Nucleosomes contribute to increase mesangial cell chemokine expression during the development of lupus nephritis

Kanapathippillai, Premasany; Hedberg, Annica; Fenton, Chris; Fenton, Kristin Andreassen

doi:10.1016/j.cyto.2013.03.016

Cited by 27 publications

(22 citation statements)

References 43 publications

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“…The elegant electron microscopy studies of Rekvig’s group demonstrated that deposited IgG co-localizes with electron-dense chromatin structures in renal biopsies from human and murine lupus nephritis [18,19]. More recently, Kanapathipillai et al showed a direct stimulatory effect of nucleosomes alone (not requiring complexed antibodies) on expression of chemokines by mesangial cells from NZB/W F1 mice [20]. There is also evidence that chemical modification of nucleosomes, specifically hyperacetylation, can alter their biological effects in SLE.…”

Section: Discussionmentioning

confidence: 99%

Serum nitrated nucleosome levels in patients with systemic lupus erythematosus: a retrospective longitudinal cohort study

et al. 2014

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IntroductionCirculating nucleosomes released from apoptotic cells are important in the pathogenesis of systemic lupus erythematosus (SLE). Both nucleosomes and anti-nucleosome antibodies are deposited in inflamed tissues in patients with SLE. Active inflammation promotes nitration of tyrosine residues on serum proteins. Our hypothesis was that levels of nitrated nucleosomes would be elevated in patients with SLE and could be associated with disease activity. We therefore carried out a retrospective longitudinal study to investigate factors affecting levels of nitrated nucleosomes (NN) in patients with SLE.MethodsA novel serum ELISA was developed to measure serum NN and modified to measure serum nitrated albumin (NA). Levels of both NN and NA were measured in 397 samples from 49 patients with SLE followed through periods of disease flare and remission for a mean of 89 months. Anti-nucleosome antibody (anti-nuc) levels were measured in the same samples. The effects of 24 different clinical, demographic and serological variables on NN, NA and anti-nuc levels were assessed by univariable and multivariable analysis.ResultsPatients with SLE had higher mean NN than healthy controls or patients with other autoimmune rheumatic diseases (P =0.01). Serum samples from 18 out of 49 (36.7%) of SLE patients were never positive for NN. This group of 18 patients was characterized by lower anti-double stranded DNA antibodies (anti-dsDNA), disease activity and use of immunosuppressants. In the remaining 63.3%, NN levels were variable. High NN was significantly associated with anti-Sm antibodies, vasculitis, immunosuppressants, hydroxychloroquine and age at diagnosis. NN levels were raised in neuropsychiatric flares. NN levels did not completely parallel NA results, thus providing additional information over measuring nitration status alone. NN levels were not associated with anti-nuc levels.ConclusionsNN are raised in a subset of patients with SLE, particularly those who are anti-Sm positive. Elevated NN may be a marker of vascular activation and neuropsychiatric flares in these patients.

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Section: Discussionmentioning

confidence: 99%

Serum nitrated nucleosome levels in patients with systemic lupus erythematosus: a retrospective longitudinal cohort study

et al. 2014

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“…26 Not much is known regarding the role of IL-17D in autoimmunity. 31 Inhibition of the CCL20-CCR6 signaling pathway tends to protect lupus-prone mice against nephritis. IL-12RB2 tends to play a dual role in the T-helper regulatory pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Their expression was found to be upregulated in nucleosome activated mesangial cells from (NZBxNZW)F1 mice probably indicating their significance in lupus nephritis. 31 Inhibition of the CCL20-CCR6 signaling pathway tends to protect lupus-prone mice against nephritis. 32 Further studies need to be carried out to clarify the role of Table 3 Comparison of serum interleukin (IL)-17A and IL-17F concentrations between patients and healthy subjects CXCL5 and CCL20 in the pathogenesis of lupus and LN.…”

Section: Discussionmentioning

confidence: 99%

Th-17 related regulatory network in the pathogenesis of Arab patients with systemic lupus erythematosus and lupus nephritis

2014

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“…The ICs may activate the mesangial cells through FcRs or TLRs to produce cytokines and chemokines that will attract infiltrating cells [7] (see below). We have recently demonstrated that nucleosomes alone can activate mesangial cells to produce cytokines and chemokines [50]. Other cells nearby, such as glomerular endothelial cells and podocytes, are believed to contribute to the subendothelial and subepithelial deposits observed within the GBM.…”

Section: Glomerular Mesangial Cells Endothelial Cells and Podocytesmentioning

confidence: 99%

“…Increased inflammation will increase the amount of dying . Antibodies were detected by immunohistochemistry using Polink-2 Plus horseradish peroxidase detection kits for tissue (Golden Bridge International, Inc., Mukilteo, WA, USA) according to the protocol described in detail in [50]. All pictures are taken at ×400, scale bar = 50 μm.…”

Section: Concluding Hypothesismentioning

confidence: 99%

The effect of cell death in the initiation of lupus nephritis

Fenton

2014

Clinical and Experimental Immunology

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The effect of cell death in the initiation of lupus nephritis OTHER ARTICLES PUBLISHED IN THIS SERIESDying autologous cells as instructors of the immune system. Clinical and Experimental Immunology 2015, 179: 1-4. Anti-dsDNA antibodies as a classification criterion and a diagnostic marker for systemic lupus erythematosus: critical remarks. Clinical and Experimental Immunology 2015, 179: 5-10 SummaryCell death and the release of chromatin have been demonstrated to activate the immune system producing autoantibodies against nuclear antigens in patients with systemic lupus erythematosus (SLE). Apoptosis, necrosis, necroptosis, secondary necrosis, autophagy and the clearance of dying cells by phagocytosis are processes believed to have a role in tolerance avoidance, activation of autoimmune lymphocytes and tissue damage by effector cells. The released chromatin not only activates the immune system; it also acts as antigen for the autoantibodies produced, including anti-dsDNA antibodies. The subsequent immune complex formed is deposited within the basement membranes and the mesangial matrix of glomeruli. This may be considered as an initiating event in lupus nephritis. The origin of the released chromatin is still debated, and the possible mechanisms and cell sources are discussed in this study.

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Nucleosomes contribute to increase mesangial cell chemokine expression during the development of lupus nephritis

Cited by 27 publications

References 43 publications

Serum nitrated nucleosome levels in patients with systemic lupus erythematosus: a retrospective longitudinal cohort study

Serum nitrated nucleosome levels in patients with systemic lupus erythematosus: a retrospective longitudinal cohort study

Th-17 related regulatory network in the pathogenesis of Arab patients with systemic lupus erythematosus and lupus nephritis

The effect of cell death in the initiation of lupus nephritis

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