Cryoglobulinemia and Fibronectin

Villar, M; García‐Bragado, F; Joven, Jorge; Biosca, Mercedes; Antolı́n, Maria; Rodrigo, M.J.

doi:10.1159/000206197

Cited by 13 publications

(8 citation statements)

References 7 publications

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“…In this regard, the constant presence of fibronectin in the cryoprecipitates from patients with cryoglobulinemia is intriguing. [40][41][42] Although its significance remains to be determined, an attractive hypothesis would be that fibronectin present in cryoglobulins may promote glomerular localization through interaction with its receptor, such as a5b1 integrin, on endothelial cells 43 and/or the extracellular matrix of the glomerular basement membrane and the mesangium. Whether the extent of terminal sialylation contributes to the interaction of cryogenic IgG3 with fibronectin is an additional issue that needs to be explored.…”

Section: Discussionmentioning

confidence: 99%

Sialylation Determines the Nephritogenicity of IgG3 Cryoglobulins

Otani

Kuroki

Kikuchi

et al. 2012

Journal of the American Society of Nephrology

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Monoclonal 6-19 IgG3 anti-IgG2a rheumatoid factor derived from lupus-prone MRL-Fas lpr mice can induce GN and cryoglobulinemia, but the features that confer nephritogenic potential are not completely understood. Asparagine-linked oligosaccharide chains of 6-19 IgG3 mAb are poorly galactosylated and hardly sialylated, possibly contributing to the pathogenic potential of 6-19 IgG3 rheumatoid factors. Here, we used the 6-19 model of cryoglobulin-associated GN to define the relative contributions of galactosylation and sialylation, in relation to cryoglobulin activity, to the nephritogenic potential of IgG3 antibodies. We generated one highly sialylated and two distinct more galactosylated 6-19 IgG3 rheumatoid factor variants. Although the mere extent of galactosylation had no effect on either the cryogenic and nephritogenic activities of 6-19 IgG3 rheumatoid factor, terminal sialylation attenuated the nephritogenic potential of 6-19 IgG3 by limiting its cryoglobulin activity. These data suggest a protective role of IgG sialylation against the development of cryoglobulin-mediated GN, highlighting the anti-inflammatory activity of sialylated IgG antibodies. Cryoglobulins are a heterogeneous group of Igs that precipitate at temperatures ,37°C, with resolution upon warming. 1,2 Most cryoglobulins are either monoclonal Ig or Ig complexes in which one component, usually IgM, has rheumatoid factor (RF) activity. 1,2 Monoclonal cryoglobulins are mainly associated with various lymphoproliferative disorders, whereas mixed cryoglobulins are often found in sera of patients with autoimmune diseases, such as SLE and rheumatoid arthritis, or with chronic infectious diseases. The presence of cryoglobulins can result in a wide range of vascular, renal, and neurologic complications, likely depending on their concentration, their temperature-dependent solubility behavior, and the nature and type of proteins involved. 2 Antibodies of the IgG3 subclass in humans and mice have the unique physicochemical property that allows them to self-associate via Fc-Fc interactions and to display cryoglobulin activity, independently of their specificities. [3][4][5][6][7][8] Nucleotide sequence analysis of the variable regions of cryogenic and noncryogenic IgG3 mAbs, in combination with the assessment of mutant antibodies, showed that cryoglobulin activity of IgG3 was associated with the presence of more positively charged amino-acid residues at positions 6 and 23 of the heavy-chain variable domain. 9,10 Moreover, structural analysis of asparagine-linked biantennary complex-type oligosaccharide chains (N-glycans) attached to the CH2 domain of different IgG3 mAbs revealed an inverse correlation

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Section: Discussionmentioning

confidence: 99%

Sialylation Determines the Nephritogenicity of IgG3 Cryoglobulins

Otani

Kuroki

Kikuchi

et al. 2012

Journal of the American Society of Nephrology

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“…The major feature of this rheumatic disorder is the presence in the circulation of cold-precipitable immune complex es (cryoglobulins) [2], These are produced as the con sequence of the interaction between rheumatoid fac tor synthesized by an expanded clone of B lympho cytes [3] and polyclonal IgG. Cryoglobulins, once formed, are responsible for widespread endothelial damage with the clinical features of multiorgan vas culitis [4], that can be partially treated by mechanical removal of these immune complexes [5], It has recent ly been shown that fibronectin (FN), a high molecular weight multifunctional plasma glycoprotein [6,7], mainly synthesized by endothelial cells and constantly present in fibrin clots [8], coprecipitates with cryoglo bulins [9,10], Moreover we recently demonstrated that circulating cross-linked fibrin degradation prod ucts are abnormally increased in EMC patients with higher values observed in those with more severe dis ease [11]. These findings suggest that chronic dissemi nated intravascular coagulation is a feature of EMC and that activation of the coagulation cascade may be involved in the pathogenesis of the disease.…”

