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PubMed1990

Complement-activated oligodendroglia: a new pathogenic entity identified by immunostaining with antibodies to human complement proteins C3d and C4d.

Clusters of oligodendroglial fibers were identified immunohistochemically in human brain tissue with antibodies to the complement proteins C3d and C4d in several neurological disorders. These included Pick's, Huntington's, Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy and Shy-Drager syndrome. These complement-activated oligodendroglia occurred in selected areas of gray and white matter. They were rarely observed in control tissue. Immunogold electron microscopy established that the C4d antibody was attached to degenerating myelin sheaths. These data indicate attachment of classical complement pathway proteins to selective oligodendroglia in several neurological disorders.

Brain Diseases↗
PubMed1989

Inhibition of complement activation in aged individuals due to increased plasma fibronectin concentration.

The influence of fibronectin levels on complement activation by immune complexes and non-immune activators in elderly humans was investigated. The present study demonstrates for the first time a shift in complement activation from the classical to the alternative pathway, if the fibronectin concentration rises above a certain level (near 1 mg/ml). Plasma of elderly individuals often contains large amounts of fibronectin, the reason for which is unknown. While C1 consumption is inhibited under these conditions, C3 depletion remains largely unaffected. This could be due to a compensatory triggering of the alternative reaction sequence caused by fibronectin deposition at and blockade of C1-activating sites. Probable physiologic implications of this changed complement activation pattern are discussed.

Adult↗
PubMed2005

[Evans' syndrome: a retrospective study from the ship (French Society of Pediatric Hematology and Immunology) (36 cases)].

UNLABELLED: Evans' Syndrome (ES) is defined as the combination of immune thrombocytopenia (ITP) and autoimmune haemolytic anemia (AIHA), in the absence of any known underlying etiology. Pathophysiology, epidemiology and outcome remain unclear. POPULATION: Thirty-six children (20 male, 16 female), who were diagnosed in the SHIP french centres (Société d'hématologie et d'immunologie pédiatrique) between 1990 and 2002 with ES, were included in this retrospective study. RESULTS: Median age at diagnosis was 4 years. In 21 children, ES occurred in the setting of consanguinity, family history of autoimmune/inflammatory disease, associated autoimmune disorder or immunoregulatory abnormalities (serum imunoglobulins, peripheral blood lymphocytes subsets, low level of the C3-C4 complement components, nuclear antibodies). Several successive treatments were used in this serie (median: 3, range: 0-10) including corticosteroid therapy (35/36), intravenous immunoglobulins (32/36), immunosuppressive agents (14/36), splenectomy (9/36) and anti CD 20 monoclonal antibodies (6/36). Patients with a low level of serum immunoglobulins were more often non-responders to corticosteroidtherapy/intravenous immunoglobulins and required more frequently further therapy (P=0.03). Three patients died (intracranial bleeding, N=2, Guillain-Barre syndrome; N=1). CONCLUSION: ES was a severe, life-threatening disease, requiring aggressive immunosuppressive therapy in as many as half the patients. Our forthcoming study aims to (i) describe homogeneously-studied and prospectively-analysed cohort of childhood ES, (ii) separate ES from specific immune deficiency (especially fas gene mutations), generalised autoimmune/inflammatory disorders and genetic diseases, (iii) identify well-defined ES subsets, (iv) establish prognostic factors and optimal treatment within these subsets.

Adolescent↗
PubMed2005

Urticarial vasculitis revealing relapsing polychondritis.

We report a case of hypocomplementemic urticarial vasculitis heralding a relapsing polychondritis in a 63-year-old woman. The patient, who had suffered in the past from polymyalgia rheumatica, suddenly experienced a generalized urticarial eruption with a dramatic decrease in C4 complement fraction and the presence of anti-C1q antibodies. Two months later, an ear chondritis occurred and the patient rapidly responded to steroids and dapsone. To our knowledge, this association has never been reported.

Journal Article↗
PubMed2006

Complement regulator CD59 deficiency fails to augment susceptibility to actively induced experimental autoimmune myasthenia gravis.

