Complement in Lupus Nephritis: New Perspectives

Background: Systemic lupus erythematosus (SLE) is an autoimmune disorder caused by loss of tolerance to self-antigens, the production of autoantibodies and deposition of complement-fixing immune complexes (ICs) in injured tissues. SLE is characterized by a wide range of clinical manifestations and targeted organs, with lupus nephritis being one of the most serious complications. The complement system consists of three pathways and is tightly controlled by a set of regulatory proteins to prevent injudicious complement activation on host tissue. The involvement of the complement system in the pathogenesis of SLE is well accepted; yet, its exact role is still not clear. Summary: Complement plays dual roles in the pathogenesis of SLE. On the one hand, the complement system appears to have protective features in that hereditary homozygous deficiencies of classical pathway components, such as C1q and C4, are associated with an increased risk for SLE. On the other hand, IC-mediated activation of complement in affected tissues is clearly evident in both experimental and human SLE along with pathological features that are logical consequences of complement activation. Studies in genetically altered mice have shown that lack of complement inhibitors, such as complement factor H (CFH) or decay-accelerating factor (DAF) accelerates the development of experimental lupus nephritis, while treatment with recombinant protein inhibitors, such as Crry-Ig, CR2-Crry, CR2-DAF and CR2-CFH, ameliorates the disease development. Complement-targeted drugs, including soluble complement receptor 1 (TP10), C1 esterase inhibitor and a monoclonal anti-C5 antibody (eculizumab), have been shown to inhibit complement safely, and are now being investigated in a variety of clinical conditions. Key Messages: SLE is an autoimmune disorder which targets multiple systems. Complement is centrally involved and plays dual roles in the pathogenesis of SLE. Studies from experimental lupus models and clinical trials support the use of complement-targeted therapy in the treatment of SLE.

Download Full-text

The complement system in lupus nephritis

F1000Research ◽

10.12688/f1000research.6562.1 ◽

2015 ◽

Vol 4 ◽

pp. 145 ◽

Cited By ~ 1

Author(s):

Lihua Bao ◽

Patrick N. Cunningham ◽

Richard J. Quigg

Keyword(s):

Lupus Nephritis ◽

Lupus Erythematosus ◽

Factor H ◽

Classical Pathway ◽

Complement Factor ◽

Dual Roles ◽

Complement Inhibitors ◽

Increased Risk ◽

Clinical Conditions ◽

The Complement System

The complement is part of the innate immune system and can be activated through one of three pathways. To prevent injury of self-tissue, complement is tightly regulated by over 30 proteins. Complement plays dual roles in the pathogenesis of systemic lupus erythematosus (SLE). On one hand, hereditary homozygous deficiencies of classical pathway components, such as C1q and C4, are associated with an increased risk for SLE, suggesting that complement is protective. On the other hand, complement is systemically consumed in both experimental and human SLE, suggesting its pathogenic role. Studies in genetically altered mice have shown that lack of complement inhibitors, such as complement factor H (CFH) or decay-accelerating factor (DAF) accelerates the development of experimental lupus nephritis; while treatment with recombinant protein inhibitors such as CR1-related protein y (Crry)-Ig, CR2-Crry, CR2-DAF and CR2-CFH ameliorates the disease development. Complement-targeted drugs, including soluble complement receptor 1 (TP10), C1 esterase inhibitor (C1-INH), and a monoclonal anti-C5 antibody (Eculizumab) have been shown to inhibit complement safely, and are now being investigated in a variety of clinical conditions. These clinical developments support their therapeutic use in lupus nephritis.

Download Full-text

Role of the Classical Pathway of Complement Activation in Experimentally Induced Polymicrobial Peritonitis

Infection and Immunity ◽

10.1128/iai.69.12.7304-7309.2001 ◽

2001 ◽

Vol 69 (12) ◽

pp. 7304-7309 ◽

Cited By ~ 26

Author(s):

Ilhan Celik ◽

Cordula Stover ◽

Marina Botto ◽

Steffen Thiel ◽

Sotiria Tzima ◽

...

