Aberrant activation of complement system in renal grafts is mediated by cold storage

2021 ◽  
Author(s):  
Sorena Lo ◽  
Li Jiang ◽  
Savannah Stacks ◽  
Haixia Lin ◽  
Nirmala Parajuli
Keyword(s):  
Cold Storage ◽  
Complement System ◽  
Complement Activation ◽  
Renal Tubules ◽  
Renal Transplants ◽  
Reducing Conditions ◽  
Tnf Α ◽  
Renal Grafts ◽  
The Impact ◽  
The Complement System

Aberrant complement activation leads to tissue damage during kidney transplantation, and it is recognized as an important target for therapeutic intervention (6, 19, 35, 64). However, it is not clear whether cold storage (CS) triggers the complement pathway in transplanted kidneys. The goal of this study was to determine the impact of CS on complement activation in renal transplants. Male Lewis and Fischer rats were used, and donor rat kidneys were exposed to 4 h or 18 h of CS followed by transplantation (CS+Transplant). To study CS-induced effects, a group with no CS was included in which the kidney was removed and transplanted back to the same rat (autotransplantation, ATx). Complement proteins (C3 and C5b-9) were evaluated with western blotting (reducing and non-reducing conditions) and immunostaining. Western blot of renal extracts or serum indicated that the levels of C3 and C5b-9 increased after CS+Transplant compared to ATx. Quite strikingly, intracellular C3 was profoundly elevated within renal tubules after CS+Transplant but was absent in Sham or ATx groups, which showed only extratubular C3. Similarly, C5b-9 immunofluorescence staining of renal sections showed an increase in C5b-9 deposits in kidneys after CS+Transplant. Real-time PCR (SYBR Green) showed increased expression of CD11b and CD11c, components of complement receptors 3 and 4, respectively, as well as inflammatory markers such as TNF-α. In addition, recombinant TNF-α significantly increased C3 levels in renal cells. Collectively, these results demonstrate that CS activates the complement system in renal transplants.

scholarly journals Pretreatment with atorvastatin ameliorates cobra venom factor-induced acute lung inflammation in mice

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Jing Guo ◽  
Min Li ◽  
Yi Yang ◽  
Lin Zhang ◽  
Li-wei Zhang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Protein Content ◽  
Complement System ◽  
Complement Activation ◽  
Lung Inflammation ◽  
Acute Lung Inflammation ◽  
Tnf Α ◽  
The Complement System

Abstract Background The complement system plays a critical role as the pathogenic factor in the models of acute lung injury due to various causes. Cobra venom factor (CVF) is a commonly used complement research tool. The CVF can cause acute inflammation in the lung by producing complement activation components. Atorvastatin (ATR) is a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor approved for control of plasma cholesterol levels. This inhibitor can reduce the acute pulmonary inflammatory response. However, the ability of ATR in treating acute lung inflammation caused by complement activation is still unknown. Therefore, we investigated the effect of ATR on lung inflammation in mice induced by activation of the complement alternative pathway in this study. Methods ATR (10 mg/kg/day via oral gavage) was administered for 7 days before tail vein injection of CVF (25 μg/kg). On the seventh day, all mice were sacrificed 1 h after injection. The lung lobe, bronchoalveolar lavage fluid (BALF), and blood samples were collected. The myeloperoxidase (MPO) activity of the lung homogenate, the leukocyte cell count, and the protein content of BALF were measured. The levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), P-selectin, and Intercellular cell adhesion molecule-1 (ICAM-1) in BALF and serum were determined by enzyme-linked immunosorbent assay. The pathological change of the lung tissue was observed by hematoxylin and eosin staining. The deposition of C5b-9 in the lung tissue was detected by immunohistochemistry. The phosphorylation of NF-κB p65 in the lung tissues was examined by immunohistochemistry and western blotting. Results The lung inflammation levels were determined by measuring the leukocyte cell numbers and protein content of BALF, the lung MPO activity, and expression and staining of the inflammatory mediators (IL-6 and TNF-α), and adhesion molecules (P-selectin and ICAM-1) for lung lesion. A significant reduction in the lung inflammation levels was observed after 7 days in ATR pre-treated mice with a CVF-induced lung disease. Deposition of C5b-9 was significantly alleviated by ATR pretreatment. Early intervention with ATR significantly reduced the development of acute lung inflammation on the basis of phosphorylation of NF-κB p65 in the lung. Conclusion These findings suggest the identification of ATR treatment for the lung inflammation induced by activating the complement system on the basis of its anti-inflammatory response. Together with the model replicating the complement activating characteristics of acute lung injury, the results may be translatable to the overactivated complement relevant diseases.

