Pathophysiology Of Lupus Nephritis Research Articles

Role of NLRP3 Inflammasome in Lupus Nephritis and Therapeutic Targeting by Phytochemicals.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune inflammatory condition that affects multiple organs and provokes extensive and severe clinical manifestations. Lupus nephritis (LN) is one of the main clinical manifestations of SLE. It refers to the deposition of immune complexes in the glomeruli, which cause kidney inflammation. Although LN seriously affects prognosis and represents a key factor of disability and death in SLE patients, its mechanism remains unclear. The NACHT, leucine-rich repeat (LRR), and pyrin (PYD) domains-containing protein 3 (NLRP3) inflammasome regulates IL-1β and IL-18 secretion and gasdermin D-mediated pyroptosis and plays a key role in innate immunity. There is increasing evidence that aberrant activation of the NLRP3 inflammasome and downstream inflammatory pathways play an important part in the pathogenesis of multiple autoimmune diseases, including LN. This review summarizes research progress on the elucidation of NLRP3 activation, regulation, and recent clinical trials and experimental studies implicating the NLRP3 inflammasome in the pathophysiology of LN. Current treatments fail to provide durable remission and provoke several sides effects, mainly due to their broad immunosuppressive effects. Therefore, the identification of a safe and effective therapeutic approach for LN is of great significance. Phytochemicals are found in many herbs, fruits, and vegetables and are secondary metabolites of plants. Evidence suggests that phytochemicals have broad biological activities and have good prospects in a variety of diseases, including LN. Therefore, this review reports on current research evaluating phytochemicals for targeting NLRP3 inflammasome pathways in LN therapy.

Identification of Molecular Markers Associated With the Pathophysiology and Treatment of Lupus Nephritis Based on Integrated Transcriptome Analysis.

Lupus nephritis (LN) is a well-known complication of systemic lupus erythematosus and is its leading cause of morbidity and mortality. Our study aimed to identify the molecular markers associated with the pathophysiology and treatment of LN. The renal tissue gene expression profiles of LN patients in the GSE32591 dataset were downloaded as a discovery cohort from the Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified; weighted gene co-expression network analysis (WGCNA) was used to identify the co-expression modules of DEGs; and gene function enrichment analysis, molecular crosstalk analysis, and immune cell infiltration analysis were performed to explore the pathophysiological changes in glomeruli and tubulointerstitia of LN patients. The crosstalk genes were validated in another RNA-sequencing cohort. DEGs common in RNA-sequencing dataset and GSE32591 were uploaded to the Connectivity Map (CMap) database to find prospective LN-related drugs. Molecular docking was used to verify the targeting association between candidate small molecular compounds and the potential target. In all, 420 DEGs were identified; five modules and two modules associated with LN were extracted in glomeruli and tubulointerstitia, respectively. Functional enrichment analysis showed that type I interferon (IFN) response was highly active, and some biological processes such as metabolism, detoxification, and ion transport were impaired in LN. Gene transcription in glomeruli and tubulointerstitia might affect each other, and some crosstalk genes, such as IRF7, HLA-DRA, ISG15, PSMB8, and IFITM3, play important roles in this process. Immune cell infiltration analysis revealed that monocytes and macrophages were increased in glomeruli and tubulointerstitia, respectively. CMap analysis identified proscillaridin as a possible drug to treat LN. Molecular docking showed proscillaridin forms four hydrogen bonds with the SH2 domain of signal transducer and activator of transcription 1 (STAT1). The findings of our study may shed light on the pathophysiology of LN and provide potential therapeutic targets for LN.

P0400DECREASED REGULATORY B CELLS AND THEIR ASSOCIATION WITH CLINICAL RESPONSE IN PATIENTS WITH NEW ONSET LUPUS NEPHRITIS

Abstract Background and Aims Studies in lupus nephritis (LN) have shown impairment in both T regulatory (Treg) number and function. However, the data on B regulatory (Breg) is limited in LN. Our objective was to study Breg and Treg populations in newly diagnosed treatment naïve LN and study their change after initiation of immunosuppression. Method Study included 25 patients of newly diagnosed LN of Class III (+V), IV (+V), V and 10 healthy controls (HC). Immunophenotyping was performed for peripheral blood mononuclear cell (PBMCs) samples using fluorochrome labelled monoclonal antibodies for Tregs (CD3+CD4+CD25hiCD127loFoxP3+) and Bregs (CD19+CD5+CD1dhi IL-10+). The cells were expressed as percentage of T and B cells. Each lymphocyte population was analysed at baseline, 2 and 6 months after initiation of immunosuppression which was given as per unit protocol. Results Bregs were significantly decreased compared to HC at baseline (p=0.002). With immunosuppression, Bregs showed significant increase at 2 and 6 months (p=0.008) and from baseline to 6 months (p=0.005). Bregs in responders significantly increased from 2 to 6 months (p= 0.017) and from baseline to 6 month (p=0.020), while they did not in non-responders. Tregs did not differ significantly from HC and did not show significant increase at 2 and 6 months, in both responders and non-responders. Conclusion Breg population in newly diagnosed LN was significantly reduced and increased significantly with immunosuppression. Bregs had an association with renal remission. This underscores the potential role of Bregs in the pathophysiology of LN and their association with clinical response. This could aid in the design of new immunotherapies for treatment of lupus nephritis.

