Bulk T-cell receptor sequencing confirms clonality in obstetric antiphospholipid syndrome and may as a potential biomarker.

The heterogeneity of the T cell receptor (TCR) repertoire critically influences the autoimmune response in obstetric antiphospholipid syndrome (OAPS) and is intimately associated with the prophylaxis of autoimmune disorders. Investigating the TCR diversity patterns in patients with OAPS is thus of paramount clinical importance. This investigation procured peripheral blood specimens from 31 individuals with OAPS, 21 patients diagnosed with systemic lupus erythematosus (SLE), and 22 healthy controls (HC), proceeding with TCR repertoire sequencing. Concurrently, adverse pregnancy outcomes in the OAPS cohort were monitored and documented over an 18-month timeframe. We paid particular attention to disparities in V/J gene utilisation and the prevalence of shared clonotypes amongst OAPS patients and the comparative groups. When juxtaposed with observations from healthy controls and SLE patients, immune repertoire sequencing disclosed irregular T- and B-cell profiles and a contraction of diversity within the OAPS group. Marked variances were found in the genomic rearrangements of the V gene, J gene, and V/J combinations. Utilising a specialised TCRß repertoire, we crafted a predictive model for OAPS classification with robust discriminative capability (AUC = 0.852). Our research unveils alterations in the TCR repertoire among OAPS patients for the first time, positing potential covert autoimmune underpinnings. These findings nominate the TCR repertoire as a prospective peripheral blood biomarker for the clinical diagnosis of OAPS and may offer valuable insights for advancing the understanding of OAPS immunologic mechanisms and prognostic outcomes.

H3K4me3-Mediated FOXJ2/SLAMF8 Axis Aggravates Thrombosis and Inflammation in ß2GPI/Anti-ß2GPI-Treated Monocytes.

Antiphospholipid syndrome (APS) is characterized by thrombus formation, poor pregnancy outcomes, and a proinflammatory response. H3K4me3-related monocytes activation are key regulators of APS pathogenesis. Therefore, H3K4me3 CUT&Tag and ATAC-seq are performed to examine the epigenetic profiles. The results indicate that the H3K4me3 signal and chromatin accessibility at the FOXJ2 promoter are enhanced in an in vitro monocyte model by stimulation with ß2GPI/anti-ß2GPI, which mimics APS, and decreases after OICR-9429 administration. Furthermore, FOXJ2 is highly expressed in patients with primary APS (PAPS) and is the highest in patients with triple-positive antiphospholipid antibodies (aPLs). Mechanistically, FOXJ2 directly binds to the SLAMF8 promoter and activates SLAMF8 transcription. SLAMF8 further interacts with TREM1 to stimulate TLR4/NF-κB signaling and prohibit autophagy. Knockdown of FOXJ2, SLAMF8, or TREM1 blocks TLR4/NF-κB and provokes autophagy, subsequently inhibiting the release of inflammatory and thrombotic indicators. A mouse model of vascular APS is established via ß2GPI intraperitoneal injection, and the results suggest that OICR-9429 administration attenuates the inflammatory response and thrombus formation by inactivating FOXJ2/SLAMF8/TREM1 signaling. These findings highlight the overexpression of H3K4me3-mediated FOXJ2 in APS, which consequently accelerates APS pathogenesis by triggering inflammation and thrombosis via boosting the SLAMF8/TREM1 axis. Therefore, OICR-9429 is a promising candidate drug for APS therapy.

ARID5B-mediated LINC01128 epigenetically activated pyroptosis and apoptosis by promoting the formation of the BTF3/STAT3 complex in ß2GPI/anti-ß2GPI-treated monocytes.

