Plasma fibronectin and microvascular damage in essential mixed cryoglobulinaemia

Toschi, Vincenzo; Renoldi, P; Motta, A.; Cimminiello, Claudio; Arpaia, Guido; Fiorini, Gianfrancesco

doi:10.1007/bf00541379

Cited by 5 publications

(6 citation statements)

References 33 publications

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“…These data are also in good agreement with our previous observa tions which demonstrated that plasma FN levels arc inversely related to microcirculatory alterations in the disease as assessed by capillaroscopy [10] and the pre sent finding of a correlation between vWF and cryocrit further supports this hypothesis.…”

Section: Discussionsupporting

confidence: 82%

“…This was measured with an enzyme-linked immu nosorbent assay (ELISA) as previously described [10], and the re sults expressed in micrograms per milliliter. FN may be digested by plasmin during manipulation and is also subject to the action of other enzymes (e.g.…”

Section: Methodsmentioning

confidence: 99%

“…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%

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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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Section: Discussionsupporting

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical Significance of Endothelial Damage Markers in Essential Mixed Cryoglobulinemia

Toschi

Fiorini²,

Motta³

et al. 1991

Acta Haematol

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“…This was performed with an enzyme-linked immunosorbent assay (ELISA) as previously described (19) which employed a goat IgG to human fibronectin (Jackson Laboratories) as first antibody (coating antibody) and a peroxidase-conjugated goat IgG to human fibronectin as second antibody. The standard curve was prepared using both commercially available purified fibronectin (Behring) and affinity-purified fibronectin prepared in our laboratory from normal human plasma (see below).…”

Section: Plasma Fibronectin Determinationmentioning

confidence: 99%

“…Experimental studies by us and others have shown that plasma fibronectin may be associated with cryoglobulins and that it may participate in cryoprecipitate formation (17 -19). We also recently demonstrated that immunoenzymatically measured plasma fibronectin concentrations are reduced in patients with essential mixed cryoglobulinaemia suggesting that an impairment in plasma opsonic activity may be a feature of the disease and can therefore contribute to the abnormal persistence of cold-insoluble complexes in the circulation and to tissue damage (19,20). However the possibility cannot be excluded that the reduced plasma fibronectin concentrations detected in cryoglobulinaemic patients are the result of an enzymatic cleavage of the molecule in vivo with loss of fragments essential for immunologic reactivity in the ELISA assays.…”

Section: Introduction -mentioning

confidence: 96%

Structural and Functional Characterization of Plasma Fibronectin in Patients with Essential Mixed Cryoglobulinaemia

Toschi¹,

Fiorini²,

Motta³

et al. 1992

Clinical Chemistry and Laboratory Medicine

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Experimental studies suggest that plasma fibronectin may be involved in the cryoprecipitation of cryoglobulins in essential mixed cryoglobulinaemia; reduced plasma concentrations of the glycoprotein have been shown in the disease. The present work was undertaken in order to verify this latter finding and to detect a possible structural alteration of plasma fibronectin as result of enzymatic digestion of the molecule in vivo. This could, in turn, induce a decreased reactivity of the protein in immunometric assays and a reduced opsonic activity, which is normally due to the affinity of fibronectin to the Clq component of complement. Moreover, since a polymorphic variant of fibronectin has been described in plasma during experimental vascular injury and in patients with autoimmune vascular diseases, the aim of this study was also to verify the presence of a polymorphism of the glycoprotein in cryoglobulinaemic vasculitis. Twenty seven patients with essential mixed cryoglobulinaemia and 26 normal subjects were included in the study. Significantly reduced concentrations of plasma fibronectin, as assessed by ELISA, were found in patients when compared with controls (231.7 ± 15.3 vs 316.1 ± 16.6 mg/1, P < 0.0002). In contrast, when affinity-purified plasma fibronectin from 10 patients with essential mixed cryoglobulinaemia and 8 healthy subjects were analysed by western blotting, employing a panel of five monoclonal antibodies to different regions of the molecule, no differences were observed between patients and controls, suggesting integrity of the glycoprotein in the disease. Moreover, plasma fibronectin from cryoglobulinaemic patients and normal subjects bound to solid phase Clq in a dose-dependent manner with identical efficiency in the two groups, further suggesting that the molecule is functionally and structurally unaltered in the disease. The production of an abnormally glycosylated form of fibronectin in patients with essential mixed cryoglobulinaemia also seems to be excluded, as SDS-PAGE revealed no differences in electrophoretic mobility and apparent molecular weight between fibronectin from patients and controls. Taken together these data are consistent with the hypothesis that plasma fibronectin concentrations are actually reduced in essential mixed cryoglobulinaemia possibly by consumption during cryoprecipitate formation, and that a polymorphic form of the protein is not released into the circulation during cryoglobulinaemic vasculitis.

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Lack of binding between cryoimmunoglobulins, immunoglobulins and fibronectin: implications for immune complex vasculitis

Brandau

O’Donnell

Kimmel-Truitt

1991

Clinical and Experimental Immunology

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SI MMARYImmunc-complex-mcdialed vasculitis is a frequent comptication of rheumatoid arthritis and sysicmtc lupus cr\'thematosus. The mechanism ofdeptisliion olimmunc complexes wtlhin the vessel wall in these diseases remains unknown, bul probably involves other proteins. Fibronectin is a likely candidate since it possesses the ability to bind to collagen, endothelial cells, and pos.sibly itnmunoglobulins and immune tomple.xes. In this study, the binding ortibroneetin to IgG and IgM eryoglobiilins. cold soluble IgM. IgCi. IgG subclasses and IgG fragments was invesiiyatcd in the solution phase. Static light scattering, fluorescence anisotropy. fluorescence intensity, and PHCi precipitation studies were used to investigate binding under ditfcreni conditions of temperature and ionic strength. These studies failed to demonstrate signitieani binding between tibronectin and IgM. IgG. IgG subclasses and IgG fragments under the eonditions studied These findings argue against solution phase binding of Rbroneclin and immunoglobulins contributing to immune complex vasculitis. The possibility of important surface interactions between these proteins has not been ruled out. KeyworcU libronectin eryoimmunoglohulins protein protein interactions

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Plasma fibronectin and microvascular damage in essential mixed cryoglobulinaemia

Cited by 5 publications

References 33 publications

Clinical Significance of Endothelial Damage Markers in Essential Mixed Cryoglobulinemia

Clinical Significance of Endothelial Damage Markers in Essential Mixed Cryoglobulinemia

Structural and Functional Characterization of Plasma Fibronectin in Patients with Essential Mixed Cryoglobulinaemia

Lack of binding between cryoimmunoglobulins, immunoglobulins and fibronectin: implications for immune complex vasculitis

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