The alternative pathway of complement is activated in the glomeruli and tubulointerstitium of mice with adriamycin nephropathy

2007 ◽  
Vol 293 (2) ◽  
pp. F555-F564 ◽  
Author(s):  
Amanda M. Lenderink ◽  
Katharine Liegel ◽  
Danica Ljubanović ◽  
Kathrin E. Coleman ◽  
Gary S. Gilkeson ◽  
...  
Keyword(s):  
Renal Disease ◽  
Complement System ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Host Cells ◽  
Renal Tubules ◽  
Wild Type ◽  
Tubulointerstitial Injury ◽  
Factor B ◽  
The Complement System

The complement system effectively identifies and clears invasive pathogens as well as injured host cells. Uncontrolled complement activation can also contribute to tissue injury, however, and inhibition of this system may ameliorate many types of inflammatory injury. Several studies have demonstrated that the filtration of complement proteins into the renal tubules, as occurs during proteinuric renal disease, causes tubular inflammation and injury. In the present study, we tested the hypothesis that activation of the complement system in the urinary space requires an intact alternative pathway. Using a model of adriamycin-induced renal injury, which induces injury resembling focal segmental glomerulosclerosis, we examined whether mice deficient in factor B would be protected from the development of progressive tubulointerstitial injury. Complement activation was attenuated in the glomeruli and tubulointerstitium of mice with congenital deficiency of factor B ( fB−/−) compared with wild-type controls, demonstrating that complement activation does occur through the alternative pathway. Deficiency in factor B did not significantly protect the mice from tubulointerstitial injury. However, treatment of wild-type mice with an inhibitory monoclonal antibody to factor B did delay the development of renal failure. These results demonstrate that complement activation in this nonimmune complex-mediated model of progressive renal disease requires an intact alternative pathway.

scholarly journals Complement modulation in the retinal pigment epithelium rescues photoreceptor degeneration in a mouse model of Stargardt disease

2017 ◽  
Vol 114 (15) ◽  
pp. 3987-3992 ◽  
Author(s):  
Tamara L. Lenis ◽  
Shanta Sarfare ◽  
Zhichun Jiang ◽  
Marcia B. Lloyd ◽  
Dean Bok ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Retinal Pigment Epithelium ◽  
Complement System ◽  
Complement Activation ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Host Cells ◽  
Etiologic Factor ◽  
Photoreceptor Degeneration ◽  
The Complement System

Recessive Stargardt macular degeneration (STGD1) is caused by mutations in the gene for the ABCA4 transporter in photoreceptor outer segments. STGD1 patients and Abca4−/− (STGD1) mice exhibit buildup of bisretinoid-containing lipofuscin pigments in the retinal pigment epithelium (RPE), increased oxidative stress, augmented complement activation and slow degeneration of photoreceptors. A reduction in complement negative regulatory proteins (CRPs), possibly owing to bisretinoid accumulation, may be responsible for the increased complement activation seen on the RPE of STGD1 mice. CRPs prevent attack on host cells by the complement system, and complement receptor 1-like protein y (CRRY) is an important CRP in mice. Here we attempted to rescue the phenotype in STGD1 mice by increasing expression of CRRY in the RPE using a gene therapy approach. We injected recombinant adeno-associated virus containing the CRRY coding sequence (AAV-CRRY) into the subretinal space of 4-wk-old Abca4−/− mice. This resulted in sustained, several-fold increased expression of CRRY in the RPE, which significantly reduced the complement factors C3/C3b in the RPE. Unexpectedly, AAV-CRRY–treated STGD1 mice also showed reduced accumulation of bisretinoids compared with sham-injected STGD1 control mice. Furthermore, we observed slower photoreceptor degeneration and increased visual chromophore in 1-y-old AAV-CRRY–treated STGD1 mice. Rescue of the STGD1 phenotype by AAV-CRRY gene therapy suggests that complement attack on the RPE is an important etiologic factor in STGD1. Modulation of the complement system by locally increasing CRP expression using targeted gene therapy represents a potential treatment strategy for STGD1 and other retinopathies associated with complement dysregulation.

