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
PROVIDER: GSE63829 | GEO | 2014/12/04
SECONDARY ACCESSION(S): PRJNA269177
REPOSITORIES: GEO
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Project description:Exploratory study to identify genome-wide changes in expression between conventional NK cells isolated from B6 WT and NK1.1+ cells from TLR7tg mice Isolated splenic NK1.1+ cells are compared between B6 WT and TLR7tg mice
2014-12-04 | E-GEOD-63829 | biostudies-arrayexpress
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: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:Foot complaints have been shown to be common in systemic lupus erythematosus (SLE) and heterogeneous in nature. We aimed to categorize self-reported foot complaints in people with SLE and foot symptoms.A self-administered validated questionnaire was posted to 406 people with SLE attending adult rheumatology clinics across three health boards in Auckland, New Zealand. In addition to foot pain, vascular complaints, dermatological lesions and neurological symptoms were included in the analysis. Pairwise correlations among the variables were undertaken followed by factor analysis to identify and categorise associations between reported foot complaints.From the questionnaires returned, 93 full datasets were analysed. Participants' were predominantly female (n = 87, 93.7%), with mean (SD) age of 50.4 (14.3) years and a mean (SD) disease duration of 13.1 (11) years. Three categories of foot complaint were determined: 'foot pain', 'skin disorders' and 'vascular insufficiency'. These three groups provided the best fit (0.91) to describe the wide range of foot complaints reported by those with SLE. Factor analysis for foot pain demonstrated a high positive loading for the inter-correlation of foot pain in past month (0.83), foot pain today (0.71), intermittent claudication (0.71), numbness (0.62), loss of balance (0.81), swelling (0.59), foot joint pain (0.77), arch pain (0.68) and tendon pain (0.77). Skin disorders demonstrated a very high positive loading for 3 factors skin rash (0.82), blistering skin rash (0.95) and foot ulceration (0.88). In vascular insufficiency a high positive loading for cold feet (0.83), chilblains (0.76) and Raynaud's phenomenon (0.70).This work suggests people with SLE report three independent categories of foot complaints; foot pain, skin disorders or vascular insufficiency.
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