Complement deficient mice are resistant to experimental autoimmune myasthenia gravis (EAMG), suggesting a pivotal role for the membrane attack complex (MAC) in EAMG pathogenesis. To test the significance of MAC regulation in EAMG pathogenesis, CD59 KO and wild type mice were immunized with acetylcholine receptor (AChR). Interestingly, deletion of CD59, the regulator of MAC assembly, failed to augment EAMG susceptibility. The CD59 KO mice had reduced serum anti-AChR IgG1, IgG2b and complement levels. Their lymph node cell IL-2 production and lymphocyte proliferation response to AChR were reduced. The data challenge the current paradigm that CD59 is solely involved in MAC regulation and suggest a role for this molecule in antigen-driven T cell and B cell activation.

Animals↗
PubMed2004

Early complement activation increases in the brain in some aged normal subjects.

Complement activation is increased in Alzheimer's disease (AD) and may contribute to the development and progression of this disorder. To compare early complement activation between normal and AD brain specimens, C4d and iC3b concentrations were measured in hippocampus, entorhinal cortex, temporal cortex, parietal cortex, and cerebellum from aged normal and AD subjects n=10-14 for both), and in hippocampus and entorhinal cortex from younger normal subjects (n=5-6). C4d and iC3b levels increased 2.3- to 4.6-fold in AD versus aged normal specimens (all P <0.05), with lowest concentrations of these activation proteins generally in cerebellum. No significant differences were present between aged and younger normal C4d and iC3b levels in hippocampus or entorhinal cortex. However, the concentrations of these proteins were markedly increased in several aged normal specimens. Normal subject age was moderately associated with both C4d (r=0.49) and iC3b (r=0.53) concentrations in the hippocampus. Increased brain complement activation in some elderly individuals may promote the subsequent development of AD.

Adult↗
PubMed2005

DNA repair and cyclin D1 polymorphisms and styrene-induced genotoxicity and immunotoxicity.

1-SO-adenine DNA adducts, DNA single-strand breaks (SBs), chromosomal aberrations (CAs), mutant frequency (MF) at the HPRT gene, and immune parameters (hematological and of humoral immunity) were studied in styrene-exposed human subjects and controls. Results were correlated with genetic polymorphisms in DNA repair genes (XPD, exon 23, XPG, exon 15, XPC, exon 15, XRCC1, exon 10, XRCC3, exon 7) and cell cycle gene cyclin D1. Results for biomarkers of genotoxicity after stratification for the different DNA repair genetic polymorphisms showed that the polymorphism in exon 23 of the XPD gene modulates levels of chromosomal and DNA damage, HPRT MF, and moderately affects DNA adduct levels. The highest levels of biomarkers were associated with the wild-type homozygous AA genotype. The exposed individuals with the wild-type GG genotype for XRCC1 gene exhibited the lowest CA frequencies, compared to those with an A allele (P < 0.05). Cyclin D1 polymorphism seems to modulate the number of leukocytes and lymphocytes in the analyzed subjects. The number of eosinophiles was positively associated with XPD variant C allele and negatively with XRCC1 variant A allele (P < 0.05) and XPC variant C allele (P < 0.05). Immunoglobulin IgA was positively associated with an XRCC3 variant T allele (P < 0.01) and negatively with XPC variant C allele (P < 0.05). Both C3- and C4-complement components were lower in individuals with XRCC3 CT (P < 0.05) and TT genotypes (P < 0.01). Adhesion molecules sL-selectin and sICAM-1 were associated with XPC genotype (P < 0.05). Individual susceptibility may be reflected in genotoxic and immunotoxic responses to environmental and occupational exposures to xenobiotics.

Adult↗
PubMed2003

C-reactive protein activates complement in infarcted human myocardium.