scholarly journals Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis

mBio ◽  
2018 ◽  
Vol 9 (5) ◽  
Author(s):  
Lisa E. Gralinski ◽  
Timothy P. Sheahan ◽  
Thomas E. Morrison ◽  
Vineet D. Menachery ◽  
Kara Jensen ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Host Defense ◽  
Complement System ◽  
Complement Activation ◽  
Fungal Infections ◽  
Central Component ◽  
Lung Pathology ◽  
Inflammatory Monocytes ◽  
The Complement System

ABSTRACT Acute respiratory distress syndrome (ARDS) is immune-driven pathologies that are observed in severe cases of severe acute respiratory syndrome coronavirus (SARS-CoV) infection. SARS-CoV emerged in 2002 to 2003 and led to a global outbreak of SARS. As with the outcome of human infection, intranasal infection of C57BL/6J mice with mouse-adapted SARS-CoV results in high-titer virus replication within the lung, induction of inflammatory cytokines and chemokines, and immune cell infiltration within the lung. Using this model, we investigated the role of the complement system during SARS-CoV infection. We observed activation of the complement cascade in the lung as early as day 1 following SARS-CoV infection. To test whether this activation contributed to protective or pathologic outcomes, we utilized mice deficient in C3 (C3–/–), the central component of the complement system. Relative to C57BL/6J control mice, SARS-CoV-infected C3–/– mice exhibited significantly less weight loss and less respiratory dysfunction despite equivalent viral loads in the lung. Significantly fewer neutrophils and inflammatory monocytes were present in the lungs of C3–/– mice than in C56BL/6J controls, and subsequent studies revealed reduced lung pathology and lower cytokine and chemokine levels in both the lungs and the sera of C3–/– mice than in controls. These studies identify the complement system as an important host mediator of SARS-CoV-induced disease and suggest that complement activation regulates a systemic proinflammatory response to SARS-CoV infection. Furthermore, these data suggest that SARS-CoV-mediated disease is largely immune driven and that inhibiting complement signaling after SARS-CoV infection might function as an effective immune therapeutic. IMPORTANCE The complement system is a critical part of host defense to many bacterial, viral, and fungal infections. It works alongside pattern recognition receptors to stimulate host defense systems in advance of activation of the adaptive immune response. In this study, we directly test the role of complement in SARS-CoV pathogenesis using a mouse model and show that respiratory disease is significantly reduced in the absence of complement even though viral load is unchanged. Complement-deficient mice have reduced neutrophilia in their lungs and reduced systemic inflammation, consistent with the observation that SARS-CoV pathogenesis is an immune-driven disease. These data suggest that inhibition of complement signaling might be an effective treatment option following coronavirus infection.

Human Mesenchymal Stem Cells Elicit Complement Activation in Human Blood.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4580-4580
Author(s):  
Katarina Le Blanc ◽  
Guido Moll ◽  
Ida Rasmusson ◽  
Kristina Nilsson Ekdahl ◽  
Graciela Elgue ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Human Blood ◽  
Complement System ◽  
Complement Activation ◽  
Immune Modulation ◽  
Effector Cell ◽  
Conflicts Of Interest ◽  
Cell Functions ◽  
The Complement System

