Immunology and Microbiology › Immunology

Complement system in diseases

Works Count: 40801

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This cluster of papers explores the role of the complement system in immune response, focusing on its involvement in thrombotic microangiopathies, hemolytic uremic syndrome, and inflammatory diseases. It delves into the genetics, regulation, and therapeutic interventions such as Eculizumab for managing complement-related disorders.

Keywords

Complement; Immune; Thrombotic Microangiopathies; Hemolytic Uremic Syndrome; Eculizumab; Innate Immunity; ADAMTS13; Regulation; Inflammatory Diseases; Genetics

Complement

2001-04-12

Mark Walport

Complement at the Interface between Innate and Adaptive ImmunityThe formation of an antibody–antigen complex (immune complex) is the principal way of activating the classical pathway of the complement system. C1q, … Complement at the Interface between Innate and Adaptive ImmunityThe formation of an antibody–antigen complex (immune complex) is the principal way of activating the classical pathway of the complement system. C1q, an integral part of the first component of complement (C1), triggers the activation process when it docks onto antibodies within these immune complexes. In this way, C1q acts to bridge the innate and adaptive immune systems.Complement also has an important role in the induction of antibody responses.62 This was shown first by Pepys, who demonstrated that the formation of antibodies against T-cell–dependent antigens was reduced in animals in . . .

Complement System Part I â€“ Molecular Mechanisms of Activation and Regulation

2015-06-02

Nicolas S. Merle , Sarah E. Church , Véronique Frémeaux‐Bacchi +1 more

Complement is a complex innate immune surveillance system, playing a key role in defense against pathogens and in host homeostasis. The complement system is initiated by conformational changes in recognition … Complement is a complex innate immune surveillance system, playing a key role in defense against pathogens and in host homeostasis. The complement system is initiated by conformational changes in recognition molecular complexes upon sensing danger signals. The subsequent cascade of enzymatic reactions is tightly regulated to assure that complement is activated only at specific locations requiring defense against pathogens, thus avoiding host tissue damage. Here, we discuss the recent advances describing the molecular and structural basis of activation and regulation of the complement pathways and their implication on physiology and pathology. This article will review the mechanisms of activation of alternative, classical, and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins, and the membrane-attack-complex. We will also discuss the importance of structure-function relationships using the example of atypical hemolytic uremic syndrome. Lastly, we will discuss the development and benefits of therapies using complement inhibitors.

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Complement System Part II: Role in Immunity

2015-05-26

Nicolas S. Merle , Rémi Noé , Lise Halbwachs‐Mecarelli +2 more

The complement system has been considered for a long time as a simple lytic system, aimed to kill bacteria infecting the host organism. Nowadays this vision has changed and it … The complement system has been considered for a long time as a simple lytic system, aimed to kill bacteria infecting the host organism. Nowadays this vision has changed and it is well accepted that complement is a complex innate immune surveillance system, playing a key role in host homeostasis, inflammation and in the defense against pathogens. This review discusses recent advances in the understanding of the role of complement in physiology and pathology. It starts with a description of complement contribution to the normal physiology (homeostasis) of a healthy organism, including the silent clearance of apoptotic cells and maintenance of cell survival. In pathology, complement can be a friend or a foe. It acts as a friend in the defense against pathogens, by inducing a direct killing by C5b-9 membrane attack complex by triggering inflammatory responses with the anaphylatoxins C3a and C5a and helps the mounting of an adaptive immune response, involving antigen presenting cells, T- and B- lymphocytes. But it can be also an enemy, when pathogens hijack complement regulators to protect themselves from the immune system. Also examples will be discussed, where inadequate complement activation becomes a disease cause, including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathies (C3G) and systemic lupus erythematosus (SLE). Age related macular degeneration (AMD) and cancer will be described as examples showing that complement contributes to a large variety of diseases, far exceeding the classical examples of diseases associated with complement deficiencies. Finally, we discuss complement as a therapeutic target.

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Guidelines on the Use of Therapeutic Apheresis in Clinical Practice – Evidence‐Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue

2019-06-01

Anand Padmanabhan , Laura Connelly‐Smith , Nicole A. Aqui +7 more

ABSTRACT The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating and categorizing indications for the evidence‐based use of therapeutic … ABSTRACT The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating and categorizing indications for the evidence‐based use of therapeutic apheresis (TA) in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the committee has incorporated systematic review and evidence‐based approaches in the grading and categorization of apheresis indications. This Eighth Edition of the JCA Special Issue continues to maintain this methodology and rigor in order to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Eighth Edition, like its predecessor, continues to apply the category and grading system definitions in fact sheets. The general layout and concept of a fact sheet that was introduced in the Fourth Edition, has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease entity or medical condition. The Eighth Edition comprises 84 fact sheets for relevant diseases and medical conditions, with 157 graded and categorized indications and/or TA modalities. The Eighth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease.

Overview of Complement Activation and Regulation

2013-10-23

Marina Noris , Giuseppe Remuzzi

Complement is an important component of the innate immune system that is crucial for defense from microbial infections and for clearance of immune complexes and injured cells. In normal conditions … Complement is an important component of the innate immune system that is crucial for defense from microbial infections and for clearance of immune complexes and injured cells. In normal conditions complement is tightly controlled by a number of fluid-phase and cell surface proteins to avoid injury to autologous tissues. When complement is hyperactivated, as occurs in autoimmune diseases or in subjects with dysfunctional regulatory proteins, it drives a severe inflammatory response in numerous organs. The kidney appears to be particularly vulnerable to complement-mediated inflammatory injury. Injury may derive from deposition of circulating active complement fragments in glomeruli, but complement locally produced and activated in the kidney also may have a role. Many kidney disorders have been linked to abnormal complement activation, including immune-complex–mediated glomerulonephritis and rare genetic kidney diseases, but also tubulointerstitial injury associated with progressive proteinuric diseases or ischemia-reperfusion.