BACKGROUND: Alterations of the trimethylation of histone 3 lysine 4 (H3K4me3) mark in monocytes are implicated in the development of autoimmune diseases. Therefore, the purpose of our study was to elucidate the role of H3K4me3-mediated epigenetics in the pathogenesis of antiphospholipid syndrome (APS). METHODS: H3K4me3 Cleavage Under Targets and Tagmentation and Assay for Transposase-Accessible Chromatin were performed to determine the epigenetic profiles. Luciferase reporter assay, RNA immunoprecipitation, RNA pull-down, co-immunoprecipitation and chromatin immunoprecipitation were performed for mechanistic studies. Transmission electron microscopy and propidium iodide staining confirmed cell pyroptosis. Primary monocytes from patients with primary APS (PAPS) and healthy donors were utilised to test the levels of key molecules. A mouse model mimicked APS was constructed with beta2-glycoprotein I (ß2GPI) injection. Blood velocity was detected using murine Doppler ultrasound. RESULTS: H3K4me3 signal and open chromatin at the ARID5B promoter were increased in an in vitro model of APS. The epigenetic factor ARID5B directly activated LINC01128 transcription at its promoter. LINC01128 promoted the formation of the BTF3/STAT3 complex to enhance STAT3 phosphorylation. Activated STAT3 interacted with the NLRP3 promoter and subsequently stimulated pyroptosis and apoptosis. ARID5B or BTF3 depletion compensated for LINC01128-induced pyroptosis and apoptosis by inhibiting STAT3 phosphorylation. In mice with APS, ß2GPI exposure elevated the levels of key proteins of pyroptosis and apoptosis pathways in bone marrow-derived monocytes, reduced the blood velocity of the ascending aorta, increased the thrombus size of the carotid artery, and promoted the release of interleukin (IL)-18, IL-1ß and tissue factor. Patients with PAPS had the high-expressed ARID5B and LINC01128, especially those with triple positivity for antiphospholipid antibodies. Moreover, there was a positive correlation between ARID5B and LINC01128 expression. CONCLUSION: This study indicated that ARID5B/LINC01128 was synergistically upregulated in APS, and they aggravated disease pathogenesis by enhancing the formation of the BTF3/STAT3 complex and boosting p-STAT3-mediated pyroptosis and apoptosis, thereby providing candidate therapeutic targets for APS. HIGHLIGHTS: The H3K4me3 mark and chromatin accessibility at the ARID5B promoter are increased in vitro model mimicked APS. ARID5B-mediated LINC01128 induces pyroptosis and apoptosis via p-STAT3 by binding to BTF3. ARID5B is high- expressed in patients with primary APS and positively correlated with LINC01128 expression. OICR-9429 treatment mitigates pyroptosis and related inflammation in vivo and in vitro models mimicked APS.

Placenta microRNA profile of patient with Obstetric Antiphospholipid Syndrome.

The onset of obstetric antiphospholipid syndrome (APS) occurs when antiphospholipid antibodies act upon the placenta. During pregnancy, APS exhibits traits such as vascular thrombosis, inflammation, and hindered trophoblast implantation. The involvement of microRNA expression has been proposed as a genetic factor contributing to the syndrome's development. MicroRNAs play a role in regulating gene expression in various cellular processes, including the formation of placental tissue. Therefore, additional research is needed to explore the control of placental miRNA in APS. In this study, we aimed to profile miRNA expressions from placenta tissue of patients with APS. Differentially expressed miRNAs were determined for its targeted genes and pathways. Agilent microarray platform was used to measure placental microRNA expressions between normal placental tissue and those obtained from patients with APS. Differentially expressed miRNAs were detected using GeneSpring GX software 14.2 and sequences were mapped using TargetScan software to generate the predicted target genes. Pathway analysis for the genes was then performed on PANTHER and REACTOME software. Selected miRNAs and their associated genes of interest were validated using qPCR. Microarray findings revealed, 9 downregulated and 21 upregulated miRNAs expressed in placenta of patients with APS. Quantitative expressions of 3 selected miRNAs were in agreement with the microarray findings, however only miR-525-5p expression was statistically significant. Pathway analysis revealed that the targeted genes of differentially expressed miRNAs were involved in several hypothesised signalling pathways such as the vascular endothelial (VE) growth factor (VEGF) and inflammatory pathways. VE-cadherin, ras homolog member A (RHOA) and tyrosine kinase receptor (KIT) showed significant downregulation while Retinoblastoma gene (RET), Dual specificity protein phosphatase 10 (DUSP10) and B-lymphocyte kinase (BLK) genes were significantly upregulated. These preliminary findings suggest the involvement of miRNAs and identified novel associated genes involvement in the mechanism of obstetric APS, particularly through the alteration of vascular-associated regulators and the inflammatory signalling cascade.

Identification of MARK2, CCDC71, GATA2, and KLRC3 as candidate diagnostic genes and potential therapeutic targets for repeated implantation failure with antiphospholipid syndrome by integrated bioinformatics analysis and machine learning.