Abstract Abstract 4580 Infusion of third-party mesenchymal stem cells (MSCs) appears to be a promising therapy for steroid-refractory acute graft-versus-host disease (GvHD). Little is known about how MSCs interact with the innate immune system after clinical infusion. In this study, we show that exposure of MSCs to ABO-compatible human blood activates the complement system, which triggers complement-mediated effector cell functions, and correlates with the immunosuppressive properties of MSCs. We found deposition of the complement component 3 (C3) derived opsonins iC3b and C3dg on MSCs, and fluid-phase generation of the chemotactic anaphylatoxins C3a and C5a. These events triggered complement receptor 3 (CD11b/CD18)-mediated effector cell activation; but could be prevented by culturing MSCs in human ABserum or by blocking complement function. Our study demonstrates the important role of the complement system as a possible mediator of immune modulation in clinical applications using MSCs, and implies that complement activation may substantially affect the treatment efficiency. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Influence of Mannan and Glucan on Complement Activation and C3 Binding by Candida albicans

2009 ◽  
Vol 78 (3) ◽  
pp. 1250-1259 ◽  
Author(s):  
Gayle M. Boxx ◽  
Thomas R. Kozel ◽  
Casey T. Nishiya ◽  
Mason X. Zhang
Keyword(s):  
Candida Albicans ◽  
Complement System ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Surface Expression ◽  
Human Neutrophils ◽  
Intact Cells ◽  
Independent Mechanism ◽  
The Complement System ◽  
Wall Components

ABSTRACT The complement system is important for host resistance to hematogenously disseminated candidiasis. However, modulation of complement activation by cell wall components of Candida albicans has not been characterized. Although intact yeast display mannan on the surface, glucan, typically located in the interior, becomes exposed during C. albicans infection. We show here the distinct effects of mannan and glucan on complement activation and opsonophagocytosis. Previous studies showed that intact cells are resistant to initiation of complement activation through the alternative pathway, and antimannan antibody reverses this resistance via an Fc-independent mechanism. The present study shows that this mannan-dependent resistance can be overcome by periodate-borohydride conversion of mannose polysaccharides to polyalcohols; cells treated with periodate-borohydride initiate the alternative pathway without the need for antibody. These observations identify an inhibitory role for intact mannan in complement activation. Next, removal of the surface-displayed mannan by acid treatment of periodate-borohydride cells exposes glucan. Glucan-displaying cells or purified β-glucan initiate the alternative pathway when incubated with the purified proteins of the alternative pathway alone, suggesting that C. albicans glucan is a natural activator of the alternative pathway. Finally, ingestion of mannan-displaying cells by human neutrophils requires anti-mannan antibody, whereas ingestion of glucan-displaying cells requires complement. These results demonstrate a contrasting requirement of natural antibody and complement for opsonophagocytosis of C. albicans cells displaying mannan or glucan. Thus, differential surface expression of mannan and glucan may influence recognition of C. albicans by the complement system.

scholarly journals Interaction Between the Complement System and Infectious Agents – A Potential Mechanistic Link to Neurodegeneration and Dementia

2021 ◽  
Vol 15 ◽  
Author(s):  
Noriko Shinjyo ◽  
Wataru Kagaya ◽  
Marcela Pekna
Keyword(s):  
Nervous System ◽  
Complement System ◽  
Complement Activation ◽  
Neural Plasticity ◽  
Measles Virus ◽  
System Development ◽  
Critical Role ◽  
Nervous System Development ◽  
Infectious Agents ◽  
The Complement System

As part of the innate immune system, complement plays a critical role in the elimination of pathogens and mobilization of cellular immune responses. In the central nervous system (CNS), many complement proteins are locally produced and regulate nervous system development and physiological processes such as neural plasticity. However, aberrant complement activation has been implicated in neurodegeneration, including Alzheimer’s disease. There is a growing list of pathogens that have been shown to interact with the complement system in the brain but the short- and long-term consequences of infection-induced complement activation for neuronal functioning are largely elusive. Available evidence suggests that the infection-induced complement activation could be protective or harmful, depending on the context. Here we summarize how various infectious agents, including bacteria (e.g., Streptococcus spp.), viruses (e.g., HIV and measles virus), fungi (e.g., Candida spp.), parasites (e.g., Toxoplasma gondii and Plasmodium spp.), and prion proteins activate and manipulate the complement system in the CNS. We also discuss the potential mechanisms by which the interaction between the infectious agents and the complement system can play a role in neurodegeneration and dementia.

scholarly journals A Computational Model for the Evaluation of Complement System Regulation under Homeostasis, Disease, and Drug Intervention