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Structure of von Willebrand Factor-cleaving Protease (ADAMTS13), a Metalloprotease Involved in Thrombotic Thrombocytopenic Purpura

2001-11-01

X. Long Zheng , Dominic W. Chung , Thomas K. Τakayama +3 more

Thrombotic thrombocytopenic purpura is associated with acquired or congenital deficiency of a plasma von Willebrand factor-cleaving protease (VWFCP). Based on partial amino acid sequence, VWFCP was identified recently as a … Thrombotic thrombocytopenic purpura is associated with acquired or congenital deficiency of a plasma von Willebrand factor-cleaving protease (VWFCP). Based on partial amino acid sequence, VWFCP was identified recently as a new member of the ADAMTS family of metalloproteases and designated ADAMTS13. The 4.6-kilobase pair cDNA sequence for VWFCP has now been determined. By Northern blotting, full-length VWFCP mRNA was detected only in liver. VWFCP consists of 1427 amino acid residues and has a signal peptide, a short propeptide terminating in the sequence RQRR, a reprolysin-like metalloprotease domain, a disintegrin-like domain, a thrombospondin-1 repeat, a Cys-rich domain, an ADAMTS spacer, seven additional thrombospondin-1 repeats, and two CUB domains. VWFCP apparently is made as a zymogen that requires proteolytic activation, possibly by furin intracellularly. Sites for Zn2+ and Ca2+ ions are conserved in the protease domain. The Cys-rich domain contains an RGDS sequence that could mediate integrin-dependent binding to platelets or other cells. Alternative splicing gives rise to at least seven potential variants that truncate the protein at different positions after the protease domain. Alternative splicing may have functional significance, producing proteins with distinct abilities to interact with cofactors, connective tissue, platelets, and von Willebrand factor.

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Improved Survival in Thrombotic Thrombocytopenic Purpura–Hemolytic Uremic Syndrome

1991-08-08

William R. Bell , Hayden G. Braine , Paul M. Ness +1 more

Thrombotic thrombocytopenic purpura—hemolytic uremic syndrome (TTP-HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever, central nervous system abnormalities, and renal dysfunction. In early reports the mortality approached 100 percent. A … Thrombotic thrombocytopenic purpura—hemolytic uremic syndrome (TTP-HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever, central nervous system abnormalities, and renal dysfunction. In early reports the mortality approached 100 percent. A treatment protocol was introduced in 1979 for patients admitted to Johns Hopkins Hospital with the diagnosis of TTP-HUS. Treatment regimens included 200 mg of prednisone a day, for patients with minimal symptoms and no central nervous system symptoms, and prednisone plus plasma exchange, for patients with rapid clinical deterioration who did not improve after 48 hours of prednisone alone and for patients presenting with central nervous system symptoms and rapidly declining hematocrit values and platelet counts.

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The complement system in regulation of adaptive immunity

2004-09-28

Michael C. Carroll

Syndromes of Thrombotic Microangiopathy

2014-08-13

James N. George , Carla Nester

This review article covers the diverse pathophysiological pathways that can lead to microangiopathic hemolytic anemia and a procoagulant state with or without damage to the kidneys and other organs. This review article covers the diverse pathophysiological pathways that can lead to microangiopathic hemolytic anemia and a procoagulant state with or without damage to the kidneys and other organs.

Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria

2007-11-01

Russell P. Rother , Scott A. Rollins , Christopher F. Mojcik +2 more

Complement and its role in innate and adaptive immune responses

2009-12-15

Jason Dunkelberger , Wen‐Chao Song

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Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies

