HGNC Approved Gene Symbol: LAIR1
Cytogenetic location: 19q13.42 Genomic coordinates (GRCh38): 19:54,351,384-54,376,088 (from NCBI)
LAIR1 is a collagen-binding inhibitory receptor encoded in the leukocyte receptor complex on chromosome 19 (Tan et al., 2016).
Natural killer (NK) cells are a subpopulation of lymphocytes capable of lysing transformed and virus-infected cells without apparent presensitization. Inhibitory receptors present on NK cells prevent excessive inflammatory responses and autoimmunity by binding major histocompatibility complex (MHC) expressed on target cells, resulting in NK cells selectively killing only targets that lack MHC on their surface. Two families of human NK cell inhibitory receptors are the killer cell inhibitory receptors of the immunoglobulin superfamily and the NKG2 receptors (e.g., KLRC1; 161555) of the C-type lectin superfamily. These inhibitory receptors possess cytoplasmic tails with immune receptor tyrosine-based inhibitory motifs (ITIMs), which bind to the SH2 domain of certain phosphatases upon phosphorylation, leading to the downregulation of cell activation. By immunizing mice with a human NK cell clone and screening antibodies for the capacity to inhibit NK cell-mediated lysis of Fc receptor (FcR)-bearing targets, Meyaard et al. (1997) isolated a monoclonal antibody that recognized LAIR1. FcR crosslinking of LAIR1 was required to deliver the negative signal and led to inhibition of cytotoxicity even in the presence of strong positive signals.
By expression cloning using flow cytometry, Meyaard et al. (1997) isolated a human NK cell cDNA encoding LAIR1. The predicted 287-amino acid LAIR1 is a type I membrane protein with a leader sequence, an extracellular domain, a transmembrane domain, and a cytoplasmic region. The 142-amino acid extracellular domain contains 1 N-linked glycosylation site, and a pair of cysteines that generates a single immunoglobulin-like domain, thus classifying LAIR1 as a member of the immunoglobulin superfamily. The 101-amino acid cytoplasmic tail contains 2 ITIMs. The LAIR1 protein shares less than 30% homology with members of the inhibitory immunoglobulin superfamily and 32% homology with members of the immunoglobulin-like transcript family. Immunoprecipitation of LAIR1 from NK cells, followed by SDS-PAGE analysis, detected 2 proteins: an approximately 40-kD monomer, which decreased to approximately 32 kD after deglycosylation, and an approximately 32-kD protein, which also decreased in size after deglycosylation. The authors detected 1.7- and 3.0-kb LAIR1 transcripts by Northern blot analysis of peripheral blood mononuclear cells. LAIR1 was expressed on the majority of human peripheral blood mononuclear leukocytes examined.
Xu et al. (2000) cloned 4 isoforms of LAIR1, which are presumably derived from alternative splicing. Isoforms LAIR1b and LAIR1c contain 270 and 269 amino acids, respectively, as well as ITIMs. The 209-amino acid LAIR1d lacks most of the intracellular segment as well as the ITIMs, and therefore cannot bind SHP1. Xu et al. (2000) attributed the initial definition of the ITIM sequence to Burshtyn et al. (1996).
By fluorescence in situ hybridization, Meyaard et al. (1997) mapped the human LAIR1 gene to 19q13.4.
Meyaard et al. (1997) found that both SH2-containing tyrosine phosphatases, SHP1 (PTPN6; 176883) and SHP2 (PTPN11; 176876), associated with tyrosine-phosphorylated LAIR1. They demonstrated that cross-linking of the LAIR-1 antigen on NK cells resulted in strong inhibition of NK cell-mediated cytotoxicity. LAIR1 did not appear to recognize class I human leukocyte antigens (HLAs).
Xu et al. (2000) demonstrated that SHP1 is associated, through its SH2 domains, with LAIR1 when LAIR1 is tyrosine-phosphorylated at residues tyr233 and tyr263.
Using a yeast 3-hybrid screen and immunoprecipitation and immunoblot analyses, Sathish et al. (2001) determined that the association of SHP1 and LAIR1 is a constitutive interaction.
