LILRB1 Intron 1 Has a Polymorphic Regulatory Region That Enhances Transcription in NK Cells and Recruits YY1

Yu, Kang; Davidson, Chelsea E; Burshtyn, Deborah N.

doi:10.4049/jimmunol.2000164

Cited by 4 publications

(6 citation statements)

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“…Our results suggest a dose effect as more patients displaying a homozygous genotype were alloimmunised; these results, however, did not reach statistical significance, possibly as the study size was underpowered. Our results confirm the important level of diversity of this gene [39,45], as each patient displayed a unique haplotype. Both of these polymorphisms have previously been associated with lower expression on the NK cell surface [39,44,45], inflammation and immune disorders, and cancer outcomes [42,43].…”

Section: Discussionsupporting

confidence: 84%

“…The highest affinity of HLA-G is for the inhibitory receptors LILRB1 and LILRB2. Both receptors harbour immunoreceptor tyrosine-based inhibitory motifs (ITIMs), aiding the inhibition of intracellular signal transduction [38,39]. LILRB1 is expressed on several distinct types of immune cells, including monocytes, B cells, dendritic cells (DCs), subsets of effector and memory T cells, and 20-70% of NK cells [40,41].…”

Section: Introductionmentioning

confidence: 99%

“…Although LILRB1 displays high levels of genetic diversity, specific polymorphisms located in its regulatory region have been associated with its surface expression level on NK cells in healthy individuals: rs1004443-A, rs3760860-G, and rs3760861-G have higher levels of LILRB1 transcript and surface expression on NK cells compared with the SNPs rs1004443-G, rs3760860-A, and rs3760861-A [41]. LILRB1 expression has been associated with clinical outcome in autoimmune and inflammatory diseases and cancers, as well as with the response to bacterial and viral infections [39,[42][43][44][45]. LILRB2 is involved in macrophage maturation and proinflammatory phenotypes, and the rs383369 SNP in a homozygous state was associated with lesser severity in inflammatory endometriosis [43], as well as in cancer response to therapy [41].…”

Section: Introductionmentioning

confidence: 99%

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HLA-F and LILRB1 Genetic Polymorphisms Associated with Alloimmunisation in Sickle Cell Disease

Bernit,

Jean,

Marlot

et al. 2023

IJMS

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Red blood cell (RBC) transfusion remains a critical component in caring for the acute and chronic complications of sickle cell disease (SCD). Patient alloimmunisation is the main limitation of transfusion, which can worsen anaemia and lead to delayed haemolytic transfusion reaction or transfusion deadlock. Although biological risk factors have been identified for immunisation, patient alloimmunisation remains difficult to predict. We aimed to characterise genetic alloimmunisation factors to optimise the management of blood products compatible with extended antigen matching to ensure the self-sufficiency of labile blood products. Considering alloimmunisation in other clinical settings, like pregnancy and transplantation, many studies have shown that HLA Ib molecules (HLA-G, -E, and -F) are involved in tolerance mechanism; these molecules are ligands of immune effector cell receptors (LILRB1, LILRB2, and KIR3DS1). Genetic polymorphisms of these ligands and receptors have been linked to their expression levels and their influence on inflammatory and immune response modulation. Our hypothesis was that polymorphisms of HLA Ib genes and of their receptors are associated with alloimmunisation susceptibility in SCD patients. The alloimmunisation profile of thirty-seven adult SCD patients was analysed according to these genetic polymorphisms and transfusion history. Our results suggest that the alloimmunisation of SCD patients is linked to both HLA-F and LILRB1 genetic polymorphisms located in their regulatory region and associated with their protein expression level.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

HLA-F and LILRB1 Genetic Polymorphisms Associated with Alloimmunisation in Sickle Cell Disease

Bernit,

Jean,

Marlot

et al. 2023

IJMS

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“…Although the precise mechanism of the LILRB1 polymorphism in human NK cells is unknown, the expression of LILRB1 on NK cells is linked to particular haplotypes and a polymorphic regulatory region. 42 The increase of LILRB1 + NK cells from certain patients with cancer was well documented. NK cells upregulated LILRB1 expression when cultured with cancer cells in vitro.…”