2012-05-25

Marie Scully , Beverley J. Hunt , Sylvia Benjamin +5 more

The guideline group was selected to be representative of UK-based medical experts. MEDLINE and EMBASE were searched systematically for publications in English, using the keywords: thrombotic thrombocytopenia purpura (TTP), ADAMTS13, … The guideline group was selected to be representative of UK-based medical experts. MEDLINE and EMBASE were searched systematically for publications in English, using the keywords: thrombotic thrombocytopenia purpura (TTP), ADAMTS13, plasma exchange (PEX) and relevant key words related to the subsections of this guideline. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the BCSH. The guideline was then reviewed by a sounding board of British haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The 'GRADE' system was used to quote levels and grades of evidence, details of which can be found at http://www.bcshguidelines.com. The objective of this guideline is to provide healthcare professionals with clear, up-to-date, and practical guidance on the management of TTP and related thrombotic microangiopathies, defined by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and small vessel thrombosis. Thrombotic thrombocytopenic purpura (TTP) is rare, with a reported incidence of six cases per million per year in the UK (Scully et al, 2008). It is an important diagnosis to make because the untreated mortality is 90%, which can be reduced with the prompt delivery of plasma exchange (PEX). Early death still occurs: approximately half of the deaths in the regional UK registry occurred within 24 h of presentation, primarily in women (Scully et al, 2008). In the last 15 years there has been a marked increase in the understanding of the pathogenesis of TTP. It is now recognized that congenital and acute acquired TTP are due to a deficiency of von Willebrand factor (VWF) cleaving protein, also known as ADAMTS1, (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 – von Willebrand factor cleaving protein) (Fujikawa et al, 2001; Levy et al, 2001). In the absence of ADAMTS13, ultra large multimers of VWF (ULVWF) released from endothelium are not cleaved appropriately, and cause spontaneous platelet aggregates in conditions of high shear, such as in the microvasculature of the brain, heart and kidneys. Congenital TTP is due to an inherited deficiency of ADAMTS13, but acquired immune TTP is due to the reduction of ADAMTS13 by autoantibodies directed against ADAMTS13 (Furlan et al, 1998a; Tsai & Lian, 1998). Other clinical forms of thrombotic microangiopathy (TMA) occur in the absence of severe deficiency. Diagnosis can be difficult, as there is clinical overlap with haemolytic uraemic syndrome (HUS), autoimmune disease and a spectrum of pregnancy-related problems. Thrombotic thrombocytopenic purpura was originally characterized by a pentad of thrombocytopenia, MAHA, fluctuating neurological signs, renal impairment and fever, often with insidious onset. However, TTP can present without the full pentad; up to 35% of patients do not have neurological signs at presentation and renal abnormalities and fever are not prominent features. The revised diagnostic criteria state that TTP must be considered in the presence of thrombocytopenia and MAHA alone (Galbusera et al, 2006). This can result in an increased referral of other TMAs (Table 1). TTP remains a diagnosis based on clinical history, examination of the patient and the blood film. ADAMTS 13 assays help to confirm the diagnosis and monitor the course of the disease and possible need for additional treatments. Presenting symptoms and signs are summarized in Table 2 and reflect widespread multi organ thromboses. Neurological impairment has multiple presentations including headache, altered personality, reduced cognition, transient ischaemic attacks, fits and fluctuating levels of consciousness including coma; the latter is a poor prognostic sign. Acute renal failure requiring haemodialysis is rare in TTP and more indicative of HUS (Coppo et al, 2006; Scully et al, 2008). Additional ischaemic complications may be seen, such as abdominal pain due to intestinal ischaemia. Consumption of platelets in platelet-rich thrombi results in thrombocytopenia. The median platelet count is typically 10–30 × 109/l at presentation (Dervenoulas et al, 2000; Vesely et al, 2003; Coppo et al, 2006; Tuncer et al, 2007; Scully et al, 2008). Mechanical fragmentation of erythrocytes during flow through partially occluded, high shear small vessels causes a MAHA. Median haemoglobin levels on admission are typically 80–100 g/l, with schistocytes in the film, low haptoglobin levels and raised reticulocyte counts due to haemolysis. The direct Coombs test is negative. The combination of haemolysis and tissue ischaemia produces elevated lactate dehydrogenase (LDH) values. The clotting screen (prothrombin time, activated partial thromboplastin time and fibrinogen) is usually normal. A virology screen pre-treatment is necessary to exclude human immunodeficency virus (HIV) and other viral-associated TTP, and as a baseline prior to plasma exposure. Troponin T levels are raised in 50% of acute idiopathic TTP cases (Hughes et al, 2009), highlighting that cardiac involvement is common. Raised troponin levels are a sinister finding, for coronary artery occlusion is a common mode of early death. The incidence of symptomatic heart failure is increased in patients who have been given a recent platelet transfusion (Gami et al, 2005) (Table 3). Blood must be taken prior to treatment to assess baseline ADAMTS13 activity. Severely reduced ADAMTS13 activity (<5%) ± the presence of an inhibitor or IgG antibodies, confirms the diagnosis (Peyvandi et al, 2004; Coppo et al, 2006; Ferrari et al, 2007; Scully et al, 2007a). Decreased ADAMTS13 activity (<40% but >5%) has been reported in a wide variety of non-TTP conditions such as uraemia, inflammatory states, post-operatively and during pregnancy (Loof et al, 2001; Mannucci et al, 2001; Moore et al, 2001). The specificity of severe ADAMTS13 deficiency (<5%) in distinguishing acute TTP from HUS is 90% (Bianchi et al, 2002; Zheng et al, 2004) ADAMTS13 assays currently available include assays of activity, antigen and neutralizing or non-neutralizing anti-ADAMTS13 autoantibodies. Functional assays measuring ADAMTS13 activity are based on the failure of the patient plasma to degrade VWF multimers or synthetic VWF peptides. Inhibitory autoantibodies can be titrated in vitro using classical mixing studies and non-neutralizing antibodies can be detected by Western blotting or enzyme-linked immunosorbent assays (Peyvandi et al, 2010). 1 The diagnosis of TTP should be treated as a medical emergency (1A). 2 The initial diagnosis of TTP should be made on clinical history, examination and routine laboratory parameters of the patient, including blood film review (1A). 