Section: Introductionmentioning

confidence: 99%

Clinical Significance of Endothelial Damage Markers in Essential Mixed Cryoglobulinemia

Toschi

Fiorini²,

Motta³

et al. 1991

Acta Haematol

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Essential mixed cryoglobulinemia (EMC) is a rheumatic disorder characterized by widespread vasculitis. To better define the nature of the vasculitic process and to possibly outline assessment methods reliable for using in a clinical context, we studied plasma levels of three endothelial related peptides: fibronectin (FN), von Willebrand factor (vWF) and tissue plasminogen activator (t-PA), and those of thrombin-antithrombin IIIcomplexes (TAT) as markers of activation of the coagulation in 21 patients and in 16 controls. In EMC we found a picture consisting of reduced FN and increased vWF, t-PA, and TAT levels, suggesting a condition of endothelial cell damage with thrombin formation in vivo. Since we previously demonstrated the presence of chronic disseminated intravascular coagulation in these patients, we may assume that endothelial cells stressed by cryoprecipitation or stimulated by soluble mediators may be actively involved in the vasculitic process and possibly express procoagulant properties. This is a good example of the complex interplay existing between autoimmunity and coagulation mechanisms. We also suggest that FN, vWF, t-PA and TAT should be considered as additional clinical parameters when evaluating patients with EMC.

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“…Annexin II can bind DNA-containing IC on MCs (Aarli et al, 1991; Yung et al, 2010) and monomeric IgG on placental cells (Kristoffersen et al, 1994), CD7 can bind IgM on lung EnCs (Nishimura et al, 2006), fibronectin can complex with cryoglobulins to bind integrins on MCs (Fujii et al, 2003; Villar et al, 1985), and the TfR can bind to IgA and IgA IC on MCs (Moura et al, 2001). However, when tested fibronectin did not mediate HA-IgG binding (Fujii et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Differential expression of functional Fc-receptors and additional immune complex receptors on mouse kidney cells

Suwanichkul

Wenderfer

2013

Molecular Immunology

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The precise mechanisms by which circulating immune complexes accumulate in the kidney to form deposits in glomerulonephritis are not well understood. In particular, the role of resident cells within glomeruli of the kidney has been widely debated. Immune complexes have been shown to bind one glomerular cell type (mesangial cells) leading to functional responses such as pro-inflammatory cytokine production. To further assess the presence of functional immunoreceptors on resident glomerular cells, cultured mouse renal epithelial, endothelial, and mesangial cells were treated with heat-aggregated mouse IgG or preformed murine immune complexes. Mesangial and renal endothelial cells were found to bind IgG complexes, whereas glomerular epithelial cell binding was minimal. A blocking antibody for Fc-gamma receptors reduced binding to mesangial cells but not renal endothelial cells, suggesting differential immunoreceptor utilization. RT-PCR and immunostaining based screening of cultured renal endothelial cells showed limited low-level expression of known Fc-receptors and Igbinding proteins. The interaction between mesangial cells and renal endothelial cells and immune complexes resulted in distinct, cell-specific patterns of chemokine and cytokine production. This novel pathway involving renal endothelial cells likely contributes to the predilection of circulating immune complex accumulation within the kidney and to the inflammatory responses that drive kidney injury.

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Cryoglobulinemia and Fibronectin

Cited by 13 publications

References 7 publications

Sialylation Determines the Nephritogenicity of IgG3 Cryoglobulins

Sialylation Determines the Nephritogenicity of IgG3 Cryoglobulins

Clinical Significance of Endothelial Damage Markers in Essential Mixed Cryoglobulinemia

Differential expression of functional Fc-receptors and additional immune complex receptors on mouse kidney cells

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