1.
Gulez, N., et al.
(författare)
Homozygosity For a Novel Mutation in the C1q C Chain Gene in a Turkish Family With Hereditary C1q Deficiency
2010
Ingår i: Journal of Investigational Allergology & Clinical Immunology. - 1698-0808. ; 20:3, s. 255-258
Tidskriftsartikel (refereegranskat) abstract
Hereditary complete deficiency of complement component C1q is associated with a high prevalence of systemic lupus erythematosus and increased susceptibility to severe recurrent infections. An 11-year-old girl was screened for immunodeficiency due to a history of recurrent meningitis and pneumonia. Immunologic studies revealed absence of classic pathway hemolytic activity and undetectable levels of C1q. Exon-specific amplification of genomic DNA by polymerase chain reaction followed by direct sequence analysis revealed a novel homozygous missense mutation at codon 48 in the C1q C gene causing a glycine-to-arginine substitution affecting the collagen-like region of C1q. No changes were seen in the exons of the A and B chains. The mutation affected both the formation and the secretion of C1q variant molecules. We describe a novel mutation in the C1q C chain gene that leads to an interchange in amino acids resulting in absence of C1q in serum.
2.
Gullstrand, Birgitta
(författare)
Apoptosis of Peripheral Blood Leukocytes in Systemic Lupus Erythematosus: Studies on Serum Induction and Complement-Dependent Clearance Mechanisms
2010
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease involving many organ systems. The cause is not known, but a complex combination of environmental and genetic factors seems to be involved. In SLE upregulation of type I interferons, a hyperactive B-cell response, presence of autoantibodies against modified nuclear components, increased complement consumption, increased apoptosis and decreased clearance of apoptotic cells are seen. The purpose of this thesis was to investigate some of these mechanisms. The thesis is based on four papers (I-IV). (Papers I and II) We found that the apoptosis inducing effect was specific for sera from SLE patients when comparing with sera from various control groups. However, the apoptosis inducing effect was not related to SLE disease activity. Serum from SLE patients was demonstrated to induce classical caspase-dependent apoptosis in monocytes and lymphocytes. The apoptosis induction was not dependent on death receptors but involvement of the mitochondrial pathway was indicated. (Paper III) Phagocytosis of apoptotic cells by macrophages and C3 deposition on apoptotic cells were investigated in the presence of sera lacking different complement proteins. We found that complement-mediated opsonisation and phagocytosis of apoptotic cells, particularly those undergoing secondary necrosis, are dependent mainly upon an intact classical pathway. C1q was not more important than other classical pathway components, suggesting a role in other pathogenetic processes than defect clearance of apoptotic cells. (Paper IV) We evaluated the roles of serum complement and antibodies against histones in relation to phagocytosis of necrotic cell material by polymorphonuclear neutrophil granulocytes (PMNs). Phagocytosis of necrotic material by PMNs and high concentration of antibodies against a broad spectrum of histones correlated with active SLE disease. The specificities of these anti-histone antibodies appear to determine the complement-dependent phagocytosis. In conclusion, sera from SLE patients have the capacity to contribute to an increased load of apoptotic cells. An efficient clearance of apoptotic and necrotic cell material is dependent on a functional classical pathway, and autoantibodies against histones reflect the presence of apoptotic or necrotic cells contributing to the autoimmune process in SLE.
3.
Lood, Christian, et al.
(författare)
Platelet activation and anti-phospholipid antibodies collaborate in the activation of the complement system on platelets in systemic lupus erythematosus.
