Extramedullary hematopoiesis and immune training drive systemic inflammation and associated organ damage in Systemic Lupus Erythematosus
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE218780 | GEO | 2024/03/20
REPOSITORIES: GEO
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Project description:Extramedullary hematopoiesis (EMH) is an emerging player in peripheral tissue injury in autoimmune disorders. Here, we use the NZBW/F1 lupus mouse model to explore the contribution of EMH to disease pathogenesis of SLE. We demonstrate that EMH takes place in the spleen of F1-L mice and show it is correlated with the activity of lupus nephritis (LN). Transcriptomic analysis demonstrated that splenic hematopoietic stem and progenitor cells (HSPC) carry a higher inflammatory potential than their bone marrow counterparts. Administration of β-glucan, an inducer of innate immunity, exacerbated splenic EMH, increased neutrophil production and worsened LN. Transcriptomic signatures of HSPCs in SLE patients with high disease activity show changes similar to the ones observed in the lupus-prone mouse model. Overall, EMH and trained immunity are ubiquitous in SLE, contributing to disease pathogenesis by sustaining and amplifying the inflammatory response and increasing the risk for flare of the disease.
2024-03-20 | GSE218779 | GEO
Project description:Extramedullary hematopoiesis (EMH) is an emerging player in peripheral tissue injury in autoimmune disorders. Here, we use the NZBW/F1 lupus mouse model to explore the contribution of EMH to disease pathogenesis of SLE. We demonstrate that EMH takes place in the spleen of F1-L mice and show it is correlated with the activity of lupus nephritis (LN). Transcriptomic analysis demonstrated that splenic hematopoietic stem and progenitor cells (HSPC) carry a higher inflammatory potential than their bone marrow counterparts. Administration of β-glucan, an inducer of innate immunity, exacerbated splenic EMH, increased neutrophil production and worsened LN. Transcriptomic signatures of HSPCs in SLE patients with high disease activity show changes similar to the ones observed in the lupus-prone mouse model. Overall, EMH and trained immunity are ubiquitous in SLE, contributing to disease pathogenesis by sustaining and amplifying the inflammatory response and increasing the risk for flare of the disease.
2024-03-20 | GSE218778 | GEO
Project description:Extramedullary hematopoiesis and immune training drive systemic inflammation and associated organ damage in Systemic Lupus Erythematosus
| PRJNA905434 | ENA
Project description:Extramedullary hematopoiesis and immune training drive systemic inflammation and associated organ damage in Systemic Lupus Erythematosus (RRBS)
| PRJNA905438 | ENA
Project description:Extramedullary hematopoiesis and immune training drive systemic inflammation and associated organ damage in Systemic Lupus Erythematosus (RNA-seq)
| PRJNA905437 | ENA
Project description:Systemic lupus erythematosus (SLE) is a disease characterized by inappropriate response to self-antigens. Genetic, environmental and hormonal factors are believed to contribute to the development of the disease. We think of SLE pathogenesis as occurring in three phases of variable duration. A series of regulatory failures during the ontogeny of the immune system lead to the emergence of auto-reactive clones and the production of auto-antibodies (phase I). As the immune response to self-antigens broadens, the auto-antibody repertoire is enriched (phase II) and clinical manifestations eventually ensue (phase III). The final result is tissue damage that if not treated will lead to the functional failure of such important organs as the kidney and brain.
| S-EPMC3153363 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that involves multiple organs and disproportionality affects females, especially African Americans from 15 to 44 years of age. SLE can lead to end organ damage including kidneys, lungs, cardiovascular and neuropsychiatric systems, with cardiovascular complications being the primary cause of death. Usually, SLE is diagnosed and its activity is assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), Systemic Lupus International Collaborating Clinics Damage Index (SLICC/ACR), and British Isles Lupus Assessment Group (BILAG) Scales, which unfortunately often occurs after a certain degree of systemic involvements, disease activity or organ damage already exists. There is certainly a need for the identification of early biomarkers to diagnose and assess disease activity as well as to evaluate disease prognosis and response to treatment earlier in the course of the disease. Here we review advancements made in the area of sphingolipidomics as a diagnostic/prognostic tool for SLE and its co-morbidities. We also discuss recent reports on differential sphingolipid metabolism and blood sphingolipid profiles in SLE-prone animal models as well as in diverse cohorts of SLE patients. In addition, we address targeting sphingolipids and their metabolism as a method of treating SLE and some of its complications. Although such treatments have already shown promise in preventing organ-specific pathology caused by SLE, further investigational studies and clinical trials are warranted.