3 In view of the high risk of preventable, early deaths in TTP, treatment with PEX should be initiated as soon as possible, preferably within 4–8 h, regardless of the time of day at presentation, if a patient presents with a MAHA and thrombocytopenia in the absence of any other identifiable clinical cause (1B). 4 Serological tests for HIV, hepatitis B virus and hepatitis C virus, autoantibody screen and when appropriate, a pregnancy test, should be performed at presentation (1A). 5 Pre-treatment samples should be obtained to measure ADAMTS13 activity levels and to detect anti-ADAMTS13 antibodies. Measurement of ADAMTS 13 antigen levels is also useful in congenital TTP cases (1B). Congenital TTP is a rare disorder, with over 100 patients described worldwide, but this is likely to be an underestimate. It has a varied phenotype and can present at any age. As a general rule, those with more severe phenotypes present early: 1 Neonates typically have severe neonatal jaundice. Blood film examination may show schistocytes together with red cell anisocytosis. (Scully et al, 2006a). 2 More frequently, the diagnosis is made later in infancy or childhood (Schiff et al, 2004), typically with thrombocytopenia, MAHA, jaundice and elevated LDH, although some children may only have an isolated thrombocytopenia. Neurological symptoms, such as hemiparesis, hemiplegia or seizures, occur in 35% of cases (Loirat et al, 2006). 3 Patients may present in adulthood. In women, pregnancy is a common precipitant and is associated with a significant neonatal morbidity and mortality (Fujimura et al, 2009). Rarely 'late-onset phenotype' cases may not develop symptoms until their 50s and 60s with isolated cerebral events or renal disease ((Fujimura et al, 2011). Asymptomatic male cases have been reported, usually detected because they have affected siblings. Patients with congenital TTP have persistently low levels of ADAMTS13, but they can be asymptomatic until a further precipitating event results in a frank TTP episode. Events include febrile episodes, infections, vaccinations, excess alcohol intake and pregnancy (Furlan et al, 1997, 1998b; Schneppenheim et al, 2003). Congenital TTP has been missed in the past, because the diagnosis has not been considered, or diagnosed as idiopathic thrombocytopenic purpura or 'atypical' HUS (Veyradier et al, 2003), illustrating the importance of consideration of the diagnosis, review of the blood film and measurement of ADAMTS13 . The diagnosis of congenital TTP is dependent on detecting ADAMTS13 activity <5%, in the absence of antibodies to ADAMTS13. In the last few years molecular diagnosis has been used to confirm the diagnosis, and either a homozygous or compound heterozygote defect in ADAMTS13 is found. Testing of siblings and other first-degree relatives at risk should be considered. 1 Congenital TTP should be considered in neonates presenting with severe jaundice. Presentation may also occur in childhood or as an adult (1A). 2 The diagnosis of congenital TTP should be considered in children and adults with unexplained thrombocytopenia (1B). 3 The diagnosis of congenital TTP is confirmed by ADAMTS13 activity <5%, absence of antibody and confirmation of homozygous or compound heterozygous defects of the ADAMTS13 gene (1A). Acute idiopathic TTP is the most common form of TTP. It is an autoimmune disease characterized by antibodies, usually IgG, directed against ADAMTS13. The incidence is four to six cases per million of the population per year in the United States (Miller et al, 2004; Terrell et al, 2005) and six cases per million per year in the UK (Scully et al, 2008). Thrombotic thrombocytopenia purpura may be the initial presenting feature of HIV disease or in those with low CD4 counts following non- compliance with antiviral treatment (Ucar et al, 1994; Gervasoni et al, 2002). Remission is dependent upon improving the immune status of the patient, for stopping highly active anti retroviral therapy (HAART) can result in acute TTP relapse (Miller et al, 2005), but continued use of HAART usually prevents further relapses. TTP in HIV-positive individuals may be associated with the presence of severe ADAMTS13 deficiency and anti-ADAMTS13 antibodies. Those with severe ADAMTS13 deficiency (<5%) have fewer acquired immunodeficiency syndrome-related complications and higher CD4+ T cell counts, compared to HIV-TTP with ADAMTS13 levels >5%, who have an increased mortality (Malak et al, 2008). Pregnancy can be the initiating event for approximately 5–25% of TTP cases (Ridolfi & Bell, 1981; Vesely et al, 2004; Scully et al, 2008), which are late onset adult congenital TTP or acute idiopathic TTP. Differentiating TTP from the more common pregnancy-related TMAs, such as pre-eclampsia, HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) and HUS is difficult, especially if TTP presents post-partum (Table 4). Thrombosis occurs in the placenta in untreated TTP pregnancies and results in fetal growth restriction, intrauterine fetal death and pre eclampsia. There is a continued risk of relapse during subsequent pregnancies. Women with normal levels of ADAMTS13 pre-pregnancy have a lower risk of relapse (Ducloy-Bouthors et al, 2003; Scully et al, 2006b). Drugs appear to be responsible for <15% of all TTP cases (Vesely et al, 2003; Scully et al, 2008). Quinine can cause an antibody-mediated idiosyncratic disorder, typically in females. Thienopyridine-associated TTP is well recognized in association with ticlodipine with an incidence of one per 1600–5000 patients treated, but it has rarely been described with clopidogrel and there is uncertainty whether there is a true association (Zakarija et al, 2009). Simvastatin (Koduri, 1998; McCarthy et al, 1998; Vesely et al, 2003; Sundram et al, 2004; Scully et al, 2008), trimethoprim (Martin et al, 2007) and peglyated interferon used to treat hepatitis C (Deutsch et al, 2007; Serrano et al, 2007; Sallee et al, 2008) have been anecdotally associated with antibody-positive TTP. There are anecdotal reports of acquired TTP associated with oestrogen-containing hormonal preparations such as the combined oral contraceptive pill (COCP) and hormone replacement therapy (Scully et al, 2008). Some chemotherapy agents, such as gemcitabine, bleomycin and mitomycin–C can cause HUS but not TTP. 1 Medications associated with precipitation of TTP include quinine and oestrogen-containing medications, which should be avoided to prevent relapse in patients with a previous episode of TTP (2C). 