Keyword(s):

Complement System ◽

Complement Activation ◽

Immune Defense ◽

Classical Pathway ◽

Complement Factor ◽

Wild Type ◽

Factor B ◽

The Complement System ◽

Deficient Mice

ABSTRACT The complement system and the natural antibody repertoire provide a critical first-line defense against infection. The binding of natural antibodies to microbial surfaces opsonizes invading microorganisms and activates complement via the classical pathway. Both defense systems cooperate within the innate immune response. We studied the role of the complement system in the host defense against experimental polymicrobial peritonitis using mice lacking either C1q or factor B and C2. The C1q-deficient mice lacked the classical pathway of complement activation. The factor B- and C2-deficient mice were known to lack the classical and alternative pathways, and we demonstrate here that these mice also lacked the lectin pathway of complement activation. Using inoculum doses adjusted to cause 42% mortality in the wild-type strain, none of the mice deficient in the three activation routes of complement (factor B and C2 deficient) survived (mortality of 100%). Mortality in mice deficient only in the classical pathway of complement activation (C1q deficient) was 83%. Application of further dilutions of the polymicrobial inoculum showed a dose-dependent decrease of mortality in wild-type controls, whereas no changes in mortality were observed in the two gene-targeted strains. These results demonstrate that the classical activation pathway is required for an effective antimicrobial immune defense in polymicrobial peritonitis and that, in the infection model used, the remaining antibody-independent complement activation routes (alternative and lectin pathways) provide a supporting line of defense to gain residual protection in classical pathway deficiency.

Download Full-text

Complement factor H contributes to mortality in humans and mice with bacterial meningitis

Journal of Neuroinflammation ◽

10.1186/s12974-019-1675-1 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 4

Author(s):

E. Soemirien Kasanmoentalib ◽

Mercedes Valls Serón ◽

Joo Yeon Engelen-Lee ◽

Michael W. Tanck ◽

Richard B. Pouw ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Bacterial Meningitis ◽

Mouse Model ◽

Adjuvant Treatment ◽

Complement System ◽

Pneumococcal Meningitis ◽

Factor H ◽

Complement Factor ◽

Wild Type ◽

The Complement System

Abstract Background The complement system is a vital component of the inflammatory response occurring during bacterial meningitis. Blocking the complement system was shown to improve the outcome of experimental pneumococcal meningitis. Complement factor H (FH) is a complement regulatory protein inhibiting alternative pathway activation but is also exploited by the pneumococcus to prevent complement activation on its surface conferring serum resistance. Methods In a nationwide prospective cohort study of 1009 episodes with community-acquired bacterial meningitis, we analyzed whether genetic variations in CFH influenced FH cerebrospinal fluid levels and/or disease severity. Subsequently, we analyzed the role of FH in our pneumococcal meningitis mouse model using FH knock-out (Cfh−/−) mice and wild-type (wt) mice. Finally, we tested whether adjuvant treatment with human FH (hFH) improved outcome in a randomized investigator blinded trial in a pneumococcal meningitis mouse model. Results We found the major allele (G) of single nucleotide polymorphism in CFH (rs6677604) to be associated with low FH cerebrospinal fluid concentration and increased mortality. In patients and mice with bacterial meningitis, FH concentrations were elevated during disease and Cfh−/− mice with pneumococcal meningitis had increased mortality compared to wild-type mice due to C3 depletion. Adjuvant treatment of wild-type mice with purified human FH led to complement inhibition but also increased bacterial outgrowth which resulted in similar disease outcomes. Conclusion Low FH levels contribute to mortality in pneumococcal meningitis but adjuvant treatment with FH at a clinically relevant time point is not beneficial.