| S-EPMC7546393 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disorder. Considerable progress has been made to delineate the genetic control of this complex disorder. In this review, selected aspects of human and mouse genetics related to SLE are reviewed with emphasis on genes that contribute to both innate and adaptive immunity and to genes that contribute directly to susceptibility to end organ damage. It is concluded that the interactions among these two major pathways will provide further insight into the pathogenesis of SLE. An interactive model of the two major pathways is proposed without emphasis on the importance of breaking tolerance to autoantigens.
| S-EPMC4274270 | biostudies-other
Project description:IntroductionDisturbed lipid metabolism was observed in systemic lupus erythematosus (SLE) patients. This study aimed to evaluate the relationships between dyslipidemia and visceral organ involvement, disease severity, inflammatory factors, and drug intake in SLE patients.MethodInpatients with SLE (n = 105) and healthy controls (HC) (n = 75) were recruited in this study. Clinical and laboratory data were collected from patient records. The concentrations of tumor necrosis factor receptors superfamily member1A (TNFRSF1A), member1B (TNFRSF1B) and adipokine angiopoietin-like 4 (ANGPTL4) in plasma were measured by ELISA.ResultCompared to HC, serum levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), and apolipoprotein B (ApoB) were significantly increased, while high-density lipoprotein (HDL) and apolipoprotein A1 (ApoA1) were decreased in SLE patients. Patients with higher disease activity and renal damage suffered from more severe dyslipidemia. Renal functional parameters were closely correlated with serum lipid levels. Inflammatory factors were associated with dyslipidemia. The levels of TNFRSF1A and TNFRSF1B were obviously increased and associated with kidney involvement in SLE patients. Patients with high-dose glucocorticoid intake showed more severe dyslipidemia.ConclusionsAttention should be paid to the dyslipidemia of SLE. Dyslipidemia is associated with inflammation and organ involvement in SLE. These findings might provide a new strategy for the treatment of SLE. Key Points • Serum levels of TG, TC, LDL, and ApoB were significantly increased, while HDL and ApoA1 were decreased in SLE patients. • Patients with higher disease activity and renal damage suffered from more severe dyslipidemia. Renal functional parameters and inflammatory factors were closely correlated with serum lipid levels. • Patients with high-dose glucocorticoid intake showed more severe dyslipidemia. • These findings might provide a new strategy for the treatment of SLE.
| S-EPMC10203001 | biostudies-literature
Project description:While it is a common practice to monitor complement levels in patients with systemic lupus erythematosus to aid in flare prediction and detection, it is unclear if this strategy is helpful in preventing subsequent organ damage. We studied longitudinal complement levels in 102 SLE patients during a median follow-up of 13.8 years (IQR 7.0, 23.1). Low complement was defined as C3?<?0.84?g/L and/or C4?<?0.08?g/L, disease activity by clinical SLEDAI-2K, and organ damage by SLICC-DI. We calculated a time averaged clinical SLEDAI score (cWAS) and performed multivariate regression models to assess the independent predictive value of low complement for organ damage at last visit. Hypocomplementemia (HC) was observed in 67% of all patients and was more often due to low C3 (97%) than low C4 (54%). Compared to patients not developing HC (33%), HC patients were more frequently positive for anti-dsDNA Ab (72% vs 36%, p < 0.01) and aPL (74% vs 40%, p < 0.01) but HC was concurrently present with anti-dsDNA Ab in only half the cases. The time-adjusted cWAS scores (1.9 vs 1.2, p = 0.9), frequency (SDI?>?0, n = 60), and type of organ damage accrual were similar for patients with and without HC (OR 1.08, p > 0.20). Intermittent or sustained HC has no predictive value for damage accrual in SLE or the underlying disease activity over time. This together with significant discrepancies in the concurrence of low C3, C4, and anti-dsDNA Ab indicates frequent activation of the complement pathway by other factors than immune complexes in SLE.
| S-EPMC6330819 | biostudies-literature