Section: Discussionmentioning

confidence: 99%

Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells

Chen

Deng

et al. 2020

J Immunother Cancer

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BackgroundCurrent immune checkpoint blockade strategies have been successful in treating certain types of solid cancer. However, checkpoint blockade monotherapies have not been successful against most hematological malignancies including multiple myeloma and leukemia. There is an urgent need to identify new targets for development of cancer immunotherapy. LILRB1, an immunoreceptor tyrosine-based inhibitory motif-containing receptor, is widely expressed on human immune cells, including B cells, monocytes and macrophages, dendritic cells and subsets of natural killer (NK) cells and T cells. The ligands of LILRB1, such as major histocompatibility complex (MHC) class I molecules, activate LILRB1 and transduce a suppressive signal, which inhibits the immune responses. However, it is not clear whether LILRB1 blockade can be effectively used for cancer treatment.MethodsFirst, we measured the LILRB1 expression on NK cells from cancer patients to determine whether LILRB1 upregulated on NK cells from patients with cancer, compared with NK cells from healthy donors. Then, we developed specific antagonistic anti-LILRB1 monoclonal antibodies and studied the effects of LILRB1 blockade on the antitumor immune function of NK cells, especially in multiple myeloma models, in vitro and in vivo xenograft model using non-obese diabetic (NOD)-SCID interleukin-2Rγ-null mice.ResultsWe demonstrate that percentage of LILRB1+ NK cells is significantly higher in patients with persistent multiple myeloma after treatment than that in healthy donors. Further, the percentage of LILRB1+ NK cells is also significantly higher in patients with late-stage prostate cancer than that in healthy donors. Significantly, we showed that LILRB1 blockade by our antagonistic LILRB1 antibody increased the tumoricidal activity of NK cells against several types of cancer cells, including multiple myeloma, leukemia, lymphoma and solid tumors, in vitro and in vivo.ConclusionsOur results indicate that blocking LILRB1 signaling on immune effector cells such as NK cells may represent a novel strategy for the development of anticancer immunotherapy.

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“…We also found that the frequency of LILRB1 D1-D2 variants shows population difference and variants 1–3 represent the three most frequent LILRB1 D1-D2 variants in worldwide populations. Additionally, polymorphisms in the introns and UTRs were also examined in several studies (Kuroki et al 2005 ; Davidson et al 2010 ; Wiśniewski et al 2015 ; Yu et al 2020 ). However, we did not include the polymorphisms in the non-coding region in our study.…”

Section: Discussionmentioning

confidence: 99%

Natural LILRB1 D1-D2 variants show frequency differences in populations and bind to HLA class I with various avidities

et al. 2022

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Leukocyte immunoglobulin-like receptor B1 (LILRB1) is widely expressed on various immune cells and the engagement of LILRB1 to HLA class I and pathogen-derived proteins can modulate the immune response. In the current study, 108 LILRB1 alleles were identified by screening the LILRB1 locus from the 1000 Genomes Phase 3 database. Forty-six alleles that occurred in three or more individuals encode 28 LILRB1 allotypes, and the inferred LILRB1 allotypes were then grouped into 9 LILRB1 D1-D2 variants for further analysis. We found that variants 1, 2, and 3 represent the three most frequent LILRB1 D1-D2 variants and the nine variants show frequency differences in populations. The binding assay demonstrated that variant 1 bound to HLA class I with the highest avidity, and all tested LILRB1 D1-D2 variants bound to HLA-C with lower avidity than to HLA-A and -B. Locus-specific polymorphisms at positions 183, 189, and 268 in HLA class I and dimorphisms in HLA-A (positions 207 and 253) and in HLA-B (position 194) affect their binding to LILRB1. Notably, the electrostatic interaction plays a critical role in the binding of LILRB1 to HLA class I as revealed by electrostatic analysis and by comparison of different binding avidities caused by polymorphisms at positions 72 and 103 of LILRB1. In this paper, we present a comprehensive study of the population genetics and binding abilities of LILRB1. The data will help us better understand the LILRB1-related diversity of the immune system and lay a foundation for functional studies. Supplementary Information The online version contains supplementary material available at 10.1007/s00251-022-01264-7.

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LILRB1 Intron 1 Has a Polymorphic Regulatory Region That Enhances Transcription in NK Cells and Recruits YY1

Cited by 4 publications

References 78 publications

HLA-F and LILRB1 Genetic Polymorphisms Associated with Alloimmunisation in Sickle Cell Disease

HLA-F and LILRB1 Genetic Polymorphisms Associated with Alloimmunisation in Sickle Cell Disease

Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells

Natural LILRB1 D1-D2 variants show frequency differences in populations and bind to HLA class I with various avidities

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