2017 ◽  
Author(s):  
Nehemiah Zewde ◽  
Dimitrios Morikis
Keyword(s):  
Computational Model ◽  
Complement System ◽  
Complement Activation ◽  
Late Stage ◽  
Inflammatory Diseases ◽  
Early Stage ◽  
Host Cells ◽  
Patient Specific ◽  
Complement Dysregulation ◽  
The Complement System

HighlightsComputational model describing dynamics of complement system activation pathwaysComplement dysregulation leads to deviation from homeostasis and to inflammatory diseasesModel identifies biomarkers to quantify the effects of complement dysregulationKnown drugs restore impaired dynamics of complement biomarkers under dysregulationDisease-specific models are suitable for diagnosis and patient-specific drug treatmentAbstractThe complement system is a part of innate immunity that rapidly removes invading pathogens and impaired host-cells. Activation of the complement system is balanced under homeostasis by regulators that protect healthy host-cells. Impairment of complement regulators tilts the balance, favoring activation and propagation that leads to inflammatory diseases. The most potent regulator of the complement system is Factor H (FH), and its impairment induces improper complement activation that leads to inflammatory diseases, such as atypical hemolytic uremic syndrome and age related macular degeneration. To understand the dynamics involved in the pivotal balance between activation and regulation, we have developed a comprehensive computational model of the alternative and classical pathways of the complement system. The model is composed of 290 ordinary differential equations with 142 kinetic parameters that describe the state of complement system under homeostasis and disorder through FH impairment. We have evaluated the state of the system by generating concentration-time profiles for the biomarkers C3, C3a-desArg, C5, C5a-desArg, Factor B (FB), Ba, Bb, and fC5b-9 that are influenced by complement dysregulation. We show that FH-mediated disorder induces substantial levels of complement activation compared to homeostasis, by generating reduced levels of C3 and FB, and to a lesser extent C5, and elevated levels of C3a-desArg, Ba, Bb, C5a-desArg, and fC5b-9. These trends are consistent with clinically observed biomarkers associated with complement-mediated diseases. Furthermore, we introduced therapy states by modeling known drugs of the complement system, a compstatin variant (C3 inhibitor) and eculizumab (a C5 inhibitor). Compstatin demonstrates strong restorative effects for early-stage biomarkers, such as C3a-desArg, FB, Ba, and Bb, and milder restorative effects for late-stage biomarkers, such as C5a-desArg and fC5b-9, whereas eculizumab has strong restorative effects on late-stage biomarkers, and negligible effects on early-stage biomarkers. These results highlight the need for patient-specific therapies that target early complement activation at the C3 level, or late-stage propagation of the terminal cascade at the C5 level, depending on the specific FH-mediated disease and the manifestations of a patient’s genetic profile in complement regulatory function.

scholarly journals Systemic complement activation levels in Stargardt disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0253716
Author(s):  
Patty P. A. Dhooge ◽  
Esmee H. Runhart ◽  
Catherina H. Z. Li ◽  
Corrie M. de Kat Angelino ◽  
Carel B. Hoyng ◽  
...  
Keyword(s):  
Disease Severity ◽  
Complement System ◽  
Complement Activation ◽  
T Test ◽  
Mean Difference ◽  
Age Related Macular Degeneration ◽  
Stargardt Disease ◽  
Blood Draw ◽  
The Complement System ◽  
Age And Sex