2 Women with previous TTP should be offered non-oestrogen containing contraception (1C). Transplant-associated microangiopathy (TAM) is a MAHA and thrombocytopenia that occurs after bone marrow transplantation. It may reflect endothelial toxicity associated with chemotherapy, infections, immunosuppressives, such as ciclosporin A (CSA), and graft-versus-host disease (GVHD). TAM has important differences from de novo TTP, namely, absence of ADAMTS13 deficiency; rare neurological symptoms; a poor response to PEX and lack of evidence of systemic microthrombi formation (Ruutu et al, 2007). Thrombotic microangiopathy occurs in association with a variety of malignancies, especially adenocarcinomas, (Kwaan & Gordon, 2001). Presentation may be either at an early stage of cancer or associated with disseminated disease. ADAMTS13 activity is not significantly reduced in these patients (Fontana et al, 2001). Microangiopathic haemolytic anaemia has recently been reported in association with acute pancreatitis, sometimes a number of days after resolution of pancreatitis. ADAMTS13 activity was only moderately reduced and did not correlate with the severity of TTP or pancreatitis. All patients were successfully treated with PEX and corticosteroids (McDonald et al, 2009). Diarrhoeapositive (D+) HUS, associated typically with verotoxin-induced bloody diarrhoea, is treated with supportive care, which in some cases includes renal dialysis. Diarrhoea negative (D−) HUS, not typically associated with bloody diarrhoea, but may sometimes be associated with multisystem symptoms, similar to TTP, should be urgently treated with PEX (Kim et al, 2011). The primary differentiating factor between HUS and TTP is the presence of oliguric/anuric renal impairment/failure in HUS. Increasingly, the role of complement defects in D−, atypical HUS is being defined (Kavanagh & Goodship, 2010) and use of the complement inhibitor, eculizumab, appears successful in these cases (Al-Akash et al, 2011; Riedl et al, 2011), but may also have a role in severe D+HUS (Lapeyraque et al, 2011). A summary of the treatment protocol is shown in Fig 1. Daily PEX, preferably with spun apheresis, is the mainstay of treatment and has reduced mortality rates, from over 90% to 10–20%. It allows removal of autoantibody, and repletes ADAMTS13. Delay in initiation of PEX leads to preventable early mortality (Pereira et al, 1995). Although PEX remains the treatment of choice, large volume plasma infusions are indicated if there is to be a delay in arranging PEX. PEX has been shown to be superior to plasma infusion at the end of the first treatment cycle and at 6 months (response rates 47% and 78% vs. 25% and 49%) (Rock et al, 1991). The duration of PEX and the number of procedures required to achieve remission is highly variable, but is longer in antibody-mediated TTP (Coppo et al, 2006). An optimal regimen has not been determined. In the Canadian apheresis trial, 1·5× plasma volume (PV) exchange was performed on the first 3 d followed by 1·0 PV exchange thereafter (Rock et al, 1991). More intensive exchange, such as twice daily PEX, may be required in resistant cases especially if there is new symptomatology, such as neurological or cardiac events. The benefit of an intensified PEX regimen has been difficult to document as other treatments are often initiated or intensified simultaneously (Nguyen et al, 2008). Daily exchanges should continue for a minimum of 2 d after complete remission, defined as normal platelet count (>150× 109/l). Tapering (reducing frequency and/or volume of PEX) has not been shown to reduce relapse rates (Bandarenko & Brecher, 1998). Cryosupernatant is at least as efficacious as standard fresh frozen plasma (FFP) (Rock et al, 1996; Brunskill et al, 2007). The UK Department of Health recommends the use of solvent/detergent-treated (S/D) plasma (O'Shaughnessy, 2006) in TTP patients to reduce the risk of transfusion-transmitted infection and adverse immune responses (Scully et al, 2007b). S/D plasma contains reduced levels of protein S, but an increased thrombotic rate has not been reported in cases where thromboprophylaxis with low molecular weight heparin (LMWH) and low dose aspirin was used routinely once the platelet count was >50 × 109/l (Scully et al, 2007b). ADAMTS13 activity is present in normal amounts in FFP, S/D plasma, methylene blue-treated FFP (MB-FFP) and psoralen-treated FFP (Yarranton et al, 2005). In the UK, single donor MB-FFP is the recommended plasma for use in all indications in those born after 1st January 1996 to minimize the risk of prion transmission (O'Shaughnessy et al, 2004). However MB-FFP has been associated with increased numbers of PEX and longer hospital stay in TTP (de la Rubia et al, 2001; Rio-Garma et al, 2008). A prospective study using psoralen–FFP compared to standard FFP showed equal efficacy and safety (Mintz et al, 2006). Plasma-related adverse events, such as allergic reactions, anaphylaxis and central venous catheter thrombosis, appeared to be more frequent prior to the use of S/D plasma (Scully et al, 2007b). 1 PEX should be started with 1·5 PV exchanges, using S/D plasma in all age groups and reassessed daily (1B). 2 The volume of exchange can be reduced to 1·0 PV when the clinical condition and laboratory test results are stabilizing (2C). 3 Intensification in frequency and or volume of PEX procedures should be considered in life-threatening cases (2B). 4 Daily PEX should continue for a minimum of 2 d after platelet count has been >150 × 10 9 /l and then stopped (2B). Plasma-derived or recombinant concentrates of ADAMTS13 are not yet available. Therefore current treatment consists of plasma infusion/exchange or the use of a virally-inactivated intermediate purity factor VIII concentrate containing ADAMTS13, such as 8Y (BPL; BioProducts Laboratory, Elstree, Herts) (Allford et al, 2000), which has a small infusion volume and can be given in the outpatient or home setting. 15–30 u/kg of 8Y has been used with reported success, although there is no guaranteed constant quantity of ADAMTS13 in such concentrates. Antibodies to ADAMTS 13 have not been detected following the use of 8Y. Despite that ADAMTS13 has a half-life of only 2–3 d (Furlan et al, 1999; Suzuki et al, 2004), the clinical effect of infusions of plasma (10–15 ml/kg) or BPL 8Y are such that infusions are required only every 10–20 d, to achieve a normal platelet and haemoglobin level. Ultimately the frequency of treatment depends on the patient's phenotype. Some require regular 'prophylactic' therapy to keep the platelet count normal and avoid relapses at times of infection and other stress situations. The phenotypically mildly affected, who have a normal platelet count most of the time, only require occasional treatment. 1 S/D plasma infusion or intermediate purity Factor VIII (eg BPL 8Y) should be used to treat congenital TTP (1C). 