Screening the full leucocyte receptor complex genomic region revealed associations with pemphigus that might be explained by gene regulation

Farias, Ticiana Della Justina; Augusto, Danillo G.; Almeida, Rodrigo Coutinho de; Malheiros, Danielle; Petzl-Erler, María Luiza

doi:10.1111/imm.13003

Cited by 14 publications

(9 citation statements)

References 64 publications

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“…The Journal of Immunology autoimmune thyroiditis (6)(7)(8)(9)(10)(11)(12)(13). Mounting evidence also supports the immune checkpoint function of LILRB1 in viral chronic infection and cancer (76)(77)(78).…”

Section: Discussionmentioning

confidence: 89%

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

Davidson

Burshtyn

2020

The Journal of Immunology

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LILRB1 is a highly polymorphic receptor expressed by subsets of innate and adaptive immune cells associated with viral and autoimmune diseases and targeted by pathogens for immune evasion. LILRB1 expression on human NK cells is variegated, and the frequency of LILRB1 + cells differs among people. However, little is known about the processes and factors mediating LILRB1 transcription in NK cells. LILRB1 gene expression in lymphoid and myeloid cells arises from two distinct promoters that are separated by the first exon and intron. In this study, we identified a polymorphic 3-kb region within LILRB1 intron 1 that is epigenetically marked as an active enhancer in human lymphoid cells and not monocytes. This region possesses multiple YY1 sites, and complexes of the promoter/enhancer combination were isolated using anti-YY1 in chromatin immunoprecipitation-loop. CRISPR-mediated deletion of the 3-kb region lowers LILRB1 expression in human NKL cells. Together, these results indicate the enhancer in intron 1 binds YY1 and suggest YY1 provides a scaffold function enabling enhancer function in regulating LILRB1 gene transcription in human NK cells.

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Section: Discussionmentioning

confidence: 89%

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

Davidson

Burshtyn

2020

The Journal of Immunology

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“…Collagen in tumor matrix and damaged tissues is a common ligand for LAIR1 in broad spectrum, inhibiting immune cell functions after ligation, while LAIR2 was found to be a soluble protein with similar extracellular domain, which could block LAIR1 binding by competing ligands (55)(56)(57)(58). Former studies also showed in autoimmune diseases, expression of LAIR2 was increased, and genetic single nucleotide polymorphism of LAIR2 was related to susceptibility of autoimmune diseases (59)(60)(61)(62). The knowledge of LAIR2 in TIME regulation is limited, however, LAIR2 could interfere platelet activation and adhesion, and secreted LAIR2 could inhibit classical and lectin pathways of complement system in killing pathogens (58,63).…”

Section: Discussionmentioning

confidence: 99%

PNOC Expressed by B Cells in Cholangiocarcinoma Was Survival Related and LAIR2 Could Be a T Cell Exhaustion Biomarker in Tumor Microenvironment: Characterization of Immune Microenvironment Combining Single-Cell and Bulk Sequencing Technology

Chen

Yan

et al. 2021

Front. Immunol.

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BackgroundCholangiocarcinoma was a highly malignant liver cancer with poor prognosis, and immune infiltration status was considered an important factor in response to immunotherapy. In this investigation, we tried to locate immune infiltration related genes of cholangiocarcinoma through combination of bulk-sequencing and single-cell sequencing technology.MethodsSingle sample gene set enrichment analysis was used to annotate immune infiltration status in datasets of TCGA CHOL, GSE32225, and GSE26566. Differentially expressed genes between high- and low-infiltrated groups in TCGA dataset were yielded and further compressed in other two datasets through backward stepwise regression in R environment. Single-cell sequencing data of GSE138709 was loaded by Seurat software and was used to examined the expression of infiltration-related gene set. Pathway changes in malignant cell populations were analyzed through scTPA web tool.ResultsThere were 43 genes differentially expressed between high- and low-immune infiltrated patients, and after further compression, PNOC and LAIR2 were significantly correlated with high immune infiltration status in cholangiocarcinoma. Through analysis of single-cell sequencing data, PNOC was mainly expressed by infiltrated B cells in tumor microenvironment, while LAIR2 was expressed by Treg cells and partial GZMB+ CD8 T cells, which were survival related and increased in tumor tissues. High B cell infiltration levels were related to better overall survival. Also, malignant cell populations demonstrated functionally different roles in tumor progression.ConclusionPNOC and LAIR2 were biomarkers for immune infiltration evaluation in cholangiocarcinoma. PNOC, expressed by B cells, could predict better survival of patients, while LAIR2 was a potential marker for exhaustive T cell populations, correlating with worse survival of patients.

