Autoimmunity, endothelium and vascular disease

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Relationship between anti-dsDNA, anti-nucleosome and anti-alpha-actinin antibodies and markers of renal disease in patients with lupus nephritis: a prospective longitudinal study.

Contains fulltext : 81686.pdf (publisher's version ) (Open Access)INTRODUCTION: Glomerulonephritis is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Deposition of autoantibodies in the glomeruli plays a key role in the development of lupus nephritis (LN). Different groups have proposed that either anti-nucleosome antibodies or antibodies that bind the intrinsic renal antigen, alpha-actinin, are central to the pathogenesis of LN. These theories have been based mainly on cross-sectional studies in patients and on experiments in animal models. No previous longitudinal studies have compared the relationships between levels of these antibodies and markers of renal function. We assessed how well anti-alpha-actinin, anti-nucleosome and anti-double-stranded DNA (anti-dsDNA) antibodies reflected renal outcome measures in patients with new-onset LN followed for up to 2 years. METHODS: Renal disease activity was monitored by measuring urine protein/creatinine ratio (PCR), serum albumin and a composite outcome of renal remission. At each time point, anti-nucleosome and anti-alpha-actinin antibodies were measured by enzyme-linked immunosorbent assay. High-avidity anti-dsDNA antibodies were measured using the Farrzyme assay. We analysed relationships between levels of the three antibodies and between antibody levels and renal outcome measures over time. RESULTS: Levels of anti-nucleosome and anti-dsDNA were positively correlated with each other (r = 0.6, P = 0.0001) but neither correlated with anti-alpha-actinin level. At baseline, mean anti-nucleosome levels were higher in patients with LN than in healthy controls (0.32 versus 0.01, P < 0.001). The same was true for anti-dsDNA antibodies (0.50 versus 0.07, P < 0.001) but not for anti-alpha-actinin (0.33 versus 0.29). Over the follow-up period, anti-nucleosome and anti-dsDNA levels associated positively with urine PCR (P = 0.041 and 0.051, respectively) and negatively with serum albumin (P = 0.027 and 0.032, respectively). Both anti-nucleosome and anti-dsDNA levels were significantly lower during renal remission than when renal disease was active (P = 0.002 and 0.003, respectively). However, there was no relationship between anti-alpha-actinin levels and urine PCR, serum albumin or remission status. CONCLUSIONS: This prospective longitudinal clinical study is the first to compare levels of anti-nucleosome, anti-dsDNA and anti-alpha-actinin antibodies in the same patients with SLE. Our results support the concept that, in the majority of patients, anti-nucleosome antibodies play a major role in pathogenesis of LN, in contrast to anti-alpha-actinin antibodies

Anti-beta2GPI-antibody-induced endothelial cell gene expression profiling reveals induction of novel pro-inflammatory genes potentially involved in primary antiphospholipid syndrome.

OBJECTIVE: To determine the effects of primary antiphospholipid syndrome (PAPS)-derived anti-beta(2)GPI antibodies on gene expression in human umbilical vein endothelial cells (HUVEC) by gene profiling using microarrays. METHODS: Anti-beta(2)GPI antibodies purified from sera of patients with PAPS or control IgG isolated from normal subjects were incubated with HUVEC for 4 h before isolation of RNA and processing for hybridisation to Affymetrix Human Genome U133A-2.0 arrays. Data were analysed using a combination of the MAS 5.0 (Affymetrix) and GeneSpring (Agilent) software programmes. For selected genes microarray data were confirmed by real-time PCR analysis or at the protein level by ELISA. RESULTS: A total of 101 genes were found to be upregulated and 14 genes were downregulated twofold or more in response to anti-beta(2)GPI antibodies. A number of novel genes not previously associated with APS were induced, including chemokines CCL20, CXCL3, CX3CL1, CXCL5, CXCL2 and CXCL1, the receptors Tenascin C, OLR1, IL-18 receptor 1, and growth factors CSF2, CSF3 IL-6, IL1beta and FGF18. The majority of downregulated genes were transcription factors/signalling molecules including ID2. Quantitative real-time RT-PCR analysis confirmed the microarray results for selected genes (CSF3, CX3CL1, FGF18, ID2, SOD2, Tenascin C). CONCLUSIONS: This study reveals a complex gene expression response in HUVEC to anti-beta(2)GPI antibodies with multiple chemokines, pro-inflammatory cytokines, pro-thrombotic and pro-adhesive genes regulated by these antibodies in vitro. Some of these newly identified anti-beta(2)GPI antibody-regulated genes could contribute to the vasculopathy associated with this disease