By expression cloning, immunoprecipitation, flow cytometry, and sequence analysis, Lebbink et al. (2006) identified transmembrane collagen XVII (COL17A1; 113811) as a ligand for LAIR1. The association was divalent cation independent and occurred cross-species. Further analysis showed that LAIR1 was a high-affinity receptor for multiple transmembrane and extracellular matrix collagens, and the collagen-LAIR1 interaction was dependent on conserved gly-pro-hyp collagen repeats. Direct cross-linking of LAIR1 by collagens inhibited degranulation of a rat basophilic leukemia cell line. Lebbink et al. (2006) concluded that the functional interaction between extracellular matrix collagens and LAIR1, an inhibitory immune receptor, represents a novel mechanism of immune regulation.
By screening plasma samples from individuals living in a malaria (see 611162)-endemic region in Kilifi, Kenya, for antibodies capable of agglutinating P. falciparum-infected erythrocytes, Tan et al. (2016) identified 2 donors whose plasma formed mixed agglutinates with all 8 parasite isolates tested. Immortalization of donor memory IgG-positive B cells and screening of culture supernatants revealed the most broadly reactive antibodies. Sequencing of these antibodies showed the presence of an insert of over 100 amino acids between the V and DJ segments. In both donors, the core of the inserts contained a sequence 85 to 96% identical to LAIR1. However, in each donor, the antibodies used a distinct VH/JH combination and had a high load of somatic mutations spanning the whole V-LAIR1-DJ region, suggesting that, within each individual, a single B-cell clone carrying a LAIR1 insert expanded after stimulation by malaria antigens. A role for RAG (179615) in the insertion process was ruled out by the presence of both LAIR1 alleles in 1 donor, indicating that LAIR1 was not inserted in a 'cut-and-paste' manner and that LAIR1 was duplicated by another mechanism; elements from chromosome 13 were also transposed into the antibody. Mutation analysis of the LAIR1 domain revealed that increased binding was associated with loss of collagen-binding residues and gain of infected erythrocyte-binding residues. The antibodies possessed both agglutinating and opsonizing activities. Tan et al. (2016) proposed that LAIR1-containing antibodies will be frequently found in malaria-endemic regions and that other sequences may also be transposed into immunoglobulin genes.
Extending the findings of Tan et al. (2016), Pieper et al. (2017) screened plasma samples from 2 large cohorts of malaria-exposed individuals in Mali and Tanzania and found that 5 to 10% of individuals had detectable levels of LAIR1-containing IgG or IgM. In contrast, no European donors from nonendemic regions had LAIR1-containing antibodies. The LAIR1-containing antibodies recognized most P. falciparum-infected erythrocytes with low affinity and conferred no enhanced protection against febrile malaria. Sequencing of cDNA and genomic DNA showed that the insertion of the LAIR1 exon and flanking intronic sequences occurred between the V and DJ segments in the CDR3 loop in some donors, whereas in other donors the insertion was located between the JH and CH1 domains. One Kenyan donor had a truncated LAIR1-containing IgG3 heavy chain without an attached light chain, leading to production of a camelid-like antibody (Muyldermans, 2013). Pieper et al. (2017) concluded that different modalities of LAIR1 insertion lead to the generation of public (i.e., high frequency) and dominant antibodies against infected erythrocytes. They proposed that insertion of templated DNA is an additional mechanism of antibody diversity that may be selected in the immune response against pathogens and be exploited for B-cell engineering.
Omiya et al. (2009) established transgenic mice expressing a Lair1-Ig decoy protein to compete with endogenous Lair1. Transgenic mice exhibited increased susceptibility to development of contact hypersensitivity, a model for allergic contact dermatitis, in association with enhanced hapten-specific T-cell responses. When T cells from hapten-sensitized donor mice were transferred to non-sensitized recipients, treatment of either donor mice or recipient mice with Lair1-Ig protein accelerated contact hypersensitivity. In vitro assays showed that Lair1 decreased production of Il6 (147620) and Il12 (see 161560) in dendritic cells and inhibited proliferation and cytokine production by both naive and memory T cells. Omiya et al. (2009) proposed that LAIR1 inhibits both the sensitization and the elicitation of hapten-reactive T cells.
Meyaard et al. (2001) presented evidence suggesting that epithelial cellular adhesion molecule (EPCAM; 185535) is a ligand for LAIR1 and LAIR2 (602993). However, the authors later retracted their paper after further studies showed that EPCAM is not a ligand for LAIR1 and LAIR2 and that their prior results were an artifact resulting from contamination.