2014
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6
Tidskriftsartikel (refereegranskat) abstract
Anti-phospholipid (aPL) antibodies are important contributors to development of thrombosis in patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE). The underlying mechanism of aPL antibody-mediated thrombosis is not fully understood but existing data suggest that platelets and the complement system are key components. Complement activation on platelets is seen in SLE patients, especially in patients with aPL antibodies, and has been related to venous thrombosis and stroke. The aim of this study was to investigate if aPL antibodies could support classical pathway activation on platelets in vitro as well as in SLE patients. Furthermore, we investigated if complement deposition on platelets was associated with vascular events, either arterial or venous, when the data had been adjusted for traditional cardiovascular risk factors. Finally, we analyzed if platelet complement deposition, both C1q and C4d, was specific for SLE. We found that aPL antibodies supported C4d deposition on platelets in vitro as well as in SLE patients (p = 0.001 and p<0.05, respectively). Complement deposition on platelets was increased in SLE patients when compared with healthy individuals (p<0.0001). However, high levels of C4d deposition and a pronounced C1q deposition were also seen in patients with rheumatoid arthritis and systemic sclerosis. In SLE, C4d deposition on platelets was associated with platelet activation, complement consumption, disease activity and venous (OR = 5.3, p = 0.02), but not arterial, thrombosis, observations which were independent of traditional cardiovascular risk factors. In conclusion, several mechanisms operate in SLE to amplify platelet complement deposition, of which aPL antibodies and platelet activation were identified as important contributors in this investigation. Complement deposition on platelets was identified as a marker of venous, but not arterial thrombosis, in SLE patients independently of traditional risk factors and aPL antibodies. Further studies are needed to elucidate the role of complement deposition on platelets in development of venous thrombosis.
4.
Truedsson, Lennart, et al.
(författare)
Serum concentrations of C4 isotypes and factor B in type I C2 deficiency suggest haplotype-dependent quantitative expression of MHC class III complement genes
1995
Ingår i: Experimental and Clinical Immunogenetics. - 0254-9670. ; 12:2, s. 66-73
Tidskriftsartikel (refereegranskat) abstract
The complement protein C4 exists as two isotypes, C4A and C4B, encoded by genes in the major histocompatibility complex (MHC) class III region. The serum concentrations of C4A4 were lower than those of C4B2 in serum from 19 individuals homozygous for type I C2 deficiency (p < 0.0002). These individuals all had the S042 complotype and most of them were homozygous for the haplotype HLA-B18,S042,DR2. In 14 individuals heterozygous for the C2Q0 gene and with the C4A4, C4B2 phenotype and in 51 individuals with the C4A3, C4B1 phenotype, the isotype concentrations were equal. Factor B concentrations in the C2-deficient individuals were lower than those in individuals with the C4A3, C4B1 phenotype (p < 0.0001). The findings strongly suggest that the quantitative expression of C4 isotypes and factor B is MHC haplotype dependent. C4 null alleles cannot be accurately determined by measuring relative C4 isotype serum concentrations.
5.
Bengtsson, Anders, et al.
(författare)
SLE serum induces classical caspase-dependent apoptosis independent of death receptors
2008
Ingår i: Clinical Immunology. - : Elsevier BV. - 1521-6616. ; 126:1, s. 57-66
Tidskriftsartikel (refereegranskat) abstract
The main source of autoantigens in systemic lupus erythematosus (SLE) is most likely apoptotic material. We have previously shown that sera from SLE patients can induce apoptosis in monocytes and lymphocytes, and here we characterized mechanisms of apoptosis induced by SLE serum. SLE serum seems to induce caspase-dependent classical apoptosis since cells exposed to SLE serum displayed morphology consistent with classical apoptosis as demonstrated by confocal microscopy, and pan-caspase inhibitor Z-VAD.fmk significantly reduced SLE serum-induced apoptosis. Death-receptor-independent pathways seemed to be involved since SLE serum induced apoptosis equally in FADD-mutant and wild-type Jurkat cell lines, and blocking of Fas and TNFR1 did not reduce apoptosis induction. Importantly, apoptosis was significantly reduced in a Bcl-2 overexpressing Jurkat cell line indicating involvement of mitochondrial pathways. Thus, based on morphology and caspase inhibition experiments, we have demonstrated that SLE serum induce classical caspase-dependent apoptosis, and this was independent of death receptor pathways.