A Study of Antinuclear Antibody Binding (ANA) in Lewis Rat Kidney Injected With Human Serum Positive For ANA

Lupus nephritis (LN) is an inflammatory condition affecting the kidneys in systemic lupus erythematosus (SLE). Pathophysiology of LN is not clearly understood. Autoantibody deposits in glomeruli can cause progressive renal damage leading to renal failure. We proposed to study the binding patterns of ANA in the kidney. Kidneys from 8 female Lewis rats (age=6 months) were harvested to study. Rats were randomly separated into 4 groups (n=2). Control group rats were injected with 300 μl of 0.9% sterile saline through the tail vein once a week for 4 weeks; the second group was a negative control injected with 250μl of ANA free human serum plus 50μl of 0.9% saline. The third group was injected with 250 μl of ANA plus 50μl of 0.9% saline. The fourth group was injected with ANA and 4 mg/kg BW of Benadryl (antihistamine). Studies have reported, that histamine can decrease glomerular permeability. Slices of frozen sections were examined by Immuno‐fluorescent staining for ANA binding. Cellular infiltration was assessed by staining the tissue slices with H&E stain. Results of this study indicate that both the ANA group and the ANA+Benadryl group show significant differences in binding as compared to the negative control group respectively (P<0.01, P<0.001). Probability of ANA binding in the ANA group and the ANA Benadryl group was significantly greater as compared to both the negative control and saline injected group. Endothelial cells were the dominant cell type in the tissues. Binding patterns of ANA in the kidney may enhance our understanding of the underlying mechanism of SLE and hence, a better therapeutic approach in treating the disease. Furthermore, it may provide a precise biomarker for future diagnosis. Support:Ball State Research Funds.

Soluble Receptor for Advanced Glycation End Products Alleviates Nephritis in (NZB/NZW)F1 Mice

To investigate the efficacy of different doses of the soluble form of the receptor for advanced glycation end products (sRAGE) (conjugated to the Fc portion of immunoglobulin) in the treatment of nephritis in lupus-prone mice, in comparison with the efficacy of combination therapy with mycophenolate mofetil plus prednisolone. Twenty-eight female (NZB/NZW)F1 mice were divided into 5 groups (untreated, sRAGE [dose groups of 0.5, 1, or 2 μg], or mycophenolate mofetil plus prednisolone). Proteinuria and histologic damage were evaluated. Immune complex deposition and the nuclear translocation of NF-κB in the kidney tissue were assessed by immunofluorescence staining. Serum concentrations of anti-double-stranded DNA (anti-dsDNA) and IgG subclasses were also measured. The population of T cells was evaluated using a fluorescence-activated cell sorter, and expression of intracellular adhesion molecule 1 and vascular cell adhesion molecule 1 in the kidney tissue was assessed by immunohistochemical staining. In comparison with untreated mice, mice treated with 1 or 2 μg sRAGE showed significantly reduced proteinuria and attenuated histologic renal damage, with efficacy comparable to that of combination therapy. Treatment with 2 μg sRAGE significantly reduced immune complex deposition and decreased the serum concentrations of anti-dsDNA, IgG2a, IgG2b, and IgG3. In addition, sRAGE interrupted the nuclear translocation of NF-κB in the kidney, resulting in reduction in the expression of downstream genes of NF-κB in vivo and in vitro. Furthermore, sRAGE effectively modified T cell populations. Treatment with sRAGE significantly improved nephritis in lupus-prone mice, with efficacy comparable to that of standard induction treatment for lupus nephritis. These data suggest that sRAGE has antiinflammatory effects on the pathophysiology of lupus nephritis and could serve as a potent new therapy for this disease.

Complement Factor H Deficiency Accelerates Development of Lupus Nephritis

Complement factor H (CfH) is a key regulator of the alternative pathway, and its presence on mouse platelets and podocytes allows the processing of immune complexes. Because of the role of immune complexes in the pathophysiology of lupus nephritis, we studied the role of CfH in the development of nephritis in MRL-lpr mice, an animal model of lupus. At 12 weeks, CfH-deficient MRL-lpr mice had significantly more albuminuria and higher BUN levels than MRL-lpr controls. Cfh-deficient MRL-lpr mice also experienced earlier mortality: at 14 weeks, 6 of 9 CfH-deficient MRL-lpr mice had died of renal failure, whereas all 11 littermate CfH-sufficient MRL-lpr mice were alive (P ≤ 0.001). Histologically, CfH-deficient MRL-lpr mice developed severe diffuse lupus nephritis by 12 weeks (glomerulonephritis scores of 2.6 ± 0.4 versus 0.4 ± 0.2 in littermate controls, P = 0.001). Similar to other CfH-deficient mouse models on nonautoimmune backgrounds, immunofluorescence staining showed extensive linear C3 staining along glomerular capillary walls. IgG was present in the mesangium and peripheral capillary walls along with excessive infiltration of macrophages and neutrophils. Ultrastructurally, there were subendothelial and subepithelial immune deposits and extensive podocyte foot process effacement. In summary, the loss of CfH accelerates the development of lupus nephritis and recapitulates the functional and structural features of the human disease. This illustrates the critical role of complement regulation and metabolism of immune complexes in the pathogenesis of lupus nephritis.