Alternative titles; symbols
HGNC Approved Gene Symbol: ICAM1
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38): 19:10,271,120-10,286,615 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.2 | {Malaria, cerebral, susceptibility to} | 611162 | 3 |
ICAM1 is an inducible glycoprotein of the immunoglobulin (Ig) superfamily that contains 5 distinct Ig-like domains, a transmembrane domain, and a short cytoplasmic tail. It was first discovered as a ligand for LFA1 (see 153370) and then as a counter receptor for MAC1 (see 120980). Like other members of the Ig superfamily of adhesion molecules, ICAM1 undergoes extensive alternative splicing to produce isoforms that differ in their expression and ligand binding (summary by Gottrand et al., 2015).
Simmons et al. (1988) analyzed a cDNA clone of the ICAM1 gene and found that it showed homology to the neural cell adhesion molecule NCAM (116930).
By Southern analysis of somatic cell hybrids, Greve et al. (1989) mapped the ICAM1 gene to human chromosome 19, which also contains the genes for a number of other picornavirus receptors, e.g., poliovirus (173850), echo 11 (129150), RD114 (109190), and coxsackievirus B3 (120050). Katz et al. (1985) had mapped the gene (which they had referred to as BB2; see 112203) to chromosome 19 by the use of a monoclonal antibody in the study of somatic cell hybrids. By fluorescence in situ hybridization, Trask et al. (1993) assigned the ICAM1 gene to 19p13.3-p13.2. Prieto et al. (1989) studied MALA-2, the mouse protein homologous to human ICAM1. Seldin et al. (1991) found that the homologous gene in the mouse, Icam1, is located close to Ldlr (606945) on chromosome 9. By means of mouse-hamster somatic cell hybrids and an interspecies backcross, Ballantyne et al. (1991) assigned the Icam1 gene to the proximal portion of mouse chromosome 9.
Greve et al. (1989) demonstrated that the ICAM1 protein is the major human rhinovirus receptor.
Bella et al. (1998) analyzed the structural features of the ICAM1 molecule that underlie its function as a receptor for the major group of human rhinoviruses and as a ligand for LFA-1.
Expression of HLA-DR antigen (see 142860) and ICAM1 in human conjunctival epithelium is upregulated in patients with dry eyes associated with Sjogren syndrome (270150). Tsubota et al. (1999) reported that this upregulation in Sjogren syndrome patients may be controlled by interferon-gamma (147570) through the activation of transcription factor NFKB (nuclear factor kappa-B; see 164011).
Pisella et al. (2000) reported that a significant increase of HLA-DR and ICAM1 expression by epithelial cells was consistently found in patients with keratoconjunctivitis sicca (Sjogren syndrome) compared with expression in normal eyes. These 2 markers were well correlated with each other and correlated inversely with tear break-up time and tear production as measured by the Schirmer test. The percentage of conjunctival goblet cells was significantly decreased in dry eye patients with a significant negative correlation with both HLA-DR and ICAM1 markers.
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 LFA-1 and alpha-4-beta-1 (see 192975 and 135630), and that the marginal zone B cells bind to the ligands ICAM1 and VCAM1 (192225). These ligands are expressed within the marginal zone in a lymphotoxin-dependent manner. Combined inhibition of LFA-1 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.
The human immunodeficiency virus-1 (HIV-1) protein Nef is important for viral replication and pathogenicity and may also protect cells from apoptosis and recognition by cytotoxic T cells. In addition, Nef, like CD40 (109535) stimulation, induces the release of the CC chemokines MIP1A (CCL3; 182283) and MIP1B (CCL4; 182284) from macrophages in an NFKB-dependent manner, possibly recruiting T lymphocytes to sites of infection. Swingler et al. (2003) found that lymphotropic HIV-1 requires the presence of macrophages infected with macrophage-tropic HIV-1 with an intact Nef. They showed that either Nef-expressing or CD40LG (300386)-stimulated macrophages render nonactivated T lymphocytes permissive to HIV-1 infection, but only in the presence of B lymphocytes expressing CD80 (112203). Swingler et al. (2003) determined that B-cell expression of CD80 and T-cell permissivity to HIV-1 infection are dependent on Nef-expressing or CD40LG-stimulated macrophages secreting the soluble forms of ICAM1 and CD23 (151445), with soluble ICAM1 being the strongest inducer of CD80 expression. Soluble CD23-stimulated B cells induced noncycling, i.e., KI67 antigen (176741)-negative, T cells, whereas soluble ICAM1-stimulated B cells induced both cycling and noncycling T cells to be permissive to HIV-1 infection. Swingler et al. (2003) concluded that while both soluble CD23 and ICAM1 promote resting cell infection, productive infection of cycling cells requires soluble ICAM1. They proposed that Nef intersects the CD40 signaling pathway in macrophages to promote the release of soluble CD23 and ICAM1, which in turn promote interactions of B and T cells, rendering the latter, even in a noncycling state, permissive to HIV-1 infection. Swingler et al. (2003) noted that these results may explain in part the existence of a resting T-cell reservoir infected with HIV-1.