Download Full-text

Association ofCFHandCFBGene Polymorphisms with Retinopathy in Type 2 Diabetic Patients

Mediators of Inflammation ◽

10.1155/2013/748435 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 9

Author(s):

Jun Wang ◽

Ming Ming Yang ◽

Yan Bo Li ◽

Guo Dong Liu ◽

Yan Teng ◽

...

Keyword(s):

Complement System ◽

Joint Effect ◽

Factor H ◽

Diabetic Patients ◽

Complement Factor ◽

Type 2 Diabetic Patients ◽

Factor B ◽

The Complement System ◽

Type 2 Diabetic

Objectives.The complement system is a key component of innate immunity and has been implicated in the pathogenesis of diabetic retinopathy (DR). This study aimed at investigating whether polymorphisms of two genes in the complement pathway, complement factor H (CFH) and complement factor B (CFB), are associated with DR.Methods.552 well-defined subjects with type 2 diabetes, consisting of 277 DR patients and 275 diabetic controls, were recruited. Four Tag-SNPs rs1048709, rs537160, rs4151657, and rs2072633 in CFB and rs800292 (I62V) in CFH were examined using TaqMan Genotyping Assays.Results.There were significant increases in the frequencies of A allele and AA genotype for rs1048709 in DR patients compared with diabetic controls (Pcorr=0.035,OR=1.42;Pcorr=0.02,OR=2.27, resp.): meanwhile, significant decreases in the frequencies of A allele and AA genotype for rs800292 were observed in DR patients compared with diabetic controls (Pcorr=0.04,OR=0.72;Pcorr=0.015,OR=0.51, resp.). Joint effect of these two loci was also identified. Moreover, rs800292/AA genotype was found to be related with delayed progression to DR.Conclusions.CFH-rs800292 and CFB-rs1048709 are associated with the presence of DR, which strengthens the concept that complement system plays an important role in the pathogenesis of DR.

Download Full-text

Association of Complement Factor D and H Polymorphisms with Recurrent Pregnancy Loss

International Journal of Molecular Sciences ◽

10.3390/ijms21010017 ◽

2019 ◽

Vol 21 (1) ◽

pp. 17

Author(s):

Hee Young Cho ◽

Han Sung Park ◽

Eun Ju Ko ◽

Chang Soo Ryu ◽

Jung Oh Kim ◽

...

Keyword(s):

Complement System ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Factor H ◽

Age Related Macular Degeneration ◽

Taqman Probe ◽

Complement Factor ◽

Genotype Combination ◽

Age Related ◽

The Complement System

Recurrent pregnancy loss (RPL) is defined as two or more consecutive pregnancy losses prior to 20 weeks of gestation, and the incidence of RPL is estimated at 1% of all pregnancies. While the etiologies of RPL are diverse, immune function is considered to be an important cause of RPL. In particular, the complement system is essential for stable development of the placenta and fetus. Moreover, complement factor D (CFD) and complement factor H (CFH) are important regulators of the complement system and are associated with diseases, such as age-related macular degeneration. Therefore, we investigated whether polymorphisms of CFD and CFH are associated with RPL in 412 women with RPL and 384 control women. Genotyping of three polymorphisms (CFD rs2230216, CFH rs1065489, and CFH rs1061170) was performed by TaqMan probe real-time PCR and PCR-restriction fragment length polymorphism. Association of three polymorphisms with RPL was evaluated by statistical analysis. The GT/TC genotype combination of CFH rs1065489 G>T/CFH rs1061170 T>C was associated with a decreased risk of RPL occurrence compared with reference genotypes (adjusted odds ratio [AOR] = 0.439; 95% confidence interval [CI] = 0.238–0.810; p = 0.008), and this association remained significant after adjustment for multiple comparisons using false discovery rate (FDR) correction (p = 0.040). In addition, the CFH rs1065489G>T polymorphism is associated with homocysteine and prolactin level and CFH rs1061170 TC genotype is related to uric acid and triglycerides level in RPL patients. Therefore, those factors could be possible clinical risk factors in RPL patients.