Background: Antiphospholipid syndrome (APS) is a group of clinical syndromes of thrombosis or adverse pregnancy outcomes caused by antiphospholipid antibodies, which increase the incidence of in vitro fertilization failure in patients with infertility. However, the common mechanism of repeated implantation failure (RIF) with APS is unclear. This study aimed to search for potential diagnostic genes and potential therapeutic targets for RIF with APS. Methods: To obtain differentially expressed genes (DEGs), we downloaded the APS and RIF datasets separately from the public Gene Expression Omnibus database and performed differential expression analysis. We then identified the common DEGs of APS and RIF. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed, and we then generated protein-protein interaction. Furthermore, immune infiltration was investigated by using the CIBERSORT algorithm on the APS and RIF datasets. LASSO regression analysis was used to screen for candidate diagnostic genes. To evaluate the diagnostic value, we developed a nomogram and validated it with receiver operating characteristic curves, then analyzed these genes in the Comparative Toxicogenomics Database. Finally, the Drug Gene Interaction Database was searched for potential therapeutic drugs, and the interactions between drugs, genes, and immune cells were depicted with a Sankey diagram. Results: There were 11 common DEGs identified: four downregulated and seven upregulated. The common DEG analysis suggested that an imbalance of immune system-related cells and molecules may be a common feature in the pathophysiology of APS and RIF. Following validation, MARK2, CCDC71, GATA2, and KLRC3 were identified as candidate diagnostic genes. Finally, Acetaminophen and Fasudil were predicted as two candidate drugs. Conclusion: Four immune-associated candidate diagnostic genes (MARK2, CCDC71, GATA2, and KLRC3) were identified, and a nomogram for RIF with APS diagnosis was developed. Our findings may aid in the investigation of potential biological mechanisms linking APS and RIF, as well as potential targets for diagnosis and treatment.

Small-Extracellular-Vesicle-Derived miRNA Profile Identifies miR-483-3p and miR-326 as Regulators in the Pathogenesis of Antiphospholipid Syndrome (APS).

Primary antiphospholipid syndrome (PAPS) is a systemic autoimmune disease associated with recurrent thrombosis and/or obstetric morbidity with persistent antiphospholipid antibodies (aPL). Although these antibodies drive endothelial injury and thrombophilia, the underlying molecular mechanism is still unclear. Small extracellular vesicles (sEVs) contain miRNAs, key players in intercellular communication. To date, the effects of miRNA-derived sEVs in PAPS are not well understood. We characterised the quantity, cellular origin and miRNA profile of sEVs isolated from thrombotic APS patients (PAPS, n = 50), aPL-carrier patients (aPL, n = 30) and healthy donors (HD, n = 30). We found higher circulating sEVs mainly of activated platelet origin in PAPS and aPL patients compared to HD, that were highly engulfed by HUVECs and monocyte. Through miRNA-sequencing analysis, we identified miR-483-3p to be differentially upregulated in sEVs from patients with PAPS and aPL, and miR-326 to be downregulated only in PAPS sEVs. In vitro studies showed that miR-483-3p overexpression in endothelial cells induced an upregulation of the PI3K-AKT pathway that led to endothelial proliferation/dysfunction. MiR-326 downregulation induced NOTCH pathway activation in monocytes with the upregulation of NFKB1, tissue factor and cytokine production. These results provide evidence that miRNA-derived sEVs contribute to APS pathogenesis by producing endothelial cell proliferation, monocyte activation and adhesion/procoagulant factors.

High-throughput sequencing technology facilitates the discovery of novel biomarkers for antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is characterized by arterial and venous thrombosis and/or morbid pregnancy, accompanied by persistent antiphospholipid antibody (aPL) positivity. However, due to the complex pathogenesis of APS and the large individual differences in the expression of aPL profiles of patients, the problem of APS diagnosis, prognosis judgment, and risk assessment may not be solved only from the antibody level. It is necessary to use new technologies and multiple dimensions to explore novel APS biomarkers. The application of next-generation sequencing (NGS) technology in diseases with a high incidence of somatic mutations, such as genetic diseases and tumors, has been very mature. Thus, we try to know the research and application progress of APS by NGS technology from genome, transcriptome, epigenome and other aspects. This review will describe the related research of NGS technology in APS and provide more reference for the deep understanding of APS-related screening markers and disease pathogenesis.

The association of APOH and NCF1 polymorphisms on susceptibility to recurrent pregnancy loss in women with antiphospholipid syndrome.