Zuccarello et al. (2002) described a distinct form of familial chronic mucocutaneous candidiasis (CANDF3; 607644) characterized by early-onset infections by different species of Candida, restricted to the nails of the hands and feet and associated with low serum concentration of ICAM1. They concluded that pedigree analysis favored autosomal dominant inheritance with incomplete penetrance, even though a few consanguineous marriages were present.
Using confocal microscopy, Barnett et al. (2012) showed that after immunization, Bcl6 (109565), Il21r (605383), and Prkcz (176982) colocalized with the microtubule-organizing center in a polarized manner to 1 side of the plane of division in mouse germinal center B cells, generating unequal inheritance of fate-altering molecules by daughter cells. Germinal center B cells from mice lacking Icam1 failed to divide asymmetrically. Barnett et al. (2012) proposed that motile cells lacking constitutive attachment can receive provisional polarity cues from the microenvironment to generate daughter cell diversity and self-renewal.
Ueda et al. (2009) found that the microRNAs MIR222 (300569) and MIR339 (615977) suppressed translation of ICAM1 via recognition sequences in the 3-prime UTR of the ICAM1 mRNA. Downregulation of cell surface ICAM1 consequently reduced susceptibility of tumor cells to cytotoxic T lymphocytes. Immunohistochemical analysis and in situ hybridization of 30 primary glioblastoma multiform samples revealed inverse expression of MIR222 and MIR339 relative to ICAM1.
Chen et al. (2007) described the crystal structure at 2.7-angstrom resolution of monomeric ICAM1 domains 3 to 5, stabilized by a specific antibody to domain 5.
Fernandez-Reyes et al. (1997) identified a mutation (K29M; 147840.0001) in the ICAM1 gene, which they designated 'ICAM1 Kilifi,' that was associated with susceptibility to cerebral malaria (611162) with relative risks of 2.23 and 1.39 for homozygotes and heterozygotes, respectively.
Because ICAM1 plays a key role in lymphocyte infiltration into the thyroid gland and the concentration of soluble ICAM1 correlates significantly with the clinical activity and treatment status in Graves disease (see 275000), Kretowski et al. (2003) evaluated the frequency of the 721G-A (G241R) and the 1405A-G (K469E) polymorphisms of the ICAM1 gene in subjects with Graves disease compared with that in healthy controls. In a group of 235 patients with Graves disease and 211 healthy controls, Kretowski et al. (2003) found that the 721G-A polymorphism was associated with an earlier age of Graves disease onset (before age 40) and that the 1405A-G polymorphism could predispose to Graves ophthalmopathy. Kretowski et al. (2003) concluded that G241R and K469E amino acid substitutions in the ICAM1 molecule could influence the intensity/duration of the autoimmunity process and the infiltration of orbital tissues.
Vischer et al. (2008) transiently transfected monkey fibroblasts with wildtype human ICAM1 and 5 ICAM1 missense variants and observed no differences in mRNA and protein expression levels for any construct. However, pulse-chase experiments showed that 2 variants, K469E and arg478 to trp (R478W), had a prolonged half-life compared with wildtype ICAM1, whereas 2 other variants, G241R and pro352 to leu (P352L), had a decreased half-life, implying differences in protein degradation.
P-selectin (SELP; 173610) and ICAM1 participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM1 (sICAM1), Barbalic et al. (2010) performed a genomewide association study in a sample of 4,115 (sP-selectin) and 9,813 (sICAM1) individuals of European ancestry. The most significant SNP association for sP-selectin was within SELP (rs6136) and for sICAM1 levels within ICAM1 (rs3093030). Both sP-selection and sICAM1 were associated with ABO (110300) gene variants (rs579459 and rs649129, respectively), and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group.
