Genome-wide analysis of atypical NK cell subset in mouse model of Systemic Lupus Erythematosus (SLE)
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Silvia Bolland
PROVIDER: E-GEOD-63829 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Chronic inflammatory conditions, such as in autoimmune disease, can disturb immune cell homeostasis and induce the expansion of normally rare cell populations. In our analysis of various murine models of lupus, we detect increased frequency of an uncommon subset identified as NK1.1(+)CD11c(+)CD122(+)MHC class II(+). These cells share characteristics with the NK cell lineage and with cells previously described as IFN-producing killer dendritic cells: 1) they depend on IL-15 and express E4BP4; 2) they are cytotoxic and produce type I and type II IFN upon activation; and 3) they are efficient APCs both through MHC class II expression and in cross-presentation to CD8s. These atypical NK cells are responsive to TLR stimulation and thus are most abundant in mice with high copy number of the Tlr7 gene. They are highly proliferative as assessed by in vivo BrdU incorporation. In adoptive transfer experiments they persist in high numbers for months and maintain their surface marker profile, indicating that this population is developmentally stable. Gene expression analyses on both mRNA and microRNAs show a modified cell cycle program in which various miR-15/16 family members are upregulated, presumably as a consequence of the proliferative signal mediated by the increased level of growth factors, Ras and E2F activity. Alternatively, low expression of miR-150, miR-181, and miR-744 in these cells implies a reduction in their differentiation capacity. These results suggest that cells of the NK lineage that undergo TLR stimulation might turn on a proliferative program in detriment of their full differentiation into mature NK cells.
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Project description:IntroductionTLR7/8 and TLR9 signaling pathways have been extensively studied in systemic lupus erythematosus (SLE) as possible mediators of disease. Monocytes are a major source of pro-inflammatory cytokines and are understudied in SLE. In the current project, we investigated sex differences in monocyte activation and its implications in SLE disease pathogenesis.MethodsHuman blood samples from 27 healthy male controls, 32 healthy female controls, and 25 female patients with SLE matched for age and race were studied. Monocyte activation was tested by flow cytometry and ELISA, including subset proportions, CD14, CD80 and CD86 expression, the percentage of IL-6-producing monocytes, plasma levels of sCD14 and IL-6, and urine levels of creatinine.ResultsMonocytes were significantly more activated in women compared to men and in patients with SLE compared to controls in vivo. We observed increased proportions of non-classic monocytes, decreased proportions of classic monocytes, elevated levels of plasma sCD14 as well as reduced surface expression of CD14 on monocytes comparing women to men and lupus patients to controls. Plasma levels of IL-6 were positively related to sCD14 and serum creatinine.ConclusionMonocyte activation and TLR4 responsiveness are altered in women compared to men and in patients with SLE compared to controls. These sex differences may allow persistent systemic inflammation and resultant enhanced SLE susceptibility.
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Project description:The indicated thymic progenitor population was sorted via FACS and then loaded into a Fluidigm C1 small cell capture chip for single-cell capture, lysis, reverse transcription, and preamplification. Preamplified products were analyzed on a BioMark HD with EvaGreen chemistry. The genes analyzed were selected based on bulk RNA sequencing data and/or prior publications, including genes relevant for gamma/delta T cells and T cell progenitors. B6=C57BL/6J, Rag=B6.Rag1-/-, Tcrd=B6.Tcrd-/-, DN1d=Live/TCRd-/Lin-/CD44+/CD25-/CD24+/cKit-, DN2=Live/TCRd-/Lin-/CD44+/CD25+/cKit+, cKit-=Live/TCRd-/Lin-/CD44+/CD25-/cKit-. Lin=CD3/CD8/CD11b/CD11c/CD19/Gr-1/NK1.1/TCRb/Ter-119 Sample naming nomenclature is as follows: MouseLine_CellPopoulation_DateCaptured_CaptureChamber_CellNumberInChamber
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Project description:ObjectiveTo assess maternal and fetal outcomes associated with subclinical (pre-systemic lupus erythematosus [SLE] and SLE presenting up to 5 years postpartum) and prevalent maternal SLE during pregnancy compared with the general population.MethodsThis prospective cohort study used population-based Swedish registers to identify 13,598 women with first singleton pregnancies registered in the Medical Birth Register (551 prevalent SLE, 65 pre-SLE within 0-2 years, 133 pre-SLE within 2-5 years, and 12,847 general population). SLE was defined as ≥2 SLE-coded discharge diagnoses in the patient register with ≥1 diagnosis from a specialist. Unadjusted risks of adverse pregnancy or birth outcomes were calculated by SLE status, and Cochran-Armitage tests evaluated trend across exposure groups.ResultsMaternal outcomes such as preeclampsia, hypothyroidism, stroke, and infection were more common among women with SLE. Sixteen percent of prevalent-SLE pregnancies were diagnosed with preeclampsia compared with 5% of those from the general population. Among the pre-SLE women, preeclampsia was found in 26% of those with SLE within 2 years postpartum and 13% in those with SLE within 2-5 years postpartum. Similarly, infant outcomes, such as preterm birth, infection, and mortality, were worse among those born to mothers with prevalent SLE and pre-SLE during pregnancy. The test for trend was significant for most outcomes.ConclusionOur data demonstrate that adverse maternal and fetal outcomes are more common in SLE pregnancies. Furthermore, these unfavorable outcomes are observed in pregnancies occurring prior to the diagnosis of SLE. Thus, the underlying immunologic profile of SLE and alterations preceding clinical SLE may contribute to these pregnancy complications.