Relationship between anti-dsDNA, anti-nucleosome and anti-alpha-actinin antibodies and markers of renal disease in patients with lupus nephritis: a prospective longitudinal study.

INTRODUCTION: Glomerulonephritis is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Deposition of autoantibodies in the glomeruli plays a key role in the development of lupus nephritis (LN). Different groups have proposed that either anti-nucleosome antibodies or antibodies that bind the intrinsic renal antigen, alpha-actinin, are central to the pathogenesis of LN. These theories have been based mainly on cross-sectional studies in patients and on experiments in animal models. No previous longitudinal studies have compared the relationships between levels of these antibodies and markers of renal function. We assessed how well anti-alpha-actinin, anti-nucleosome and anti-double-stranded DNA (anti-dsDNA) antibodies reflected renal outcome measures in patients with new-onset LN followed for up to 2 years. METHODS: Renal disease activity was monitored by measuring urine protein/creatinine ratio (PCR), serum albumin and a composite outcome of renal remission. At each time point, anti-nucleosome and anti-alpha-actinin antibodies were measured by enzyme-linked immunosorbent assay. High-avidity anti-dsDNA antibodies were measured using the Farrzyme assay. We analysed relationships between levels of the three antibodies and between antibody levels and renal outcome measures over time. RESULTS: Levels of anti-nucleosome and anti-dsDNA were positively correlated with each other (r = 0.6, P = 0.0001) but neither correlated with anti-alpha-actinin level. At baseline, mean anti-nucleosome levels were higher in patients with LN than in healthy controls (0.32 versus 0.01, P < 0.001). The same was true for anti-dsDNA antibodies (0.50 versus 0.07, P < 0.001) but not for anti-alpha-actinin (0.33 versus 0.29). Over the follow-up period, anti-nucleosome and anti-dsDNA levels associated positively with urine PCR (P = 0.041 and 0.051, respectively) and negatively with serum albumin (P = 0.027 and 0.032, respectively). Both anti-nucleosome and anti-dsDNA levels were significantly lower during renal remission than when renal disease was active (P = 0.002 and 0.003, respectively). However, there was no relationship between anti-alpha-actinin levels and urine PCR, serum albumin or remission status. CONCLUSIONS: This prospective longitudinal clinical study is the first to compare levels of anti-nucleosome, anti-dsDNA and anti-alpha-actinin antibodies in the same patients with SLE. Our results support the concept that, in the majority of patients, anti-nucleosome antibodies play a major role in pathogenesis of LN, in contrast to anti-alpha-actinin antibodies

Anti-Endothelial Antibodies and Neuropsychiatric Systemic Lupus Erythematosus

The pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) has been attributed to autoantibody-mediated neural dysfunction, vasculopathy, and coagulopathy. Several autoantibodies specificities have been reported in serum and cerebrospinal fluid of NPSLE patients (i.e., antineuronal, antiribosomal P proteins, antiglial fibrillary acidic proteins, antiphospholipid, and anti-endothelial antibodies). We have recently demonstrated an association between serum anti-endothelial antibodies and psychosis or depression in patients with SLE. Subsequently, by screening a cDNA library from human umbilical artery endothelial cells with serum from a SLE patient with psychosis, one positive strongly reactive clone was identified encoding the C-terminal region (C-ter) of Nedd5, an intracytoplasmatic protein of the septin family. Anti-Nedd5 antibodies have been found significantly associated with psychiatric manifestations in SLE patients, strengthening the view of a possible implication of autoantibodies in the development of psychiatric disorders. © 2006 New York Academy of Sciences