Abstract:SUMMARY.— Six patients with vasculitis and cryoglobulinaemia have been investigated. In all but 1 the cryoglobulins were of the mixed variety. On immunofluorescence of the acute vasculitis lesions deposits of immunoglobulins of the same classes as those found in the cryoglobulins were detected in 4 patients; other immunoglobulins not present in the cryoglobulin were additionally present in 2 of the 4 and no or only weak deposits were present in 2. Fibrin and complement were found in all.
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“…The deposition of immune complexes is believed to be important in the pathogenesis of certain types of vasculitis such as the vasculitis a.ssociated with chronic hepatitis B carriage [1], and the small vessel vasculitis associated with mixed essential cryoglobulinaemia [2] and systemic lupus erythematosus (SLE) [3). There is no firm evidence that circulating immune complexes react directly with endtJthelial cells [4][5][6], although cells infected with herpes viruses have been shown to express C3b and Fc receptors which may facilitate immune complex binding [7.8].…”
SLMMARYThe deposition of circulating immune reactants in blood vessels, an important event in the pathogenesis of certain types of vasculitis, requires an increase in permeability in the endothelial monolayer. An in vitro model to examine the integrity of endothelial cell monolayers and their response to inflammatory mediators has been developed. Human umbiiieal vein endothelial cells were grown to confluence on an FITC-labellcd matrix and monolayer integrity was assessed by the exclusion of a '-M-anti-FITC antibody. Alteration in endothelial monolayer penneability was associated with an increase in uptake of '^^I-anti-FITC antibody, expressed as a percentage ofthe maximal uptake of antibody on to FITC-matdx frotn which endothelial cells had been stripped. We determined the effects on endothelial monolayer permeability of acute agonists (thrombin and histamine). cytokines (tumour necrosis factor-alpha (TNF-a). interferon-gamma (IFN-y), IL-I and IL-4) and combinations of acute agonists and cytokines. Addition of thrombin in concentrations ranging from 05 to 15 U/ml led to an increased uptake of'-'l-anti-FITC antibody from 2% to 15% relative to unstimulated endothelium. For other agonists and cyiokines the increases in permeability were: (i) histamine (50-400 pmo!/ml) increased uptake 5-22%: (ii) TNF (12 5-100 ng/ml) increased uptake 2-12%: (iii) IFN-7 (125-250 U/ml) inereased uptake I 5-3%. IL-l/i (50-100 U/ml) and U.-4 (50-100 U/ml) had no effect. Synergistic interactions on endothelial monolayer permeability were seen with the following combinations: (i) IL-4 (100 U/ml) and TNF (12-5 ng/ml) uptake 11 %; (ii) IL-4 (100 U/ml)and IFN-7 (125 U/ml) uptake6-5%; (iii)TNF(12-5ng/ml) and IFN-v (125 ng/ml) uptake 7%; (iv) thrombin (0 5 U/ml) and histamine (50 pmol/ml) uptake 13 5"/;,: and (v) TNF (12-5 ng/ml) and thrombin (0 5 U/ml) uptake 8 5'^. These observations suggest that interactions between cytokines and acute inflammatory mediators such as thrombin and histamine may be important in determining whether immune complexes are deposited in vessel walls. This model system may now be useful for the further investigation in vitro ofthe mechanisms involved in the pathogenesis of immune complex-mediated vascular damage.