2 Treatment regimens for congenital TTP should be individualized according to the patient's phenotype (1A). Diagnosis of pregnancy-associated TTP is especially difficult if it develops postnatally. In any mother with a TMA, and uncertainty as to the diagnosis (and recognizing that pre-eclampsia and HELLP can present in the postnatal period), PEX should be considered. If TTP develops in the first trimester, regular PEX may allow continuation of pregnancy with delivery of a live infant (Ambrose et al, 1985; Rozdzinski et al, 1992; Mokrzycki et al, 1995; Scully et al, 2006b). Delivery is the definitive treatment of choice for pregnancy-associated TMA, although delivery does not guarantee remission of TTP. Pre-treatment ADAMTS13 assays will distinguish congenital and acquired TTP from other pregnancy-associated TMAs. In pre-eclampsia and HELLP syndrome ADAMTS13 activity is reduced (median 31% range 12–43%) but antibodies to ADAMTS13 are not found. Close liaison with an obstetrician with expertise in thrombosis and fetomaternal medicine is required. Serial fetal monitoring with uterine artery dopplers should be used to assess if there is adequate fetal growth and to assess placental blood flow. Plasma infusions alone may be sufficient in mothers with congenital TTP. However, at delivery PEX may be required to ensure adequate levels of ADAMTS13. The ideal frequency of plasma replacement during pregnancy is unknown. In acquired TTP, it is difficult to predict future relapse in pregnancy. A reduction in ADAMTS13 activity (<10%) at the start of pregnancy may require elective therapy to prevent microvascular thrombosis during pregnancy. Rituximab has been used in pregnancy in autoimmune disorders and lymphoma (Chakravarty et al, 2011). 1 If a TMA cannot be fully explained by a non-TTP pregnancy-related TMA, then the diagnosis of TTP must be considered and PEX should be started (2B). 2 Mothers with congenital TTP should attend a specialist centre and receive ADAMTS13 supplementation regularly throughout pregnancy and the post-partum period (1A). 3 Close liaison with an obstetrician with a special interest in feto-maternal medicine is required in mothers with TTP (1A). 4 In mothers with acquired TTP, ADAMTS13 activity should be monitored throughout pregnancy to help predict the need for adjuvant therapy and outcome (1B). 5 Pre-conceptual counselling is advised for subsequent pregnancies and women of child bearing age should be counselled about potential risks of pregnancy and COCP (2B). In those with severe ADAMTS13 deficiency, there is normalization in ADAMTS13 activity, as the CD4 count recovers and HIV viral load falls, after treatment with HAART and PEX. Occasionally, further therapy is required, for example with rituximab or steroids, which do not cause a significant increase in infectious complications (Hart et al, 2011). Practically, HAART should be given immediately after PEX to allow for maximal time for absorption. 1 If a patient with TTP is found to have HIV infection then viral load should be measured and an HIV physician should be closely involved in management (1A). 2 TTP should be considered in an HIV-positive individual with a MAHA and thrombocytopenia (1A). 3 PEX in conjunction with HAART (triple or quadruple therapy) should be started as soon as the diagnosis of HIV-associated TTP is made (1B). 3 HAART should be given immediately after PEX therapy to maximize time for absorption (1A). 4 HAART should be continued after remission to prevent further relapse (1B). 5 In resistant HIV-related TTP, rituximab could be considered (2B). Management is difficult, as stopping CSA or switching to another immunosuppressive, such as tacrolimus, may worsen GVHD. No benefit has been shown with PEX; indeed in a retrospective review it was associated with an increased mortality (George et al, 2004). There is anecdotal experience of successful use of defibrotide (Bayik et al, 1993; Pogliani et al, 2000). Plasma exchange has no benefit (Werner et al, 2007). The treatment of the underlying cancer is the mainstay of therapy. 1 PEX is not indicated in the management of malignancy and bone marrow transplant-associated TMA (1A). 2 In cancer associated TMA, further treatment for the underlying cancer should be considered (1A). Steroids are widely used in combination with PEX in the initial treatment of acute immune TTP. Higher dose pulsed steroids have shown to be associated with an improved patient outcome and usually have minimal side effects (Balduini et al, 2010). However there is no randomized controlled trial addressing whether a combination of PEX and corticosteroids is superior to PEX alone. Intravenous daily methylprednisolone (e.g. 1 g/d for three consecutive days – adult dose) or high dose oral prednisolone (e.g. 1 mg/kg/d) should be considered (1B). Prospective studies have shown that rituximab is effective and safe in immune TTP, when patients failed to respond to daily PEX and methylprednisolone and in relapsed acute idiopathic TTP (Fakhouri et al, 2005; Scully et al, 2007a). Typically, 375 mg/m2 has been used weekly for 4 weeks. Patients receiving rituximab showed reductions in anti-ADAMTS13 IgG antibody levels and increased ADAMTS13 activity (Scully et al, 2007a). The risk of relapse appears to be reduced with rituximab use (Heidel et al, 2007; Scully et al, 2011). Ideally PEX should be withheld for at least 4 h after completing a rituximab infusion (Hull & Eichbaum, 2006; Scully et al, 2007a). Giving rituximab more frequently than weekly e.g. every 3–4 d, may overcome removal during PEX (McDonald et al, 2010). There is no evidence of increased infection risk with rituximab in TTP patients. A recent Phase II UK study has shown benefit in using rituximab as a first line therapy at presentation of TTP (Scully et al, 2011). 1 In acute idiopathic TTP with neurological/cardiac pathology, which are associated with a high mortality, rituximab should be considered on admission, in conjunction with PEX and steroids (1B). 2 Patients with refractory or relapsing immune-mediated TTP should be offered rituximab (1B). Ciclosporin A was used successfully in one patient with relapsing TTP (Pasquale et al, 1998), but further relapses occurred after cessation of therapy. In a clinical trial of PEX with either steroids or CSA (2–3 mg/kg twice daily), initial remission occurred in 89%, 14% subsequently relapsed while on CSA and there was a 33% relapse after stopping 6 months of CSA treatment. None of the eight CSA-treated patients suffered a relapse in the first 30 d compared with 6/10 of the steroid-treated patients. Overall 16/18 patients achieved a remission with an increase in ADAMTS13 activity and decrease in antibodies to ADAMTS13 (Cataland et al, 2007a,b). In patients with renal impairment, tacrolimus is an alternative therapy, but side effects may preclude medium and long-term use. CSA may be considered as second line therapy in patients with acute or chronic relapsing acquired TTP (1C). With the demonstrated utility and relative safety of rituximab, other drugs previously used for refractory and remitting cases, such as vincristine and cyclophosphamide, whose use is associated with severe side effects, and whose efficacy has been documented in small numbers of patients (Mazzei et al, 1998; Bohm et al, 2005), are not recommended except as part of a clinical trial. The mortality of open splenectomy in acute TTP was reported to be approximately 40% (Rutkow, 1978). In a retrospective case series of 33 patients splenectomized for acute refractory and relapsed disease, the 10-year relapse-free survival was 70% (Bohm et al, 2005; Kappers-Klunne et al, 2005). Splenectomy may rarely be considered in the non-acute period of immune-mediated TTP but has limited proven benefit (2C). The Italian Co-operative Group randomized 72 TTP patients to PEX and steroids with and without aspirin and dipyramidole (Bobbio-Pallavicini et al, 1997). There was no difference in response rate or excessive haemorrhage and a non-significant decreased rate of early death in the first 15 d in the antiplatelet-treated group (13·5% vs. 2·8%) (Bobbio-Pallavicini et al, 1997). 