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“…A genome-wide expression profiling with approximately 55,000 probes revealed that several genes in 19q13 were differentially expressed in CD4+ lymphocytes when comparing FS patients and controls, as well as between different FS clinical forms ( Malheiros et al , 2014 ). Motivated by this result, recently the whole 1.5 Mb LRC was screened in a case-control study using genotype data of 527 tag SNPs of which three were associated with differential susceptibility to FS ( Farias et al , 2019 ). The intergenic SNP rs465169 is in a region that regulates several immune-related genes, including VSTM1, LAIR1, LILRA3-6, LILRB2, NLRP12, and LENG8.…”

Section: Pemphigus Geneticsmentioning

confidence: 99%

Beyond the HLA polymorphism: A complex pattern of genetic susceptibility to pemphigus

Petzl-Erler

2020

Genet. Mol. Biol.

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Pemphigus is a group of autoimmune bullous skin diseases that result in significant morbidity. As for other multifactorial autoimmune disorders, environmental factors may trigger the disease in genetically susceptible individuals. The goals of this review are to summarize the state of knowledge about the genetic variation that may affect the susceptibility and pathogenesis of pemphigus vulgaris and pemphigus foliaceus-both the endemic and the sporadic forms-, to compare and discuss the possible meaning of the associations reported, and to propose recommendations for new research initiatives. Understanding how genetic variants translate into pathogenic mechanisms and phenotypes remains a mystery for most of the polymorphisms that contribute to disease susceptibility. However, genetic studies provide a strong foundation for further developments in this field by generating testable hypotheses. Currently, results still have limited influence on disease prevention and prognosis, drug development, and clinical practice, although the perspectives for future applications for the benefit of patients are encouraging. Recommendations for the continued advancement of our understanding as to the impact of genetic variation on pemphigus include these partially overlapping goals: (1) Querying the functional effect of genetic variants on the regulation of gene expression through their impact on the nucleotide sequence of cis regulatory DNA elements such as promoters and enhancers, the splicing of RNA, the structure of regulatory RNAs and proteins, binding of these regulatory molecules to regulatory DNA elements, and alteration of epigenetic marks; (2) identifying key cell types and cell states that are implicated in pemphigus pathogenesis and explore their functional genomes; (3) integrating structural and functional genomics data; (4) performing disease-progression longitudinal studies to disclose the causal relationships between genetic and epigenetic variation and intermediate disease phenotypes; (5) understanding the influence of genetic and epigenetic variation in the response to treatment and the severity of the disease; (6) exploring gene-gene and genotype-environment interactions; (7) developing improved pemphigus-prone and non-prone animal models that are appropriate for research about the mechanisms that link genotypes to pemphigus. Achieving these goals will demand larger samples of patients and controls and multisite collaborations.

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Screening the full leucocyte receptor complex genomic region revealed associations with pemphigus that might be explained by gene regulation

Cited by 14 publications

References 64 publications

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

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

PNOC Expressed by B Cells in Cholangiocarcinoma Was Survival Related and LAIR2 Could Be a T Cell Exhaustion Biomarker in Tumor Microenvironment: Characterization of Immune Microenvironment Combining Single-Cell and Bulk Sequencing Technology

Beyond the HLA polymorphism: A complex pattern of genetic susceptibility to pemphigus

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