Adverse Effects of Clinical Intervention on the Complement System

Svehag, Sven‐Erik

doi:10.1159/000463207

Cited by 6 publications

(6 citation statements)

References 38 publications

(53 reference statements)

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“…By measuring these biochemical and cellular markers, we found that there are substantial differences between plasma types in complement activation, TAT values and, to a minor extent, FXIIa concentrations. Our results for complement activation in source plasma prepared by apheresis technology confirmed previous reports of complement activation on membranes via the alternative pathway [ 44 , 52 , 53 , 54 ]. The most striking differences between the plasma types we investigated were, however, in the residual cell content and cell‐associated proteins.…”

Section: Discussionsupporting

confidence: 91%

Biochemical and cellular markers differentiate recovered, in‐line filtered plasma, and plasma obtained by apheresis methods

et al. 2021

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Background and Objectives: Assessment of plasma quality often focuses on the common safety tests for minimizing the risk of transmitting blood-borne pathogens.Little attention is paid to the possible quality attributes that ensure a consistent biochemical composition of plasma for fractionation. We therefore investigated the suitability of selected biochemical and haematological attributes that could be used as markers of plasma quality obtained by different separation and pre-treatment procedures.Material and Methods: We characterized six plasma types, including source plasma, plasma recovered by classic means and in-line filtered plasma, by determining the analytical attributes protein content, coagulation factors and markers of coagulation, contact and complement activation. Residual cell content and cell-specific variables were also measured. Results:We found relevant differences between the plasma types in complement activation, as indicated by C3a measurements, while thrombin antithrombin complex values and, to a minor extent, activated factor XII concentrations indicated only moderate differences in activation levels of coagulation and contact systems. The most striking differences, however, were detected in residual cell content and concentrations of the platelet-associated proteins, platelet factor 4 and β-thromboglobulin. We showed that leucocyte reduction filters disrupt cells. This includes platelets, thereby releasing the platelet-associated proteins platelet factor 4 and β-thromboglobulin, and leucocytes as demonstrated by the release of elastase from polymorphonuclear leucocytes. Furthermore, the filtration processing of whole blood can lead to activation of the complement system. Conclusion:Our results show that biochemical and cellular surrogate markers are valuable discriminators of plasma types.

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Section: Discussionsupporting

confidence: 91%

Biochemical and cellular markers differentiate recovered, in‐line filtered plasma, and plasma obtained by apheresis methods

et al. 2021

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“…Additional evidence includes the increased NMO pathology in mice and rats lacking complement regulator protein CD59 following passive transfer of AQP4-IgG into the central nervous system [15, 17, 18]. NMO therapeutics that target components of the complement activation pathway can be associated with significant infectious and autoimmune side effects, as can agents that target B cells or other immune effectors [19, 20]. As an alternative approach, as motivated by the consequences of CD59 knockout [15, 17, 18], inhibition [15], and overexpression [21] in experimental animal models of NMO, here we investigate the therapeutic utility of pharmacological upregulation of complement regulator proteins in astrocytes.…”

Section: Introductionmentioning

confidence: 99%

CD55 upregulation in astrocytes by statins as potential therapy for AQP4-IgG seropositive neuromyelitis optica

Tradtrantip

Duan

Yeaman

2019

J Neuroinflammation

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Background Neuromyelitis optica spectrum disorder (herein called NMO) is an inflammatory demyelinating disease that can be initiated by binding of immunoglobulin G autoantibodies (AQP4-IgG) to aquaporin-4 on astrocytes, causing complement-dependent cytotoxicity (CDC) and downstream inflammation. The increased NMO pathology in rodents deficient in complement regulator protein CD59 following passive transfer of AQP4-IgG has suggested the potential therapeutic utility of increasing the expression of complement regulator proteins. Methods A cell-based ELISA was developed to screen for pharmacological upregulators of endogenous CD55 and CD59 in a human astrocyte cell line. A statin identified from the screen was characterized in cell culture models and rodents for its action on complement regulator protein expression and its efficacy in models of seropositive NMO. Results Screening of ~ 11,500 approved and investigational drugs and nutraceuticals identified transcriptional upregulators of CD55 but not of CD59. Several statins, including atorvastatin, simvastatin, lovastatin, and fluvastatin, increased CD55 protein expression in astrocytes, including primary cultures, by three- to four-fold at 24 h, conferring significant protection against AQP4-IgG-induced CDC. Mechanistic studies revealed that CD55 upregulation involves inhibition of the geranylgeranyl transferase pathway rather than inhibition of cholesterol biosynthesis. Oral atorvastatin at 10–20 mg/kg/day for 3 days strongly increased CD55 immunofluorescence in mouse brain and spinal cord and reduced NMO pathology following intracerebral AQP4-IgG injection. Conclusion Atorvastatin or other statins may thus have therapeutic benefit in AQP4-IgG seropositive NMO by increasing CD55 expression, in addition to their previously described anti-inflammatory and immunomodulatory actions.

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“…Further, there is iticreasing evidence that efficient Cl activators possess low-affinity binding sites for both the Clq and the Clr2S2 subunits of Cl (26). Certain polyionic activators also bind Cls (19,29), but whether lipoteichoic acid possesses this quality is not known. A type la group B streptococcus has, however, a capsular polysaccharide with multiple binding sites for Cl.…”

Section: Lipoteiehoic Acid Complement Activation 75mentioning

confidence: 99%

In vitro activation of the classical pathway of complement by a streptococcal lipoteichoic acid

Monefeldt¹,

Helgeland²,

Tollefsen³

1994

Oral Microbiology and Immunology

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The purpose of this study was to find whether a glycerolphosphate-containing lipoteichoic acid prepared from Streptococcus sobrinus OMZ 176 cells would activate the classical pathway of complement while in solution. Reference activators were lipopolysaccharide from Escherichia coli 0111:B4 and heat-aggregated immunoglobulin G. Serum samples were taken from healthy students. Analysis through crossed immunoelectrophoresis showed that lipoteichoic acid caused an almost complete dissociation of the C1qrs macromolecule. All activators decreased the area of and slowed the electrophoretic mobility of the C4 protein peaks, with lipoteichoic acid causing the most pronounced alterations. Electroimmunoassays showed that lipoteichoic acid separately, yielded detectable amounts of free C1r2s2 subunits; it also generated significantly more trimer complexes between C1r, C1s and C1 inhibitor (C1INH) than did the other two activators. Lipoteichoic acid was, however, a comparatively weak inducer of tetramer C1INH-C1r-C1s-C1INH complexes. Analysis through Western blotting showed that all activators accelerated consumption of C1r, induced complex formations between C1INH and C1s and produced cleavage products of C2. Altogether, the immunochemical analysis gave clear evidence of classical pathway activation by lipoteichoic acid, but its activation profile differed from those seen with lipopolysaccharide and aggregated immunoglobulin G.

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Adverse Effects of Clinical Intervention on the Complement System

Cited by 6 publications

References 38 publications

Biochemical and cellular markers differentiate recovered, in‐line filtered plasma, and plasma obtained by apheresis methods

Biochemical and cellular markers differentiate recovered, in‐line filtered plasma, and plasma obtained by apheresis methods

CD55 upregulation in astrocytes by statins as potential therapy for AQP4-IgG seropositive neuromyelitis optica

In vitro activation of the classical pathway of complement by a streptococcal lipoteichoic acid

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