BACKGROUND: Recurrent pregnancy loss (RPL) is the main manifestation of pathological pregnancy in antiphospholipid syndrome (APS) women. The immune state plays a significant role in the occurrence/development of APS and RPL susceptibility, but there is little research on genetic factors. METHOD: Previous studies have described the important role of APOH and NCF1 in APS and pregnancy. To explore the association of APOH and NCF1 gene variants with RPL susceptibility in APS patients, we collected and analyzed 871 controls, 182 APS and RPL, and 231 RPL patients. Four single nucleotide polymorphisms (SNPs) (rs1801690, rs52797880, and rs8178847 of APOH and rs201802880 of NCF1) were selected and genotyped. RESULTS: We found rs1801690 (p = 0.001, p = 0.003), rs52797880 (p = 8.73e-04, p = 0.001), and rs8178847 (p = 0.001, p = 0.001) of APOH and rs201802880 (p = 3.77e-26, p = 1.31e-26) of NCF1 showed significant differences between APS and RPL patients and controls in allelic and genotype frequencies respectively. Moreover, rs1801690, rs52797880, and rs8178847 showed strong linkage disequilibrium. Especially, our results revealed a complete linkage disequilibrium (D' = 1) between rs52797880 and rs8178847. Furthermore, higher serum TP (total protein) level was described in APOH rs1801690 CG/GG (p = 0.007), rs52797880 AG/GG (p = 0.033), and rs8178847 CT/TT (p = 0.033), while the higher frequency of positive serum ACA-IgM was found in NCF1 rs201802880 GA (p = 0.017) in APS and RPL patients. CONCLUSION: Rs1801690, rs52797880, and rs8178847 of APOH and rs201802880 of NCF1 were associated with RPL susceptibility in APS patients.

[Application progress of high-throughput sequencing in antiphospholipid syndrome].

Antiphospholipid syndrome (APS) is characterized by arterial and venous thrombosis and(or) morbid pregnancy, accompanied by persistent antiphospholipid antibody (aPL) positivity. However, due to the complex pathogenesis of APS and the large individual differences in the expression of aPL profiles of patients, the problem of APS diagnosis, prognosis judgment and risk assessment may not be solved only from antibody level. It is necessary to use new technologies and multiple dimensions to explore novel APS biomarkers. The application of next generation sequencing (NGS) technology in diseases with high incidence of somatic mutations, such as genetic diseases and tumors, has been very mature. Thus, gradually understanding the research and application progress of APS by NGS technology from genome, transcriptome, epigenome and other aspects is meaningful. This article reviews the related research of NGS technology in APS, and provide more reference for the deep understanding of the APS-related screening markers and disease pathogenesis.

Catastrophic antiphospholipid syndrome accompanied by complement regulatory gene mutation.

BACKGROUND: Antiphospholipid syndrome (APS), particularly the catastrophic antiphospholipid syndrome (CAPS), is one of the rare causes of thrombotic microangiopathy (TMA). CAPS is the most severe form of APS, especially when accompanied by complement dysregulation, causes progressive microvascular thrombosis and failure in multiple organs. In this report, a case of CAPS with TMA accompanied by a genetic defect in the complement system is presented. CASE: A 13-year-old girl was admitted to the hospital with oliguric acute kidney injury, nephrotic range proteinuria, Coombs positive hemolysis, refractory thrombocytopenia, a low serum complement C3 level and anti-nuclear antibody (ANA) positivity. The kidney biopsy was consistent with TMA. She was first diagnosed with primary APS with clinical and pathological findings and double antibody positivity. As initial treatments, plasmapheresis (PE) was performed and eculizumab was also administered following pulsesteroid and intravenous immunoglobulin treatments. Her renal functions recovered and she was followed up with mycophenolate mofetil, hydroxychloroquine, low dose prednisolone and low molecular weight heparin treatments. The patient presented with severe chest pain, vomiting and acute deterioration of renal functions a few months after the diagnosis of TMA. A CAPS attack was considered due to radiological findings consistent with multiple organ thrombosis and intravenous cyclophosphamide (CYC) was given subsequent to PE. After pulse CYC and PE treatments, her renal functions recovered, she is still being followed for stage-3 chronic kidney disease. Complement factor H-related protein I gene deletion was detected in the genetic study. CONCLUSIONS: The clinical course of complement mediated CAPS tends to be worse. Complement system dysregulation should be investigated in all CAPS patients, and eculizumab treatment should be kept in mind if detected.

lncRNAs dysregulation in monocytes from primary antiphospholipid syndrome patients: a bioinformatic and an experimental proof-of-concept approach.