6.
7.
Enocsson, Helena, et al.
(författare)
C-Reactive Protein Levels in Systemic Lupus Erythematosus Are Modulated by the Interferon Gene Signature and CRP Gene Polymorphism rs1205
2021
Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
Tidskriftsartikel (refereegranskat) abstract
Objectives: Patients with systemic lupus erythematosus (SLE) often display modest elevations of C-reactive protein (CRP) despite raised disease activity and increased interleukin (IL-) 6. We asked to what extent IL-6 levels, the CRP polymorphism rs1205, and the type I interferon (IFN) gene signature affects the basal CRP levels in patients with SLE during a quiescent phase of the disease. Methods: CRP and IL-6 were analyzed in plasma from 57 patients meeting established classification criteria for SLE. The CRP polymorphism rs1205 was assessed and gene expression analyzed including four type I IFN-regulated genes (IGS). Results: CRP was increased in patients with detectable IL-6 levels (p=0.001) and decreased among IGS-positive subjects (p=0.033). A multiple linear regression model revealed IL-6 to have a positive association with CRP levels, whereas both IGS-positivity and CRP genotype (rs1205) AA/GA were negatively associated with CRP-levels. Conclusion: Our data offer an explanation to the modest CRP levels seen in viral infections and IFN-α driven autoimmunity and corroborate prior observations showing an IFN-α dependent downregulation of CRP. The latter observation, together with the fact that the CRP-lowering polymorphism rs1205 is overrepresented in human SLE, could explain low basal CRP and inadequate CRP-responses among patients with active SLE.
8.
Enocsson, Helena, et al.
(författare)
Comparison of Surrogate Markers of the Type I Interferon Response and Their Ability to Mirror Disease Activity in Systemic Lupus Erythematosus
2021
Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 12
Tidskriftsartikel (refereegranskat) abstract
Objectives: Type I interferons (IFNs) are central and reflective of disease activity in systemic lupus erythematosus (SLE). However, IFN-alpha levels are notoriously difficult to measure and the type I IFN gene signature (IGS) is not yet available in clinical routine. This study evaluates galectin-9 and an array of chemokines/cytokines in their potential as surrogate markers of type I IFN and/or SLE disease activity.Methods: Healthy controls and well-characterized Swedish SLE patients from two cross-sectional cohorts (n=181; n=59) were included, and a subgroup (n=21) was longitudinally followed. Chemokine/cytokine responses in immune complex triggered IFN-alpha activity was studied in healthy donor peripheral blood mononuclear cells (PBMC). Levels of chemokines/cytokines and galectin-9 were measured by immunoassays. Gene expression was quantified by qPCR.Results: The IGS was significantly (p<0.01) correlated with galectin-9 (rho=0.54) and CXCL10 (rho=0.37) levels whereas serum IFN-alpha correlated with galectin-9 (rho=0.36), CXCL10 (rho=0.39), CCL19 (rho=0.26) and CCL2 (rho=0.19). The strongest correlation was observed between galectin-9 and TNF (rho=0.56). IFN-alpha and disease activity (SLEDAI-2K) were correlated (rho=0.20) at cross-sectional analysis, but no significant associations were found between SLEDAI-2K and galectin-9 or chemokines. Several inflammatory mediators increased at disease exacerbation although CCL19, CXCL11, CXCL10, IL-10 and IL-1 receptor antagonist were most pronounced. Immune complex-stimulation of PBMC increased the production of CCL2, CXCL8 and TNF.Conclusion: Galectin-9 and CXCL10 were associated with type I IFN in SLE but correlated stronger with TNF. None of the investigated biomarkers showed a convincing association with disease activity, although CXCL10 and CCL19 performed best in this regard.
9.
Gullstrand, Birgitta, et al.