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Project description:Juvenile-onset systemic lupus erythematosus (jSLE) is an autoimmune disorder with multifaceted clinical findings in different organ systems. Neuropsychiatric manifestations affect more than half of SLE patients, and there is increasing evidence that anorexia nervosa (AN), a feeding and eating disorder (FED) characterized by significantly reduced energy intake, is among them. Herein, a review of the literature on the potential association between jSLE and AN was performed. Reported clinical cases were identified, and putative pathophysiological mechanisms were sought that could potentially explain the observed relationship between these two pathological entities. Four reports of isolated cases and a case series including seven patients were identified. In this limited patient pool, the diagnosis of AN preceded that of SLE in the majority of cases, whereas in all cases both entities were diagnosed within a time span of two years. Many explanations for the observed relationships have been proposed. AN has been associated with the stress of chronic disease diagnosis; on the other hand, the chronic inflammation associated with AN may contribute to the development/appearance of SLE. Adverse childhood experiences, concentrations of leptin, shared autoantibodies, and genetic traits appear to be important factors in this well-established interplay. In essence, it seems important to increase clinician awareness of the concomitant development of AN and SLE and invite further research on the subject.
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Project description:Systemic lupus erythematosus (SLE) is an autoimmune disease associated with widespread inflammation and tissue damage. It is more common and severe among Blacks, Hispanics, and Asians; with higher incidence in women. While the goals of medical treatment are to prevent flares and reduce organ damage, up to 50% of patients perceive their health to be suboptimal with unaddressed needs including fatigue and pain. Recent SLE treatment guidelines focus on improving quality of life. Yoga has shown improvements in quality-of-life and fatigue in various diagnoses. While there is growing evidence that yoga therapy may help osteoarthritis and rheumatoid arthritis symptoms, there is only one reference in the literature related to SLE. METHODS/SETTING:An adjunct study was undertaken to evaluate adapting the Yoga as Self Care for Arthritis in Minority Communities study for a bilingual population living with SLE in the Washington, DC area. Informants included 7 patients enrolled onto the study, and 3 yoga instructors living with SLE. Qualitative methods included journals and semi-structured interviews. RESULTS:Enrolling patients clarified revisions for intake questionnaires, and symptoms that may impact class participation. Participants demonstrated increased balance, body awareness, and tolerated a faster-paced yoga class when compared to those in the parent study. Yoga instructors' recommendations included modifying yoga based on energy levels and frequent changes in physical ability. CONCLUSION:This paper shares perspectives from various informants and affirms the feasibility of progressing to a larger study. It summarizes our findings and recommendations towards creating a randomized controlled trial, as there are currently none in the literature.
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Project description:The NK cell pool is composed of distinct NK cell subsets with divergent phenotypic and functional features. In order to determine whether DX5- and DX5+ NK cells from murine livers represent different NK cell subsets, DX5- and DX5+ liver NK cells of adult mice were respectively sorted for gene expression analysis using the Affymetrix GeneChip Mouse Genome 430 2.0 arrays. DX5-NK1.1+CD3- cells and DX5+NK1.1+CD3- cells were sorted from the liver of naive B6 wild-type mice. RNA of each sample was then extracted and hybridized on Affymetrix microarrays to detail differences between DX5- and DX5+ liver NK cells in gene expression.
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Project description:We recently identified ten novel SLE susceptibility loci in Asians and uncovered several additional suggestive loci requiring further validation. This study aimed to replicate five of these suggestive loci in a Han Chinese cohort from Hong Kong, followed by meta-analysis (11,656 cases and 23,968 controls) on previously reported Asian and European populations, and to perform bioinformatic analyses on all 82 reported SLE loci to identify shared regulatory signatures. We performed a battery of analyses for these five loci, as well as joint analyses on all 82 SLE loci. All five loci passed genome-wide significance: MYNN (rs10936599, Pmeta?=?1.92?×?10-13, OR?=?1.14), ATG16L2 (rs11235604, Pmeta?=?8.87?×?10?-12, OR?=?0.78), CCL22 (rs223881, Pmeta?=?5.87?×?10-16, OR?=?0.87), ANKS1A (rs2762340, Pmeta?=?4.93?×?10-15, OR?=?0.87) and RNASEH2C (rs1308020, Pmeta?=?2.96?×?10-19, OR?=?0.84) and co-located with annotated gene regulatory elements. The novel loci share genetic signatures with other reported SLE loci, including effects on gene expression, transcription factor binding, and epigenetic characteristics. Most (56%) of the correlated (r2?>?0.8) SNPs from the 82 SLE loci were implicated in differential expression (9.81?×?10-198?<?P?<?5?×?10-3) of cis-genes. Transcription factor binding sites for p53, MEF2A and E2F1 were significantly (P?<?0.05) over-represented in SLE loci, consistent with apoptosis playing a critical role in SLE. Enrichment analysis revealed common pathways, gene ontology, protein domains, and cell type-specific expression. In summary, we provide evidence of five novel SLE susceptibility loci. Integrated bioinformatics using all 82 loci revealed that SLE susceptibility loci share many gene regulatory features, suggestive of conserved mechanisms of SLE etiopathogenesis.
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