BACKGROUND: Antiphospholipid syndrome (APS) is the main cause of acquired thrombophilia where peripheral circulating cells such as monocytes have a key role. Currently, several studies have linked long non-coding RNAs (lncRNAs) in different inflammatory and autoimmune processes, including lupus. However, the role of lncRNAs in antiphospholipid syndrome is unknown, therefore, we aimed to select and measure expression levels of three lncRNAs based on its abundance in monocytes from APS patients. METHODS: Selection of lncRNAs candidates were carried out based on its abundance in monocytes and their relationship with Perez-Sanchez miRNA signature by using miRNet 2.0 bioinformatic tool, then lncRNAs expression levels was measured in monocytes by RT-qPCR. RESULTS: This is the first study to report that lncRNAs: FGD5-AS1, OIP5-AS1 and GAS5 are promising candidates for play a role on APS monocytes and they are expressed differently between patients and controls. CONCLUSIONS: OIP5-AS1, FGD5-AS1 and GAS5 are downregulated on monocytes from APS patients.

TIMELESS is a key gene mediating thrombogenesis in COVID-19 and antiphospholipid syndrome.

Abnormal coagulation and increased risk of thrombosis are some of the symptoms associated with COVID-19 severity. Anti-phospholipid antibodies (aPLs) present in critically ill COVID-19 patients contribute to systemic thrombosis. The aim of this study was to identify key common genes to characterize genetic crosstalk between COVID-19 and antiphospholipid syndrome (APS) using bioinformatics analysis and explore novel mechanisms of immune-mediated thrombosis in critically ill COVID-19 patients. The transcriptome data of mononuclear cells from severe COVID-19 patients and APS patients were evaluated to obtain the common genes. The protein-protein interaction network and cytoHubba module analysis in Cytoscape software were used to find the associated hinge genes and hub genes. Among the common differentially expressed genes, TIMELESS depletion was identified only in patients with severe COVID-19 and not in patients with mild COVID-19, and it was validated with the GSE159678 dataset. Functional analyses using gene ontology terms and the Kyoto Encyclopedia of Genes and Genomes pathway suggested that TIMELESS might contribute to the production of antiphospholipid antibody and thrombosis in both COVID-19 and APS patients. The potential role of TIMELESS and autophagy genes in momonuclear cells were further investigated, and GSK3B was found to be associated with TIMELESS. Autophagy targeting agents have a therapeutic potential against COVID-19 and thrombogenesis in APS, which may be related to the role of autophagy genes in the modification of circadian clock proteins. Interference with TIMELESS and other genes associated with it to regulate autoantibody expression may be a potential strategy for immunotherapy against thrombogenesis in severe COVID-19 patients.

Epigenetics-mediated pathological alternations and their potential in antiphospholipid syndrome diagnosis and therapy.

APS (antiphospholipid syndrome) is a systematic autoimmune disease accompanied with venous or arterial thrombosis and poor pregnant manifestations, partly attributing to the successive elevated aPL (antiphospholipid antibodies) and provoked prothrombotic and proinflammatory molecules production. Nowadays, most researches focus on the laboratory detection and clinic features of APS, but its precise etiology remains to be deeply explored. As we all know, the dysfunction of ECs (endothelial cells), monocytes, platelets, trophoblasts and neutrophils are key contributors to APS progression. Especially, their epigenetic variations, mainly including the promoter CpGs methylation, histone PTMs (post-translational modifications) and ncRNAs (noncoding RNAs), result in genes expression or silence engaged in inflammation initiation, thrombosis formation, autoimmune activation and APOs (adverse pregnancy outcomes) in APS. Given the potential of epigenetic markers serving as diagnostic biomarkers or therapeutic targets of APS, and the encouraging advancements in epigenetic drugs are being made. In this review, we would systematically introduce the epigenetic underlying mechanisms for APS progression, comprehensively elucidate the functional mechanisms of epigenetics in boosting ECs, monocytes, platelets, trophoblasts and neutrophils. Lastly, the application of epigenetic alterations for probing novel diagnostic, specific therapeutic and prognostic strategies would be proposed.

The wide phenotypic and genetic spectrum of ABCB4 gene deficiency: A case series.