To test the role of Icam1 in intact animals, Sligh et al. (1993) disrupted the gene in murine embryonic stem cells by gene targeting. Homozygous deficient animals developed normally, were fertile, and had a moderate granulocytosis. Studies were consistent with complete loss of surface expression of the protein. Deficient mice exhibited prominent abnormalities of inflammatory responses including impaired neutrophil emigration in response to chemical peritonitis and decreased contact hypersensitivity to 2,4-dinitrofluorobenzene. Mutant cells provided negligible stimulation in the mixed lymphocyte reaction, although they proliferated normally as responder cells.
Gottrand et al. (2015) noted that some mouse strains with disrupted Icam1, including that reported by Sligh et al. (1993), express soluble, truncated Icam1 isoforms lacking the transmembrane domain, but not full-length Icam1, and are therefore not truly Icam1 deficient. Using 1 such mouse strain lacking full-length Icam1, Gottrand et al. (2015) examined the role of Icam1 in T-cell development and regulatory T cell (Treg) function. Flow cytometric analysis demonstrated impaired thymocyte development, peripheral T-cell distribution, T-cell activation, and Treg suppressive activity in vitro and in vivo in mutant mice. Gottrand et al. (2015) concluded that full-length ICAM1 has a major role in Treg development and suppressive function.
The malarial parasite Plasmodium falciparum has acted as a potent selective force on the human genome. The particular virulence of this organism was thought to be due to the adherence of parasitized red blood cells to small vessel endothelium through several receptors, including CD36 (173510), thrombospondin (THBS1; 188060), and ICAM1, and parasite isolates differ in their ability to bind to each. Immunohistochemical studies implicated ICAM1 as having potential importance in the pathogenesis of cerebral malaria, leading Fernandez-Reyes et al. (1997) to reason that if any single receptor were involved in the development of cerebral malaria, then in view of the high mortality of that complication, natural selection should have produced variants with reduced binding capacity. Fernandez-Reyes et al. (1997) amplified and sequenced the N-terminal immunoglobulin-like domain of the ICAM1 gene from the genomic DNA of 24 asymptomatic children in Kilifi, Kenya. The only mutation found was an A-to-T transversion at nucleotide 179, causing a lys29-to-met substitution (K29M), which the authors called 'ICAM1 Kilifi.' In studies of the association of the K29M polymorphism with cerebral malaria, they found, to their surprise, that the homozygous ICAM1 Kilifi genotype was associated with susceptibility to cerebral malaria (611162) with a relative risk of 2.23, and heterozygotes with a relative risk of 1.39. The frequency of the K29 allele was 0.668 and the frequency of the M29 Kilifi allele was 0.332. Fernandez-Reyes et al. (1997) noted that, while this association strengthened the link between ICAM1 and cerebral malaria, a mutation that confers susceptibility is unlikely to have arisen at such high frequency in the absence of some counteractive selective advantage. These counterintuitive results had implications for the mechanism of malaria pathogenesis, resistance to other infectious agents, and transplant immunology. The Kilifi allele was not identified in 99 unrelated Caucasians or in 40 multigeneration families from the CEPH collection. Screening of 20 Gambian samples produced a similar frequency of the Kilifi allele to that seen in Kenya.
Bellamy et al. (1998) found no association between the ICAM1 Kilifi variant and cerebral malaria in a case-control study of West Africans.
Hill (1999) reviewed the genetic basis of susceptibility or resistance to malaria, including the role of the Kilifi variant of ICAM1.
Craig et al. (2000) performed functional assays using both forms (Kilifi and a reference form) of ICAM1 as soluble Fc chimeric fusion proteins. ICAM1-Kilifi displayed reduced avidity for LFA-1 (the major leukocyte beta-2 integrin; 600065) compared with ICAM1-ref, and binding to soluble fibrinogen was completely abolished with the Kilifi variant. In P. falciparum adhesion assays, binding of the ITO4-A4u strain to ICAM1-Kilifi was reduced compared with binding to the reference form. The authors speculated that although homozygotes for ICAM1-Kilifi are at increased risk for cerebral malaria, there may be a beneficial immunomodulatory effect to reduce leukocyte-mediated tissue damage in an environment whose population is chronically exposed to infectious agents.
By resequencing 6 kb of ICAM1 in 416 unrelated geographically and ethnically diverse African and non-African individuals, Gomez et al. (2013) showed that the ICAM1 Kilifi allele and SNPs in linkage disequilibrium with it were correlated with malaria endemicity. They concluded that this variant may be a candidate for protection against malaria.
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