Download Full-text

Profiling Complement System Components in Primary CNS Vasculitis

Cells ◽

10.3390/cells10051139 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1139

Author(s):

Milani Deb-Chatterji ◽

Christian W. Keller ◽

Simon Koch ◽

Heinz Wiendl ◽

Christian Gerloff ◽

...

Keyword(s):

Complement System ◽

Complement Activation ◽

Factor H ◽

Classical Pathway ◽

Cns Vasculitis ◽

Inflammatory Conditions ◽

Csf Levels ◽

General Activation ◽

The Complement System ◽

Multiplex System

Complement activation has been implicated in the pathogenesis of many vasculitic syndromes such as anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Using an array-based multiplex system, we simultaneously quantified serum and CSF levels of activated and regulatory complement system proteins in patients with primary CNS vasculitis (PACNS; n = 20) compared to patients with non-inflammatory conditions (n = 16). Compared to non-inflammatory controls, levels of C3a, C5a, and SC5b-9, indicative for general activation of the complement system, of C4a, specific for the activation of the classical pathway, Ba and Bb, reflective for alternative complement activation as well as concentrations of complement-inhibitory proteins factor H and factor I were unchanged in patients with PACNS. Our study does not support the hypothesis that complement activation is systemically increased in patients with PACNS.

Download Full-text

Complement Factor D as a Strategic Target for Regulating the Alternative Complement Pathway

Frontiers in Immunology ◽

10.3389/fimmu.2021.712572 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jonathan Barratt ◽

Ilene Weitz

Keyword(s):

Complement System ◽

Complement Activation ◽

Alternative Pathway ◽

Treatment Options ◽

Underlying Disease ◽

Alternative Complement Pathway ◽

Complement Factor ◽

Complement Pathway ◽

Alternative Complement ◽

The Complement System

The complement system is central to first-line defense against invading pathogens. However, excessive complement activation and/or the loss of complement regulation contributes to the development of autoimmune diseases, systemic inflammation, and thrombosis. One of the three pathways of the complement system, the alternative complement pathway, plays a vital role in amplifying complement activation and pathway signaling. Complement factor D, a serine protease of this pathway that is required for the formation of C3 convertase, is the rate-limiting enzyme. In this review, we discuss the function of factor D within the alternative pathway and its implication in both healthy physiology and disease. Because the alternative pathway has a role in many diseases that are characterized by excessive or poorly mediated complement activation, this pathway is an enticing target for effective therapeutic intervention. Nonetheless, although the underlying disease mechanisms of many of these complement-driven diseases are quite well understood, some of the diseases have limited treatment options or no approved treatments at all. Therefore, in this review we explore factor D as a strategic target for advancing therapeutic control of pathological complement activation.

Download Full-text

Complement Factor H in Human Platelets: Implications for Atypical HUS.

Blood ◽

10.1182/blood.v112.11.1833.1833 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1833-1833

Author(s):

Walter H.A. Kahr ◽

Fred G Pluthero ◽

Christoph Licht

Keyword(s):

