A LILRB1 variant with a decreased ability to phosphorylate SHP-1 leads to autoimmune diseases

Inborn errors of immunity are known to cause not only immunodeficiencies and allergies but also autoimmunity. Leukocyte immunoglobulin-like receptor B1 (LILRB1) is a receptor on leukocytes playing a role in regulating immune responses. No phenotypes have been reported to be caused by germline mutations in LILRB1. We aimed to identify the causative variant in a three-generation family with nine members suffering from one of the three autoimmune diseases-Graves' disease, Hashimoto's thyroiditis, or systemic lupus erythematosus. Whole-genome linkage study revealed a locus on chromosome 19q13.4 with the maximum LOD score of 2.71. Whole-exome sequencing identified a heterozygous missense variant, c.479G > A (p. G160E) in LILRB1, located within the chromosomal-linked region, in all nine affected members. The variant has never been previously reported. Jurkat cells transfected with the mutant LILRB1, compared with those with the wild-type LILRB1, showed decreased phosphorylation of both LILRB1 and its downstream protein, SHP-1. Flow cytometry was used to study immunophenotype and revealed that LILRB1 was significantly lower on the surface of activated regulatory T lymphocytes (Treg) cells of patients. Single-cell RNA sequencing showed substantially increased M1-like monocytes in peripheral blood mononuclear cells of affected individuals. This study, for the first time, implicates LILRB1 as a new disease gene for autoimmunity.
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Thivaratana Sinthuwiwat, Supranee Buranapraditkun, Wuttichart Kamolvisit, Siraprapa Tongkobpetch, Wanna Chetruengchai, Chalurmpon Srichomthong, Adjima Assawapitaksakul, Chureerat Phokaew, Patipark Kueanjinda, Tanapat Palaga, Tadech Boonpiyathad, Kanya Suphapeetiporn, Nattiya Hirankarn, Vorasuk Shotelersuk

  • Sci Rep
  • 4.6
  • 2022 Sep 14;12(1):15420.
  • Human
  • 抗体芯片
  • 免疫/内分泌
  • 单核细胞
  • 自身免疫性疾病
  • 2B4/SLAMF4,FcRH1/IRTA5,NKp46/NCR1,BLAME/SLAMF8,FcRH2/IRTA4,NKp80/KLRF1,BTLA,FcRH4/IRTA1,NTB-A/SLAMF6,CD3 epsilon,FcRH5/IRTA2,PD-1,CD5,ILT2/CD85j,PECAM/CD31),CD6,ILT3/CD85k,SHIP-1,CD28,ILT4/CD85d,SHP-1,CD84/SLAMF5,ILT5/CD85a,SHP-2,CD229/SLAMF3,ILT6/CD85e,Siglec-2/CD22,CEACAM-1,Integrin beta 3/CD61,Siglec-3/CD33,CLEC-1,KIR2DL4,Siglec-5,CLEC-2,LAIR-1,Siglec-7,CRACC/SLAMF7,LAIR-2,Siglec-9,CTLA-4/CD152,LMIR1/CD300A,Siglec-10,DCIR/CLEC4A,LMIR2/CD300C,SIRP-beta 1,Dectin-1/CLEC7A,LMIR3/CD300LF,SLAM/CD150,DNAM-1,LMIR6/CD300LE,TREM-1,Fc epsilon RII/CD23,MDL-1/CLEC5A,TREM-2,Fc gamma RIIA,NKp30/NCR3,TREML1/TLT-1,Fc gamma RIIIA/B,NKp44/NCR2

相关货号

LXAH059-1

Abstract

Inborn errors of immunity are known to cause not only immunodeficiencies and allergies but also autoimmunity. Leukocyte immunoglobulin-like receptor B1 (LILRB1) is a receptor on leukocytes playing a role in regulating immune responses. No phenotypes have been reported to be caused by germline mutations in LILRB1. We aimed to identify the causative variant in a three-generation family with nine members suffering from one of the three autoimmune diseases-Graves' disease, Hashimoto's thyroiditis, or systemic lupus erythematosus. Whole-genome linkage study revealed a locus on chromosome 19q13.4 with the maximum LOD score of 2.71. Whole-exome sequencing identified a heterozygous missense variant, c.479G > A (p. G160E) in LILRB1, located within the chromosomal-linked region, in all nine affected members. The variant has never been previously reported. Jurkat cells transfected with the mutant LILRB1, compared with those with the wild-type LILRB1, showed decreased phosphorylation of both LILRB1 and its downstream protein, SHP-1. Flow cytometry was used to study immunophenotype and revealed that LILRB1 was significantly lower on the surface of activated regulatory T lymphocytes (Treg) cells of patients. Single-cell RNA sequencing showed substantially increased M1-like monocytes in peripheral blood mononuclear cells of affected individuals. This study, for the first time, implicates LILRB1 as a new disease gene for autoimmunity.
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