Circulating levels of C-reactive protein (CRP) constitute a cardiovascular risk marker. Immunohistochemical studies have revealed co-localization of CRP and activated complement in human infarcted myocardium suggesting CRP to enhance inflammation in ischemic myocardium by inducing local complement activation. The aim was to establish whether CRP activates complement in infarcted human myocardium and to assess the relationship between this activation and the duration of infarction. Myocardial tissue samples from 56 patients that had died from acute myocardial infarction were evaluated. Specimens were taken from infarcted as well as noninfarcted sites of the heart. CRP-mediated complement activation was assessed by immunohistochemistry and by measuring levels of complement, CRP, and CRP-complement complexes, specific markers for CRP-mediated activation, in homogenates of the heart. Infarctions of 12 hours to 5 days had significantly more extensive depositions of complement and CRP and contained significantly more CRP, activated complement, and CRP-complement complexes than infarctions that were less than 12 hours old. Levels of CRP complexes correlated significantly with CRP and complement concentrations in the infarctions, as well as with the extent of complement and CRP depositions as measured via immunohistochemistry. Specific activation products of CRP-mediated activation of complement are increased in infarcts of more than 12 hours in duration and correlate with the extent of complement depositions. Hence, CRP seems to enhance local inflammatory reactions ensuing in human myocardial infarcts of more than 12 hours duration.

C-Reactive Protein↗
PubMed2000

Temporal accrual of complement proteins in amyloid plaques in Down's syndrome with Alzheimer's disease.

The complement system constitutes a series of enzymatic steps involved in the inflammatory response and is activated in Alzheimer's disease (AD). Using Down's syndrome (DS) brains as a temporal model for the progression of AD, we examined components of the complement cascade and their relationship to other principal events in AD pathology: Abeta42 deposition, neuritic changes, neurofibrillary tangles (NFTs), and gliosis (reactive astrocytes, activated microglia). Adjacent sections of frontal cortex from 24 DS subjects ranging in age from 12 to 73 years were immunohistochemically examined for immunoreactivity (IR) of classical complement proteins (Clq and C3), markers indicating activation of complement (C4d and C5b-9), the complement inhibitor apolipoprotein J (apo J), and markers of AD neuropathology. Abeta42-labeled diffuse plaques were first detected in a 12-year-old DS subject and were not labeled by any of the complement antibodies. Colocalization of Abeta42 with Clq, C3, C4d, and/or apo J was first detected in compacted plaques in the brain of a 15-year-old DS patient with features of mature AD pathology, such as reactive astrocytes, activated microglia, dystrophic neurites, and a few NFTs. IR for C4d and C5b-9 (membrane attack complex, MAC) was observed in small numbers of plaque-associated dystrophic neurites and in focal regions of pyramidal neurons in this 15-year-old. The only other young (</=30 years) DS brain to show extensive complement IR was that of a 29-year-old DS subject who also displayed the full range of AD neuropathological features. All middle-aged and old DS brains showed IR for Clq and C3, primarily in compacted plaques. In these cases, C4d IR was found in a subset of Abeta42 plaques and, along with C5b-9 IR, was localized to dystrophic neurites in a subset of neuritic plaques, neurons, and some NFTs. Our data suggest that in AD and DS, the classical complement cascade is activated after compaction of Abeta42 deposits and, in some instances, can progress to the local neuronal expression of the MAC as a response to Abeta plaque maturation.

Adolescent↗
PubMed1988

Complement activation in cardiopulmonary bypass, with special reference to anaphylatoxin production in membrane and bubble oxygenators.

Complement activation by cardiopulmonary bypass (CPB) was studied in 82 patients divided into membrane (MOG) and bubble oxygenator groups (BOG). The influence of primed homologous to circulating autologous blood volume (H/A) ratio was also evaluated. C4a increased very slowly during CPB in both groups, maintaining slightly higher levels in the BOG than in the MOG, with the exception of a marked initial rise in the BOG with a high H/A ratio (greater than or equal to 20%). Anaphylatoxin C3a levels increased more steeply in the BOG than in the MOG. An obvious rise in anaphylatoxin C5a production was observed in the BOG alone. The influence of high H/A ratio perfusion on complement activation was milder in the MOG than in the BOG. In 20 monkeys (Macaca fascicularis), continuous intraaortic infusion with bubbled autologous blood increased C4a and C3a levels, while autologous blood extracorporeally contacted with nylon increased C3a levels alone. In vitro studies revealed that human immunoglobulin fractions denatured by oxygen bubbling produced C4a, C3a, and C5a in a dose-dependent manner, although human albumin treated identically as human immunoglobulin did not produce these complements. It was thus inferred that (1) during CPB, complement is predominantly activated via the classical pathway in the BOG and via the alternative pathway in the MOG; (2) higher anaphylatoxin levels in the BOG than in the MOG are related to mode and grade of blood trauma; (3) anaphylatoxin level differences in both groups tend to increase with high H/A perfusion; and (4) immunoglobulin-free sera may reduced classical pathway activation.