Complement System ◽

Thrombin Generation ◽

Pearson Correlation ◽

Immunoblot Analysis ◽

Factor H ◽

Laser Fluorescence ◽

Cell Surface Receptor ◽

Complement Factor ◽

Blood Samples ◽

The Complement System

Abstract Atypical hemolytic uremic syndrome (aHUS) is a severe kidney disease that mainly affects children, where risks of progression to renal failure and death remain significant. aHUS pathology is associated with hyperactivity of the complement system and activation of platelet-dependent clotting leading to the formation of platelet-rich thromboemboli that occlude the glomerular microvasculature. These events have been linked to defects in the regulation of the alternative complement pathway, with >25% of pediatric aHUS cases being associated with mutations in the soluble complement activation inhibitor Factor H (CFH), or inhibitory autoantibodies. There is also evidence that interactions between platelets and the complement system are important in the progression of aHUS (Stahl AL et al., Blood. 2008;111:5307–5315). Immunoblot analysis detected the presence of CFH in washed cell lysates from serumfree cultured megakaryocytes, normal circulating platelets and platelets from an ARC syndrome patient lacking a-granules. CFH was also detected in supernatants recovered after in vitro activation of normal platelets with thrombin and other agonists. The location of CFH in resting platelets was determined via immunostaining of fixed cells followed by laser fluorescence confocal microscopic (LFCM) imaging. CFH staining was observed inside and on the surface of platelets and microparticles, and was not confined to granules or other secretory vesicles. Deconvolved LFCM images were used for colocalization analysis (Volocity software) with known platelet proteins. CFH showed significant colocalization (p<0.05; Pearson correlation coefficient) with actin (cytoplasmic), tubulin (cytoskeletal) and GPIIIa (CD61, cell surface receptor), but not with α-granule proteins Von Willebrand Factor and fibrinogen, or dense granule/lysosomal proteins CD63 (tetraspanin) and LAMP-1. CFH surface staining was observed to intensify uniformly during the early stages of platelet activation and then subside and disperse to patches on fully-activated platelets. Blood samples were taken from an aHUS patient lacking CFH due to mutation before and after therapeutic fresh frozen plasma (FFP) infusion, and over the following 14 days. Immunoblot analysis of plasma and lysates from washed circulating platelets showed rapid platelet uptake of CFH in vivo after FFP treatment, with the level of platelet CFH declining in parallel with plasma CFH levels. Laboratory assays of blood clotting via thromboelastography showed blood samples from pediatric aHUS patients to have a consistent hypercoagulable tendency. Thrombin generation assays via calibrated automated thrombography of aHUS patient plasmas revealed an elevated level of platelet-dependent, but not platelet-independent, thrombin generation compared to normal. We conclude that CFH in circulating platelets is likely derived from both megakaryocyte synthesis and plasma uptake. CFH uptake and secretion by platelets does not appear to be granule-dependent and may be surface-mediated, with platelets developing a transient increase in CFH affinity early in activation. Pediatric aHUS patients have a tendency towards hypercoagulability, which may be associated with constitutively elevated platelet-dependent thrombin generation. These observations support the hypothesis that loss of CFH-mediated complement inhibition contributes to increased platelet procoagulant activity, which may contribute to the progression of aHUS, and possibly other thrombosis-associated diseases.

Download Full-text

Increased plasma complement factor H is associated with geriatric depression

International Psychogeriatrics ◽

10.1017/s1041610218000558 ◽

2018 ◽

Vol 31 (1) ◽

pp. 101-108 ◽

Cited By ~ 3

Author(s):

Cheolmin Shin ◽

Byung-Joo Ham ◽

Young-Hoon Ko ◽

Chi-Un Pae ◽

Moon Ho Park ◽

...

Keyword(s):

Plasma Level ◽

Complement System ◽

Alternative Pathway ◽

Factor H ◽

Complement Factor H ◽

Complement Factor ◽

Geriatric Depression ◽

Elderly Individuals ◽

Comparison Sample ◽

The Complement System

ABSTRACTBackground:Complement factor H (CFH) plays a key role in regulating the cascade of the alternative pathway of the complement system. Dysregulation of CFH may be involved in the pathophysiology of various inflammation-mediated diseases including neuropsychiatric illnesses. This study aimed to investigate this relationship by examining determining CFH levels in elderly individuals with and without depression.Methods:A total of 152 elderly individuals (major depressive disorder (MDD) group, n = 76; comparison sample, n = 76) were selected from the Ansan Geriatric study. The plasma level of CFH was measured. MDD was diagnosed with the Mini-International Neuropsychiatric Interview as per DSM-IV criteria. The severity of depression was evaluated with the geriatric depression scale (GDS). Mean CFH levels were compared using the Mann–Whitney U test. After adjusting for possible confounding factors including age, sex, marital status, education, alcohol use, hemoglobin levels, and the Korean version of the Mini-Mental State Examination (MMSE-KC), a multiple regression analysis was conducted. The GDS score and plasma level of CFH were analyzed using Spearman's correlation.Results:Plasma CFH level was significantly higher in individuals with MDD than in the comparison sample (289.51 ± 21.16 vs. 339.67 ± 66.23, p < 0.001). In a regression model adjusted for possible confounders, CFH was significantly associated with geriatric depression (p < 0.001). CFH levels were not significantly related to GDS scores in the depressed group.Conclusion:This study revealed an association between high plasma levels of CFH and geriatric depression, thereby suggesting the alternative pathway of the complement system contributing to the development of geriatric depression.