Burshtyn, D. N., Scharenberg, A. M., Wagtmann, N., Rajagopalan, S., Berrada, K., Yi, T., Kinet, J.-P., Long, E. O. Recruitment of tyrosine phosphatase HCP by the killer cell inhibitor receptor. Immunity 4: 77-85, 1996. [PubMed: 8574854] [Full Text: https://doi.org/10.1016/s1074-7613(00)80300-3]
Lebbink, R. J., de Ruiter, T., Adelmeijer, J., Brenkman, A. B., van Helvoort, J. M., Koch, M., Farndale, R. W., Lisman, T., Sonnenberg, A., Lenting, P. J., Meyaard, L. Collagens are functional, high affinity ligands for the inhibitory immune receptor LAIR-1. J. Exp. Med. 203: 1419-1425, 2006. [PubMed: 16754721] [Full Text: https://doi.org/10.1084/jem.20052554]
Meyaard, L., Adema, G. J., Chang, C., Woollatt, E., Sutherland, G. R., Lanier, L. L., Phillips, J. H. LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes. Immunity 7: 283-290, 1997. [PubMed: 9285412] [Full Text: https://doi.org/10.1016/s1074-7613(00)80530-0]
Meyaard, L., van der Vuurst de Vries, A.-R., de Ruiter, T., Lanier, L. L., Phillips, J. H., Clevers, H. The epithelial cellular adhesion molecule (Ep-CAM) is a ligand for the leukocyte-associated immunoglobulin-like receptor (LAIR). J. Exp. Med. 194: 107-112, 2001. Note: Retraction: J. Exp. Med. 198: 1129 only, 2003. [PubMed: 11435477] [Full Text: https://doi.org/10.1084/jem.194.1.107]
Muyldermans, S. Nanobodies: natural single-domain antibodies. Ann. Rev. Biochem. 82: 775-797, 2013. [PubMed: 23495938] [Full Text: https://doi.org/10.1146/annurev-biochem-063011-092449]
Omiya, R., Tsushima, F., Narazaki, H., Sakoda, Y., Kuramasu, A., Kim, Y., Xu, H., Tamura, H., Zhu, G., Chen, L., Tamada, K. Leucocyte-associated immunoglobulin-like receptor-1 is an inhibitory regulator of contact hypersensitivity. Immunology 128: 543-555, 2009. [PubMed: 19930044] [Full Text: https://doi.org/10.1111/j.1365-2567.2009.03140.x]
Pieper, K., Tan, J., Piccoli, L., Foglierini, M., Barbieri, S., Chen, Y., Silacci-Fregni, C., Wolf, T., Jarrossay, D., Anderle, M., Abdi, A., Ndungu, F. M., and 10 others. Public antibodies to malaria antigens generated by two LAIR1 insertion modalities. Nature 548: 597-601, 2017. [PubMed: 28847005] [Full Text: https://doi.org/10.1038/nature23670]
Sathish, J. G., Johnson, K. G., Fuller, K. J., LeRoy, F. G., Meyaard, L., Sims, M. J., Matthews, R. J. Constitutive association of SHP-1 with leukocyte-associated Ig-like receptor-1 in human T cells. J. Immun. 166: 1763-1770, 2001. [PubMed: 11160222] [Full Text: https://doi.org/10.4049/jimmunol.166.3.1763]
Tan, J., Pieper, K., Piccoli, L., Abdi, A., Foglierini, M., Geiger, R., Tully, C. M., Jarrossay, D., Ndungu, F. M., Wambua, J., Bejon, P., Fregni, C. S., and 9 others. A LAIR1 insertion generates broadly reactive antibodies against malaria variant antigens. Nature 529: 105-109, 2016. [PubMed: 26700814] [Full Text: https://doi.org/10.1038/nature16450]
Xu, M., Zhao, R., Zhao, Z. J. Identification and characterization of leukocyte-associated Ig-like receptor-1 as a major anchor protein of tyrosine phosphatase SHP-1 in hematopoietic cells. J. Biol. Chem. 275: 17440-17446, 2000. [PubMed: 10764762] [Full Text: https://doi.org/10.1074/jbc.M001313200]