Glomerular endothelial glycocalyx-derived heparan sulfate inhibits glomerular leukocyte influx and attenuates experimental glomerulonephritis

Proliferative forms of glomerulonephritis are characterized by the influx of leukocytes, albuminuria, and loss of kidney function. The glomerular endothelial glycocalyx is a thick carbohydrate layer that covers the endothelium and is comprised of heparan sulfate (HS), which plays a pivotal role in glomerular inflammation by facilitating endothelial-leukocyte trafficking. We hypothesize that the exogenous glomerular glycocalyx may reduce the glomerular influx of inflammatory cells during glomerulonephritis. Indeed, administration of mouse glomerular endothelial cell (mGEnC)-derived glycocalyx constituents, or the low-molecular-weight heparin enoxaparin, reduced proteinuria in mice with experimental glomerulonephritis. Glomerular influx of granulocytes and macrophages, as well as glomerular fibrin deposition, was reduced by the administration of mGEnC-derived glycocalyx constituents, thereby explaining the improved clinical outcome. HSglx also inhibited granulocyte adhesion to human glomerular endothelial cells in vitro. Notably, a specific HSglx fraction inhibited both CD11b and L-selectin binding to activated mGEnCs. Mass spectrometry analysis of this specific fraction revealed six HS oligosaccharides, ranging from tetra- to hexasaccharides with 2-7 sulfates. In summary, we demonstrate that exogenous HSglx reduces albuminuria during glomerulonephritis, which is possibly mediated via multiple mechanisms. Our results justify the further development of structurally defined HS-based therapeutics for patients with (acute) inflammatory glomerular diseases, which may be applicable to non-renal inflammatory diseases as well.Nephrolog

Idiopathic giant oesophageal ulcer and leucopoenia after renal transplantation

Item does not contain fulltextA 45-year-old male recipient of a renal allograft was admitted because of a giant oesophageal ulcer coinciding with leucopoenia. An extensive workup revealed no explanation for the ulcer and leucopoenia. Our final diagnosis by exclusion was an idiopathic giant oesophageal ulcer and late-onset neutropenia as consequences of rituximab induction therapy given during the transplant procedure. The patient fully recovered after treatment with prednisone. However, after four months, the ulcer and leucopoenia recurred and again successfully responded to treatment with prednisone

Effect of administration of apoptotic blebs on disease development in lupus mice.

Item does not contain fulltextINTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by the formation of autoantibodies against nuclear components. Disturbed apoptosis and reduced clearance of apoptotic material have been assigned a role in the pathogenesis of SLE. During apoptosis, apoptotic blebs are formed, in which SLE autoantigens are clustered. In vitro, apoptotic blebs can induce maturation of dendritic cells (DC), which in turn can stimulate IL-17 production by T cells. Here, we investigated the effects of administration of apoptotic blebs, separate or in combination with dendritic cells, on disease progression and autoantibody production in lupus and normal mice. METHODS: A preparation of apoptotic blebs, with or without DC, was intravenously administered to MRL/lpr and CBA mice at weeks 7, 9, and 11 of age. T-cell responses against autoantigens present in blebs were examined by delayed type hypersensitivity reactions. Disease progression of the mice was evaluated by determining proteinuria and the titers of anti-DNA, anti-histone, and anti-nucleosome autoantibodies in plasma. RESULTS: Repeated administration of apoptotic blebs, with or without DC, had no effect on the course of proteinuria or on anti-DNA, anti-histone and anti-nucleosome autoantibody levels in MRL/lpr mice. Intravenous injections of apoptotic blebs resulted in a decrease in the DTH response towards s.c. administered blebs in MRL/lpr mice and in reduced anti-nucleosome antibody titers in CBA mice. These tolerizing effects were lost when apoptotic blebs were administered together with syngeneic DC after 2 hours of co-incubation. DISCUSSION AND CONCLUSIONS: In contrast to previous studies with apoptotic cells, and deviating from our in vitro findings with apoptotic blebs, we observed no stimulating effect of the administration of apoptotic blebs on disease progression in MRL/lpr lupus mice. The tolerogenic effects that were observed may be associated with rapid removal of i.v. administered blebs by phagocytes in an immune-silencing way.1 juni 201

Both early and late apoptotic blebs are taken up by DC and induce IL-6 production.

Contains fulltext : 80827.pdf (publisher's version ) (Closed access)During apo blebs, containing nuclear components, are formed at the cells' surfaces. When these blebs separate from the dying cell an apo cell body remains. The contents of apo blebs are modified and can be released, especially in patients with systemic lupus erythematosus (SLE) since impaired clearance of apo material has been observed in this autoimmune condition. Accordingly, autoantibodies present in subjects with SLE bind to apo blebs. Based on AnxA5 binding, and permeability for PI, we show that apo blebs can be categorized as early (AnxA5(+)/PI(- )) or late (AnxA5(+)/PI(+)) apo ones. Both forms of blebs contain apo-induced chromatin modifications and are efficiently phagocytosed by dendritic cell (DC). Uptake by DC of late, but also early apo blebs, stimulate DC to produce IL-6. This bleb-induced effect on DC may be an important step in the initiation of the autoimmune responses in SLE

Benefits derived from weight training by men with cervical spinal cord injuries

In addition to disturbed apoptosis and insufficient clearance of apoptotic cells, there is recent evidence for a role of neutrophils in the aetiopathogenesis of systemic lupus erythematosus (SLE). In response to various stimuli, neutrophils can rapidly release DNA fibres decorated with citrullinated histones and anti-microbial peptides. These structures are referred to as neutrophil extracellular traps (NETs). In addition to apoptotic cell-derived microparticles, these NETs may comprise a further source of autoantigens, able to drive the autoimmune response in SLE. Our group recently identified specific histone modifications occurring during apoptosis that play an important role in the autoimmune response in SLE. In the current study, we evaluated the presence and immunostimulatory potential of these previously identified histone modifications in NETs. Compared to NETs from healthy donors, the histones present in NETs formed by SLE-derived neutrophils contain increased amounts of acetylated and methylated residues, which we previously observed to be associated with apoptosis and SLE. Treatment of neutrophils with histone deacetylase (HDAC) inhibitor Trichostatin A (TSA), prior to induction of NETosis, induced NETs containing hyperacetylated histones, endowed with an increased capacity to activate macrophages. This implies that specific histone modifications, in particular acetylation, might enhance the immunostimulatory potential of NETs in SLE

Coexistence of systemic lupus erythematosus, tuberous sclerosis and aggressive natural killer-cell leukaemia: coincidence or correlated?

Among patients with systemic lupus erythematosus (SLE) there is an increased risk of haematological malignancies, especially non-Hodgkin lymphoma. However, the association of SLE with aggressive CD3 negative natural killer (NK)-cell leukaemia has not been reported so far. We present a case of a 39-year-old woman with SLE, aggressive NK-cell leukaemia and tuberous sclerosis complex. The prior probability of developing the combination of these three rare diseases by coincidence is extremely low (<10(-13)). Possible underlying immunological, genetic and toxic/environmental pathways are discussed

Altered composition of urinary heparan sulfate in patients with COPD

Contains fulltext : 22674.PDF (publisher's version ) (Open Access

Anti-ribosomal P antibodies as a single serological marker in SLE: lupus in disguise

Item does not contain fulltext2 p