Download Full-text

Isotypes of autoantibodies against novel differential 4-hydroxy-2-nonenal-modified peptide adducts in serum is associated with rheumatoid arthritis in Taiwanese women

BMC Medical Informatics and Decision Making ◽

10.1186/s12911-020-01380-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Kai-Leun Tsai ◽

Che-Chang Chang ◽

Yu-Sheng Chang ◽

Yi-Ying Lu ◽

I-Jung Tsai ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Machine Learning ◽

Disease Activity ◽

Characteristic Curve ◽

Factor H ◽

Protein Adducts ◽

Complement Factor ◽

Increased Risk ◽

Tandem Mass Spectrometric ◽

Peptide Adducts

Abstract Background Rheumatoid arthritis (RA) is an autoimmune disorder with systemic inflammation and may be induced by oxidative stress that affects an inflamed joint. Our objectives were to examine isotypes of autoantibodies against 4-hydroxy-2-nonenal (HNE) modifications in RA and associate them with increased levels of autoantibodies in RA patients. Methods Serum samples from 155 female patients [60 with RA, 35 with osteoarthritis (OA), and 60 healthy controls (HCs)] were obtained. Four novel differential HNE-modified peptide adducts, complement factor H (CFAH)1211–1230, haptoglobin (HPT)78–108, immunoglobulin (Ig) kappa chain C region (IGKC)2–19, and prothrombin (THRB)328–345, were re-analyzed using tandem mass spectrometric (MS/MS) spectra (ProteomeXchange: PXD004546) from RA patients vs. HCs. Further, we determined serum protein levels of CFAH, HPT, IGKC and THRB, HNE-protein adducts, and autoantibodies against unmodified and HNE-modified peptides. Significant correlations and odds ratios (ORs) were calculated. Results Levels of HPT in RA patients were greatly higher than the levels in HCs. Levels of HNE-protein adducts and autoantibodies in RA patients were significantly greater than those of HCs. IgM anti-HPT78−108 HNE, IgM anti-IGKC2−19, and IgM anti-IGKC2−19 HNE may be considered as diagnostic biomarkers for RA. Importantly, elevated levels of IgM anti-HPT78−108 HNE, IgM anti-IGKC2−19, and IgG anti-THRB328−345 were positively correlated with the disease activity score in 28 joints for C-reactive protein (DAS28-CRP). Further, the ORs of RA development through IgM anti-HPT78−108 HNE (OR 5.235, p < 0.001), IgM anti-IGKC2−19 (OR 12.655, p < 0.001), and IgG anti-THRB328−345 (OR 5.761, p < 0.001) showed an increased risk. Lastly, we incorporated three machine learning models to differentiate RA from HC and OA, and performed feature selection to determine discriminative features. Experimental results showed that our proposed method achieved an area under the receiver operating characteristic curve of 0.92, which demonstrated that our selected autoantibodies combined with machine learning can efficiently detect RA. Conclusions This study discovered that some IgG- and IgM-NAAs and anti-HNE M-NAAs may be correlated with inflammation and disease activity in RA. Moreover, our findings suggested that IgM anti-HPT78−108 HNE, IgM anti-IGKC2−19, and IgG anti-THRB328−345 may play heavy roles in RA development.

Download Full-text