BACKGROUND: ABCB4-gene mutations are responsible for several cholestatic diseases with a heterogeneous clinical spectrum. AIMS: To analyse phenotype/genotype relationships in ABCB4-mutations. METHODS: Retrospective characterization of adult patients with ABCB4-variations diagnosed between 2015 and 2020. Genotype-phenotype correlations were analysed and compared with previously reported data. RESULTS: Twenty patients from 12 families were included. Thirteen patients presented recurrent elevated liver tests, eight fulfilled Low-Phospholipid-Associated-Cholelithiasis syndrome criteria, five had Intrahepatic Cholestasis of Pregnancy and three patients developed Drug-Induced-Liver-Injury. ABCB4 screening identified eight different mutations. Five patients were homozygotes to the variant c.504T > C. Ten patients had one mutation in heterozygote-state and five patients had two mutations in compound-heterozygosity. Portal fibrosis occurred in two patients. One of these patients presented progressive fibrosis and progression of cholestasis despite ursodeoxycholic-acid treatment, this patient also harbours a ABCB11 polymorphism. CONCLUSION: Although, phenotype-genotype relationships have not been clearly defined, an early diagnosis of ABCB4-variants may have an important role in management decisions and patient outcomes. To our knowledge, we describe a not previously reported deletion (c.1181delT) in ABCB4. The c.504T > C polymorphism, although a silent mutation at the protein level, seems to be associated to different cholestatic diseases. The role of other genes variants, namely ABCB11, as co-factor for progression, needs to be clarified.

Βeta-2-glycoprotein I exerts antithrombotic function through its domain V in mice.

Little is known about the physiological role of beta-2-glycoprotein I (ß2GPI) despite it being the major auto-antigen in the antiphospholipid syndrome. A systematic study of the role of ß2GPI in thrombus formation in vivo has not been performed to date. Herein, we report that ß2GPI deficient (-/-) mice have enhanced thrombus formation compared to wild type (WT) mice in a laser-induced arteriole and venule model of thrombosis. Furthermore, neutrophil accumulation and elastase activity was enhanced in thrombi of ß2GPI -/- compared with WT mice. The antithrombotic function of ß2GPI is dependent on its fifth domain (domain V); intravenous administration of the ß2GPI domain deletion mutant lacking domain V (human recombinant domain I-IV) had no effect on platelet and fibrin thrombus size in ß2GPI -/- or WT mice. On the contrary, intravenous administration of human recombinant domain V significantly inhibited platelet and fibrin thrombus size in both ß2GPI -/- mice and WT mice. These findings reveal a major role for ß2GPI as a natural anticoagulant and implicate domain V of ß2GPI as a potential antithrombotic therapy.

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

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.

Possible effect of the HLA-DQ2/DQ8 polymorphism on autoimmune parameters and lymphocyte subpopulation in recurrent pregnancy losses.

Recurrent pregnancy loss (RPL) affects 1-2 % of women. Allo- and autoimmune disorders are a recognized factor for RPL and poor pregnancy outcomes. There is a link between antiphospholipid syndrome (APS), Hashimoto's thyroiditis or coeliac disease, and pregnancy losses. The prevalence of the HLA-DQ2/DQ8 polymorphism and genetic susceptibility to the development of celiac disease may be higher in women who experience RPL. A total of 95 women who had experienced two or more miscarriages were qualified into the study: 49 women with the HLA-DQ2/DQ8 polymorphism as the study group, and 46 as the control group. The prenatal test results of the women were evaluated, which revealed that the foetuses from the study group had higher nuchal translucency measurements than those of controls (1.85 mm vs 1.50 mm; p = 0.0024). A higher level of anticardiolipin antibodies (aCL) in the IgG class (18.38 GP L vs 11.37 GP L; p = 0.0039) and antithyroid peroxidase antibodies (aTPO) (87.67 IU/mL vs 11.87 IU/mL; p = 0.0062) was observed when compared to the control group. The presence of the HLA-DQ2.2 polymorphism was observed when higher nuchal translucency measurements and a higher aTPO concentration occurred. A relationship between the aTPO concentration and a higher birth weight of newborns was also shown. No significant differences between the groups were observed for peripheral blood lymphocyte subsets. A statistically significant relationship between the HLA-DQ2/DQ8 polymorphism and the increased concentrations of indicators of autoimmune disorders was indicated.