1 The clinical efficacy of antiplatelet agents in TTP is unproven but they are relatively safe (1B). 2 Low dose aspirin (75 mg OD) may be given during platelet recovery (platelet count >50 × 10 9 /l) (2B). Red cell transfusion and folic acid supplementation are required during active haemolysis. It has been shown that transfusion in the critically ill is safe using a transfusion trigger of 70 g/l. However this trigger was not applicable to those with cardiac disease (Hebert et al, 1999) and, as cardiac microvascular thrombosis is a feature of TTP, a higher haemoglobin level may be required in those with evidence of cardiac involvement and acute haemolysis. Due to the risk of precipitating further thrombotic events, platelet transfusions are contra-indicated unless there is life-threatening haemorrhage. The risk of venous thromboembolism has never been formally quantified in acute TTP but is likely to be increased due to immobility and acute illness. Therefore routine LMWH thromboprophylaxis should be given once the platelet count has recovered to >50 × 109/l (Yarranton et al, 2003). Hepatitis B vaccination should be considered in TTP, once a platelet threshold of 50 × 109/l has been achieved, but studies of efficacy are required in the face of continued PEX and/or immunosuppression with rituximab. 1 Red cell transfusion should be administered according to clinical need especially if there is cardiac involvement (1A). 2 Folate supplementation is required during active haemolysis (1A). 3 Platelet transfusions are contra-indicated in TTP unless there is life-threatening haemorrhage (1A). 4 Thromboprophylaxis with LMWH is recommended once platelet count has reached >50 × 10 9 /l (1B). There is a subgroup of patients who present with TTP who subsequently show a slow or incomplete response to PEX ± corticosteroids. Refractory disease was previously arbitrarily defined as persistent thrombocytopenia or LDH elevation after a total of seven daily PEX procedures. LDH is not however, a reliable marker of disease activity. We have therefore redefined refractory disease as progression of clinical symptoms or persistent thrombocytopenia despite PEX. Intensification of PEX with the introduction of 12-hourly or double PV exchanges and the addition of further steroids have provided some benefit (Shumak et al, 1995; Bobbio-Pallavicini et al, 1997; Bandarenko & Brecher, 1998; Kahwash & Lockwood, 2004; Nguyen et al, 2008). Rituximab is the current agent of choice in refractory disease (Scully et al, 2007a). Increased frequency of PEX and addition of rituximab can be considered in refractory TTP (1B). Relapse is defined as an episode of acute TTP more than 30 d after remission, and occurs in 20–50% of cases (Shumak et al, 1995; Bandarenko & Brecher, 1998; Willis & Bandarenko, 2005). The Canadian Apheresis Group estimated that over a 10-year follow up, 36% of patients would relapse (Shumak et al, 1995). Patients with ADAMTS13 activity <10% or an anti-ADAMTS13 antibody in remission had a 3-fold increase in relapse over 1 year (Peyvandi et al, 2008). In a further study, if ADAMTS13 was <5% in remission, relapse occurred in 38·5%, but if ADAMTS13 activity was >15%, only 5% relapsed (Ferrari et al, 2007). The use of rituximab in an acute epsiode reduces and delays the incidence of relapse (Scully et al, 2011). Prior to discharge all patients should be counselled regarding the risk and the symptoms and signs of relapse. In patients who have had previous TTP episodes and where a reduction of ADAMTS 13 activity from detectable levels to <5% is demonstrated, elective rituximab therapy has been successfully used, with normalization of ADAMTS 13 activity (Scully et al, 2007a; Bresin et al, 2009). Patients require long-term follow up with ADAMTS 13 assay monitoring. 1 Increased PEX and/or rituximab therapy are the agents of choice in relapsing disease (1B). 2 Patients should be counselled about symptoms, signs and risk of relapse before discharge with verbal and written information (1A). 3 In patients with a documented reduction of ADAMTS 13 activity to <5%, elective therapy with rituximab can be considered (1B). Haemolytic uraemic syndrome is characterized by MAHA, thrombocytopenia and acute renal failure. It maybe associated with extensive multi-organ involvement, e.g. neurological, hepatic complications, and cardiac problems and therefore diagnostic overlap with TTP can occur. It is important to differentiate between D + HUS, atypical HUS and TTP because the prognosis and management are different (Table 5). The reader is referred to (Ariceta et al, 2009) and (Taylor et al, 2010) for further guidance in children and adults, respectively. TTP and other TMAs remain diagnostically difficult. The current challenge is to ensure that haematologists, physicians, obstetricians and paediatricians are aware of the need to treat acute TTP as a medical emergency to prevent unnecessary early mortality. The development of new drugs and recombinant proteins, trialled in the developing networks should lead to better treatments in the future. While the advice and information in these guidelines is believed to be true and accurate at the time of going to press, neither the authors, the British Society for Haematology nor the publishers accept any legal responsibility for the content of these guidelines . In 2003, the British Society for Haematology (BCSH) published the first evidence-based guidelines for the diagnosis and management of thrombotic microangiopathies (Allford et al, 2003). We have revised these based on new evidence available between 2003 and 2011. Separate guidelines for atypical haemolytic-uraemic syndrome (HUS) (Taylor et al, 2010) and diarrhoea-positive HUS (Ariceta et al, 2009) are now available, so these sections have been reduced. Dr Michael J Desborough, Academic Clinical Fellow, Oxford Deanery UK for review of Fig 1 and Ms Lucy MacKillop, Obstetric Physician, Oxford Universities Hospital Trust for review of Table 4. The Haemostasis Research unit, UCL has received an unrestricted educational grant from Octapharma, UK.