Animals↗
PubMed1999

Upregulation of ICAM-1 on cardiomyocytes in jeopardized human myocardium during infarction.

OBJECTIVE: Impaired perfusion of the myocardium induces a local inflammatory response. In animal models, there is ample evidence that polymorphonuclear leucocytes (PMNs) infiltrating infarcted myocardium contribute significantly to infarct size. METHODS: To explore a possible role for PMNs in the tissue damage of human myocardial infarction, we investigated localization of intercellular adhesion molecule-1 (ICAM-1) and CD66b (previously clustered as CD67), a marker of degranulation of human PMNs, in relation to deposition of complement in tissue specimens of infarcted and healthy parts of the heart obtained from 20 patients, who had died following acute myocardial infarction. RESULTS: ICAM-1 was transiently expressed by endothelium and for a longer period (few days) on myofibers of infarcted myocardium. This expression only occurred in parts that stained positive for complement. PMN infiltration exclusively occurred in areas with ICAM-1 expression, but not every ICAM-1-positive area contained PMN infiltrates. CD66b was found in PMNs but was also fixed to the plasma membrane of myofibers that stained positive for complement and ICAM-1. CONCLUSION: These findings indicate that, in infarcted human myocardium, PMNs are degranulated, possibly upon interaction with ICAM-1 and activated complement.

Aged↗
PubMed2000

Measurement of nine human milk proteins by nephelometric immunoassays: application to the determination of mature milk protein profile.

OBJECTIVES: Microparticle-enhanced nephelometric immunoassays for six human milk proteins (beta-casein, kappa-casein, alpha-lactalbumin, serum albumin, lactoferrin, and lysozyme) and conventional immunonephelometry assays for immunoglobulin A, C3, and C4 complement proteins were developed and characterized. DESIGN AND METHODS: Microparticle-enhanced nephelometric immunoassays are competitive assays based on the nephelometric quantification of the inhibition of microparticle-protein conjugates immunoagglutination by the proteins to be assayed. RESULTS: High precision (CVs ranged from 1% to 14% in within- and between-assays) and recovery (linear recovery in dilution-overloading assay) ensure a reliable determination of the main human milk proteins by single-step homogeneous nephelometric immunoassays, accurate over wide ranges of concentration. These immunoassays were easily applied to a large number of mature human milk samples (between 373 and 503 according to the proteins tested). CONCLUSIONS: The immunoassays developed could be applied to the fast determination of human milk protein profile usable for nursery milk bank and fortification.

Calibration↗
PubMed1980

Preparation of an R3 reagent (serum depleted of the third component of human complement (C3)) by immunoadsorption. Application to the hemolytic assay of human C3.

We have devised a simple one-step preparation of C3 depleted serum (R3). Fresh normal human serum, with complement activation inhibitors, was depleted of C3 by affinity chromatography on a Sepharose anti-C3c. To prevent non-specific interactions, a high ionic strength buffer containing saccharose was used. Immunochemical analysis and complement activity assays demonstrate that this C3 depleted serum is a suitable R3 reagent. This R3 reagent has been used successfully for titration of hemolytic activity of C3 in normal and abnormal sera. Two simple, specific and sensitive assays are described.

Animals↗
PubMed1990

Functional consequences of the genetic polymorphism of the third component of complement.

The third component of complement, the central protein of the complement cascade, occurs in two principal allotypes, C3S and C3F. An excess frequency of the F allotype has been implicated in a number of disease states, including some forms of glomerulonephritis. These associations have been explained by functional differences between C3S and C3F. We examined several complement functions, using purified preparations of C3S or C3F. The C3S allotype was 1.3 times more efficient than C3F in a hemolytic assay employing sensitized sheep erythrocytes; this difference was shown to arise from a slightly more efficient deposition of C3F on the cell surface. These differences are trivial and of much less magnitude than the functional differences between C4A and C4B. There were no differences between allotypes in their ability to be converted to inactive C3b (C3bi) by complement factors H and I or by CR1 and factor I. No significant differences were seen between the allotypes and their ability to support solubilization of preformed immune complexes.

Animals↗