Dataset Information

P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance.

ABSTRACT: B cell self-tolerance is maintained through multiple checkpoints, including restraints on intracellular signaling and cell trafficking. P2RY8 is a receptor with established roles in germinal center (GC) B cell migration inhibition and growth regulation. Somatic P2RY8 variants are common in GC-derived B cell lymphomas. Here, we identify germline novel or rare P2RY8 missense variants in lupus kindreds or the related antiphospholipid syndrome, including a "de novo" variant in a child with severe nephritis. All variants decreased protein expression, F-actin abundance, and GPCR-RhoA signaling, and those with stronger effects increased AKT and ERK activity and cell migration. Remarkably, P2RY8 was reduced in B cell subsets from some SLE patients lacking P2RY8 gene variants. Low P2RY8 correlated with lupus nephritis and increased age-associated B cells and plasma cells. By contrast, P2RY8 overexpression in cells and mice restrained plasma cell development and reinforced negative selection of DNA-reactive developing B cells. These findings uncover a role of P2RY8 in immunological tolerance and lupus pathogenesis.

SUBMITTER: He Y

PROVIDER: S-EPMC8669517 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance.

He Yuke Y Gallman Antonia E AE Xie Chengmei C Shen Qian Q Ma Jianyang J Wolfreys Finn D FD Sandy Moriah M Arsov Todor T Wu Xiaoqian X Qin Yuting Y Zhang Pingjing P Jiang Simon S Stanley Maurice M Wu Philip P Tan Jingjing J Ding Huihua H Xue Haiyan H Chen Wei W Xu Jinping J Criswell Lindsey A LA Nititham Joanne J Adamski Marcin M Kitching A Richard AR Cook Matthew C MC Cao Lanfang L Shen Nan N Cyster Jason G JG Vinuesa Carola G CG

The Journal of experimental medicine 20211210 1

B cell self-tolerance is maintained through multiple checkpoints, including restraints on intracellular signaling and cell trafficking. P2RY8 is a receptor with established roles in germinal center (GC) B cell migration inhibition and growth regulation. Somatic P2RY8 variants are common in GC-derived B cell lymphomas. Here, we identify germline novel or rare P2RY8 missense variants in lupus kindreds or the related antiphospholipid syndrome, including a "de novo" variant in a child with severe ne ...[more]

PMID: 34889940

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Project description:BackgroundThe chemokine receptor CCR7 is a key organizer of the immune system. Gene targeting in mice revealed that Ccr7-deficient animals are severely impaired in the induction of central and peripheral tolerance. Due to these defects, Ccr7-deficient mice spontaneously develop multi-organ autoimmunity showing symptoms similar to those observed in humans suffering from connective tissue autoimmune diseases. However, it is unknown whether mutations of CCR7 are linked to autoimmunity in humans.ResultsDNA samples were collected from 160 patients suffering from connective tissue autoimmune disease (Sjogren's syndrome, n = 40; systemic lupus erythematosus, SLE, n = 20 and systemic sclerosis, n = 100) and 40 health subjects (n = 40). All participants in this study were of German descent. Samples were screened for single nucleotide polymorphisms (SNP) by sequencing the coding region of the CCR7 gene as well asthe exon flaking intron sites and parts of the regions encoding for the 5'- and 3'-UTR. CCR7 variants were rare. We identified six different sequence variants, which occurred in heterozygosis. The identified SNP were observed at position -60 C/T (observed 1x), +6,476 A/G (7x), +6,555 C/T (15x), +6,560 C/T (6x), +10,440 A/G (3x) and +11,475 C/A (1x). Four of these variants (+6,476 A/G, +6,555 C/T, +6,560 C/T and +10,440 A/G) display allelic frequencies between 1% and 5 % and were present in both patients and control groups. The variants +6,476 A/G, +6,555 C/T, +6,560 C/T are located in the intron 2, while the +10,440 A/G variant corresponds to a silent mutation in exon 3. The variants -60 C/T and +11,475 C/A which are located at the 5'-UTR and 3-UTR respectively, display allelic frequencies below 1%. No correlation between these variants and the autoimmune diseases investigated could be observed. However, reporter gene expression assay demonstrated that the mutation at the -60 C/T position in homozygosis leads to reduced luciferase activity.ConclusionThese results suggest that variants of CCR7 gene occur at an extremely low frequency in the German population and that neither Sjogren's syndrome, systemic lupus erythematosus, nor systemic sclerosis are associated with these variants. Nevertheless, the decreased luciferase activity observed in cells transfected with the promoter region bearing the -60 C/T mutation suggests that this CCR7 variant could potentially lead to increased susceptibility to autoimmunity.

Project description:OBJECTIVE:Phenome-wide association studies (PheWAS) scan across billing codes in the electronic health record (EHR) and re-purpose clinical EHR data for research. In this study, we examined whether PheWAS could function as an EHR-based discovery tool for systemic lupus erythematosus (SLE) and identified novel clinical associations in male versus female patients with SLE. METHODS:We used a de-identified version of the Vanderbilt University Medical Center EHR, which includes more than 2.8 million subjects. We performed EHR-based PheWAS to compare SLE patients with age-, sex-, and race-matched control subjects and to compare male SLE patients with female SLE patients, controlling for multiple testing using a false discovery rate (FDR) P value of 0.05. RESULTS:We identified 1,097 patients with SLE and 5,735 matched control subjects. In a comparison of patients with SLE and matched controls, SLE patients were shown to be more likely to have International Classification of Diseases, Ninth Revision codes related to the SLE disease criteria. In the PheWAS of male versus female SLE patients, with adjustment for age and race, male patients were shown to be more likely to have atrial fibrillation (odds ratio 4.50, false discovery rate P = 3.23 × 10-3 ). Chart review confirmed atrial fibrillation, with the majority of patients developing atrial fibrillation after the SLE diagnosis and having multiple risk factors for atrial fibrillation. After adjustment for age, sex, race, and coronary artery disease, SLE disease status was shown to be significantly associated with atrial fibrillation (P = 0.002). CONCLUSION:Using PheWAS to compare male and female patients with SLE, we identified a novel association of an increased incidence of atrial fibrillation in male patients. SLE disease status was shown to be independently associated with atrial fibrillation, even after adjustment for age, sex, race, and coronary artery disease. These results demonstrate the utility of PheWAS as an EHR-based discovery tool for SLE.

Dataset Information

P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance.

Publications

P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance.

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