(författare)
Complement classical pathway components are all important in clearance of apoptotic and secondary necrotic cells.
2009
Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 156, s. 303-311
Tidskriftsartikel (refereegranskat) abstract
Summary Inherited deficiencies in components of the classical complement pathway are strong disease susceptibility factors for the development of systemic lupus erythematosus (SLE) and there is a hierarchy among deficiency states, the strongest association being with C1q deficiency. We investigated the relative importance of the different complement pathways regarding clearance of apoptotic cells. Phagocytosis of labelled apoptotic Jurkat cells by monocyte-derived macrophages in the presence of sera from individuals with complement deficiencies was studied, as well as C3 deposition on apoptotic cells using flow cytometry. Sera from individuals deficient in C1q, C4, C2 or C3 all showed decreased phagocytosis. Mannose binding lectin (MBL) and the alternative pathway did not influence phagocytosis. Notably, the components of the complement classical pathway, including C1q, were equally important in clearance of apoptotic cells. This indicates that deposition of C3 fragments is of major significance; we therefore studied C3 deposition on apoptotic cells. Experiments with MBL-deficient serum depleted of C1q or factor D confirmed the predominance of the classical pathway. At low dilution, sera deficient of C1q, C4 or C2 supported C3 fragment deposition demonstrating alternative pathway activation. In conclusion, we have found that complement-mediated opsonization and phagocytosis of apoptotic cells, particularly those undergoing secondary necrosis, are dependent mainly upon an intact classical pathway. The alternative pathway is less important, but may play a role in some conditions. C1q was not more important than other classical pathway components, suggesting a role in additional pathogenetic processes in SLE other than clearance of apoptotic cells.
10.
Jönsson, Göran, et al.
(författare)
Increased serum bactericidal activity of autologous serum in C2 deficiency after vaccination against Haemophilus influenzae type b, and further support for an MBL-dependent C2 bypass mechanism
2021
Ingår i: Vaccine. - : Elsevier BV. - 0264-410X. ; 39:8, s. 1297-1302
Tidskriftsartikel (refereegranskat) abstract
Deficiencies of C2 and other components of the classical pathway of complement are associated with increased risk of infections with encapsulated bacteria, such as Haemophilus (H.) influenzae. Defense against H. influenzae is dependent on specific antibodies and complement, which mediate serum bactericidal activity (SBA) and opsonization. Due to lack of normal classical and lectin complement pathway function in C2 deficiency (C2D), SBA would have to depend either on the alternative pathway or on C2 bypass mechanisms. Here we studied SBA against H. influenzae type b (Hib) before and after vaccination in a group of C2-deficient persons, as the bactericidal capacity of antibodies in autologous complement in relation to vaccination has not been investigated at group level in C2D. Sera from 22 persons with C2D and 26 healthy controls were available. Out of these, 18 persons with C2D and all controls had been vaccinated with Act-HIB®. SBA against Hib bacteria was analyzed with autologous serum as the only complement source. Antibodies to Hib capsular polysaccharide had been analyzed previously. Concentrations of mannose-binding lectin (MBL) and other complement components were measured in serum. SBA of both C2-deficient persons and controls was significantly more efficient after vaccination (p = 0.002 and p < 0.0001, respectively). After vaccination, all but two C2-deficient sera and one control serum showed sufficient SBA (<50% surviving bacteria). Before vaccination, SBA of C2-deficient sera was negatively correlated to serum concentrations of MBL (lower proportion of surviving bacteria with higher MBL concentration; r = −0.55, p = 0.008). After vaccination, SBA of C2-deficient sera was negatively correlated to serum concentrations of IgG Hib antibodies (r = −0.56, p = 0.01). In conclusion, SBA against Hib in autologous serum is increased after vaccination in persons with C2D. In unvaccinated C2-deficient persons SBA was correlated to MBL concentration, providing further support for an MBL-dependent C2 bypass mechanism operating in C2D.