“…The deposition of immune complexes is believed to be important in the pathogenesis of certain types of vasculitis such as the vasculitis a.ssociated with chronic hepatitis B carriage [1], and the small vessel vasculitis associated with mixed essential cryoglobulinaemia [2] and systemic lupus erythematosus (SLE) [3). There is no firm evidence that circulating immune complexes react directly with endtJthelial cells [4][5][6], although cells infected with herpes viruses have been shown to express C3b and Fc receptors which may facilitate immune complex binding [7.8].…”
SLMMARYThe deposition of circulating immune reactants in blood vessels, an important event in the pathogenesis of certain types of vasculitis, requires an increase in permeability in the endothelial monolayer. An in vitro model to examine the integrity of endothelial cell monolayers and their response to inflammatory mediators has been developed. Human umbiiieal vein endothelial cells were grown to confluence on an FITC-labellcd matrix and monolayer integrity was assessed by the exclusion of a '-M-anti-FITC antibody. Alteration in endothelial monolayer penneability was associated with an increase in uptake of '^^I-anti-FITC antibody, expressed as a percentage ofthe maximal uptake of antibody on to FITC-matdx frotn which endothelial cells had been stripped. We determined the effects on endothelial monolayer permeability of acute agonists (thrombin and histamine). cytokines (tumour necrosis factor-alpha (TNF-a). interferon-gamma (IFN-y), IL-I and IL-4) and combinations of acute agonists and cytokines. Addition of thrombin in concentrations ranging from 05 to 15 U/ml led to an increased uptake of'-'l-anti-FITC antibody from 2% to 15% relative to unstimulated endothelium. For other agonists and cyiokines the increases in permeability were: (i) histamine (50-400 pmo!/ml) increased uptake 5-22%: (ii) TNF (12 5-100 ng/ml) increased uptake 2-12%: (iii) IFN-7 (125-250 U/ml) inereased uptake I 5-3%. IL-l/i (50-100 U/ml) and U.-4 (50-100 U/ml) had no effect. Synergistic interactions on endothelial monolayer permeability were seen with the following combinations: (i) IL-4 (100 U/ml) and TNF (12-5 ng/ml) uptake 11 %; (ii) IL-4 (100 U/ml)and IFN-7 (125 U/ml) uptake6-5%; (iii)TNF(12-5ng/ml) and IFN-v (125 ng/ml) uptake 7%; (iv) thrombin (0 5 U/ml) and histamine (50 pmol/ml) uptake 13 5"/;,: and (v) TNF (12-5 ng/ml) and thrombin (0 5 U/ml) uptake 8 5'^. These observations suggest that interactions between cytokines and acute inflammatory mediators such as thrombin and histamine may be important in determining whether immune complexes are deposited in vessel walls. This model system may now be useful for the further investigation in vitro ofthe mechanisms involved in the pathogenesis of immune complex-mediated vascular damage.
“…Beaucoup de ces patients ont un fac teur rhumatoïde positif, des anticorps anti nucléaires à un taux faible et une hypocomplémentémie. Dans ce syndrome, des dépôts d'immunoglobulines et de complément ont été démontrés au niveau des vaisseaux [3] ainsi que le long de la membrane basale des glomérules [7], Ce syndrome peut s'accom pagner de glomérulonéphrite sévère [16]. Le type d'atteinte rénale que présente notre pre mière patiente (prolifération mésengiale) peut également se rencontrer dans la cryo globulinémie mixte [17].…”
2 cases of cutaneous vasculitis associated with chronic hepatitis and mixed cryoglobulinaemia are reported. Further studies revealed in the first case hypocomplementaemia and glomerulonephritis. The cutaneous lesions of this patient responded dramatically to plasma exchange whereas prednisolone 20 mg/day and azathioprine 50 mg/day for 10 months showed no effect. The second case (chronic active hepatitis with acute colitis) responded well to prednisolone and azathioprine. The cutaneous lesions (vascularitis) may be the only clinical symptom of a chronic hepatitis and the study of those cases sometimes allows an early diagnosis of renal failure to be made.
“…Since these mixed cryoglobulins sediment at a temperature near zero, and only after a prolonged incubation of up to 96 hours, more careful investigation may be necessary to reveal the presence of this type of cryoglobulins in other cases of BHGP. In addition, Cream (7) and Giannetti, Serri and Bernasconi (8) have demonstrated on purpuric lesions in patients with cryoglobulinemia. the presence of blood vessel deposits of immune complexes which they interpreted as being cryoglobulinemic.…”
Primary hypergammaglobulinemic purpura in an 84 year old woman is described. In addition to her advanced age, she also showed cryoglobulinemia. The patient was further studied by immunofluorescent staining of the skin biopsy specimen, which showed deposition of IgG, IgM, fibrinogen and β1C in the vessel walls.
These findings would seem to indicate involvement of the complement system in the pathogenesis of the vasculitis in this entity.
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