Purpose Preclinical research provides evidence for the complement system as a potential common pathway in Stargardt disease (STGD1) and age-related macular degeneration (AMD) leading to retinal pigment epithelium (RPE) loss. However, systemic complement activation has not yet been assessed in STGD1 patients. We conducted a cross-sectional case-control study to assess systemic complement activation in STGD1 patients and its association with disease severity. Methods Systemic concentrations of complement component C3 and its degradation product C3d were compared between 80 STGD1 patients and 80 controls that were frequency matched for age and sex. The C3d/C3 ratio was used as parameter of systemic complement activation. Within the STGD1 cohort, we additionally examined the association between the C3d/C3 ratio, demographic and behavioural factors (age, sex, smoking and BMI), and measures of disease severity (age at onset, visual acuity, and area of atrophy). Results The C3d/C3 ratio did not significantly differ between patients (mean C3d/C3 ratio 3.5±1.4) and controls (mean C3d/C3 ratio 3.6±1.0), mean difference -0.156 (p = 0.804, independent samples t-test). The overall effect size was 8% (95% confidence interval, 3–15%). Elevated C3d/C3 ratios (>8.1) were found in three patients who all had a concomitant inflammatory condition at the time of blood draw. Within the patient cohort, C3 levels were associated with sex (mean difference -134, p = 0.001, independent samples t-test) and BMI (correlation coefficient 0.463, p<0.001, Spearman’s Correlation). Conclusions Systemic complement levels were not elevated in STGD1 patients compared to age and sex matched controls and was not associated with STGD1 severity. Considering the continued absent proof of a systemic contribution of the complement system to RPE loss in STGD1 patients, we hypothesize that complement activation in STGD1 is more likely a local process. In light of upcoming complement-targeted therapies, further studies are needed that measure complement levels in the eye of STGD1 patients.

scholarly journals Time-Dependent Activation of Complement system during Storage of Platelet Product

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4287-4287
Author(s):  
Jian Chen ◽  
Shangbin Yang ◽  
Spero R Cataland ◽  
Haifeng M Wu
Keyword(s):  
Complement System ◽  
Complement Activation ◽  
Research Funding ◽  
Storage Time ◽  
Adverse Reactions ◽  
Alternative Pathway ◽  
Pathway Activation ◽  
The Complement System ◽  
Transfusion Reactions

Abstract Platelet transfusion is known for carrying a high incidence of clinically significant transfusion reactions such as febrile nonhemolytic transfusion reaction. The mechanism responsible for these transfusion-associated adverse events, however, is poorly understood. In this study, we hypothesize that prolonged in vitro storage activates the complement system in the platelet product that in turn causes a high frequency of transfusion reactions. Fresh platelet units obtained from three blood donors were stored on a temperature controlled platelet rotator between 22-24 C°. An aliquot of platelet product was obtained using sterile techniques from each unit on day 2 through day 7. The platelet product from each collection was then immediately centrifuged to obtain platelet poor plasma for the study of complement activation levels. For all study samples, C4d levels were assayed to evaluate the activation of the classical pathway, factor Bb levels were measured to determine the status of the complement alternative pathway, C3a levels were used to examine common pathway activation, and C5a and C5b-9 were assayed for determination of the terminal pathway activation of the complement system. The reference range for each complement factor was determined using citrated plasma from 40 healthy donors. As shown in table 1, both C4d and C3a demonstrated time-dependent increases relevant to storage time. On day 7, C4d and C3a levels were five-fold higher than their baseline levels measured on day 2. In contrast, factor Bb levels remained stable and within the normal range throughout the study. Over a storage span of seven days, the terminal complement factors C5a and C5b-9 were also significantly increased, although not as dramatically as C4d and C3a. Figure 1 illustrates a progressive increase of C3 activation in all three study donors over the time of storage (2-7 days). This report, for the first time, provides strong evidence that substantial complement activation occurs in the platelet products under standard storage conditions. A longer storage time of platelet product in vitro is accompanied by a remarkable elevation of complement activation biomarkers. By examining the pattern of complement profiles in the stored platelets, we further demonstrated that the activation of the classic pathway, rather than alternative pathway, appears to be the driving event that leads up to a level of over-reactivity of the complement system. Given the fact that complement hyperactivation is known to disrupt host homeostasis and cause disease, the adverse reactions seen in platelet recipients is likely related to the infusion of C3a and C5a which are known to be potent inflammatory cytokines. The observations from this study therefore provide a new perspective in understanding the pathophysiology responsible for adverse reactions from platelet transfusions. Further studies will be required to fully evaluate the clinical impact of complement activation in transfused platelet products. Figure 1 Figure 1. Disclosures Cataland: Alexion Corporation: Honoraria, Research Funding, Speakers Bureau. Wu:Alexion Corporation: Honoraria, Research Funding, Speakers Bureau.

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