock/liver injury [31].
• On the other hand, SP slightly induced LFA-1 mRNA translation and activation signals for integrins [32].
• However, anti-ICAM-1 mAb and anti-LFA-1 mAb did not alter either 1,25D- or PTH-stimulated receptor activator of NF-kappaB ligand (RANKL) mRNA transcription in bone marrow cultures [33].

Other interactions of Itgal

• These results suggest that an adhesion cascade, which includes L-selectin/PNAd, alpha4beta1 integrin/VCAM-1, and LFA-1, targets specific lymphocyte subsets to BALT [34].
• Both alpha4beta1, interacting with ligand VCAM-1, and also LFA-1 participate in substantial lymphocyte recirculation through bone marrow [35].
• The LFA-1 and Mac-1 beta chains are highly homologous or identical, whereas the alpha chains are highly different by tyrosyl tryptic peptide mapping (Kürzinger, K., Ho, M. K., and Springer, T. A. (1982) Nature (Lond.) 296, 668-670) [2].
• Serum levels of IL-10 in LFA-1(+/-) mice were only marginally affected by macrophage depletion [31].
• Thus, we propose that (1) peptide-MHC density and (2) accessory molecules such as LFA-1 determine T helper polarization by regulation of CD40L [36].

Analytical, diagnostic and therapeutic context of Itgal

• Furthermore, anti-Ly-15.2 and anti-LFA-1 antibodies coprecipitate the same molecule from thymocyte lysates, and peptide mapping studies show that the Ly-15.2 and LFA-1 alpha chains are identical, as are the beta chains [16].
• Previous studies demonstrate that combined anti-lymphocyte function-associated antigen-1 (LFA-1) plus anti-CD154 therapy results in a robust form of islet allograft tolerance not observed with either individual monotherapy [37].
• On fetal days 14 and 15, 40 to 50% of thymocytes coexpress high levels of LFA-1 and ICAM-1, as determined by flow cytometry [17].
• Indefinite survival of neonatal porcine islet xenografts by simultaneous targeting of LFA-1 and CD154 or CD45RB [37].
• Addition of anti-ICAM-1 or anti-LFA-1 antibodies to fetal thymic organ cultures results in the impaired generation of CD4+8+ cells [17].

References