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NEW CYTOPLASMIC COMPONENTS IN ARTERIAL ENDOTHELIA

1964-10-01

Ewald R. Weibel , George E. Palade

A hitherto unknown rod-shaped cytoplasmic component which consists of a bundle of fine tubules, enveloped by a tightly fitted membrane, was regularly found in endothelial cells of small arteries in … A hitherto unknown rod-shaped cytoplasmic component which consists of a bundle of fine tubules, enveloped by a tightly fitted membrane, was regularly found in endothelial cells of small arteries in various organs in rat and man. It is about 0.1 micro thick, measures up to 3 micro in length, and contains several small tubules, approximately 150 A thick, embedded in a dense matrix, and disposed parallel to the long axis of the rod. In some of these cells, the cisternae of the endoplasmic reticulum are greatly distended by the accumulation of a dense, finely granular material. The nature and significance of these cytoplasmic components are yet unknown.

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The Complement Inhibitor Eculizumab in Paroxysmal Nocturnal Hemoglobinuria

2006-09-21

Peter Hillmen , Neal S. Young , Jörg Schubert +7 more

We tested the safety and efficacy of eculizumab, a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation, in patients with paroxysmal nocturnal hemoglobinuria (PNH). We tested the safety and efficacy of eculizumab, a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation, in patients with paroxysmal nocturnal hemoglobinuria (PNH).

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Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat.

1986-06-01

Sharon Anderson , Helmut G. Rennke , Barry M. Brenner

Micropuncture and morphologic studies were performed in six groups of male Munich-Wistar rats after removal of the right kidney and segmental infarction of two-thirds of the left kidney. Groups 1 … Micropuncture and morphologic studies were performed in six groups of male Munich-Wistar rats after removal of the right kidney and segmental infarction of two-thirds of the left kidney. Groups 1 and 4 received no specific therapy. Groups 2 and 5 were treated with the angiotensin I-converting enzyme inhibitor, enalapril, 50 mg/liter, in the drinking water. Groups 3 and 6 were treated with reserpine (5 mg/liter), hydralazine (80 mg/liter), and hydrochlorothiazide (25 mg/liter). All rats were fed standard chow. Groups 1-3 underwent micropuncture study 4 wk after renal ablation. Untreated group 1 rats exhibited systemic hypertension and elevation of the single nephron glomerular filtration rate (SNGFR) due to high average values for the mean glomerular transcapillary hydraulic pressure gradient (delta P) and glomerular plasma flow rate (QA). In group 2 rats, treatment with enalapril prevented systemic hypertension and maintained delta P at near-normal levels without significant reduction in SNGFR and QA. In contrast, triple drug therapy normalized systemic hypertension, but failed to lower delta P in group 3 rats. Groups 4-6 were followed for 12 wk after renal ablation. Untreated group 4 rats demonstrated continuous systemic hypertension, progressive proteinuria, and glomerular structural lesions, including mesangial expansion and frequent areas of segmental sclerosis. In group 5 rats, treatment with enalapril maintained systemic blood pressure at normal levels over the 12-wk period and dramatically limited the development of proteinuria and glomerular lesions. Despite equivalent systemic blood pressure control in group 6 rats, failure of triple drug therapy to control glomerular hypertension was associated with progressive proteinuria and glomerular lesions comparable to those seen in untreated group 4 rats. Thus, unless glomerular capillary hypertension is corrected, control of systemic blood pressure is insufficient to prevent progressive renal injury in rats with reduced renal mass.

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Thrombotic thrombocytopenic purpura : report of 16 cases and review of the literature

1966-01-01

El Amorosi

ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions

2002-11-14

Jing-fei Dong , Joel L. Moake , Leticia Nolasco +7 more

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Complement regulators and inhibitory proteins

2009-09-04

Peter F. Zipfel , Christine Skerka

Mannose-binding lectin: the pluripotent molecule of the innate immune system

1996-11-01

Malcolm Turner

Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies

1998-05-01

Marina Botto , Chiara Dell' Agnola , Anne E. Bygrave +6 more

The complement system

2010-09-13

J. Vidya Sarma , Peter A. Ward

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Soluble Human Complement Receptor Type 1: In Vivo Inhibitor of Complement Suppressing Post-Ischemic Myocardial Inflammation and Necrosis

1990-07-13

Harlan F. Weisman , Todd A. Bartow , Michelle K. Leppo +7 more

The complement system is an important mediator of the acute inflammatory response, and an effective inhibitor would suppress tissue damage in many autoimmune and inflammatory diseases. Such an inhibitor might … The complement system is an important mediator of the acute inflammatory response, and an effective inhibitor would suppress tissue damage in many autoimmune and inflammatory diseases. Such an inhibitor might be found among the endogenous regulatory proteins of complement that block the enzymes that activate C3 and C5. Of these proteins, complement receptor type 1 (CR1; CD35) has the most inhibitory potential, but its restriction to a few cell types limits its function in vivo. This limitation was overcome by the recombinant, soluble human CR1, sCR1, which lacks the transmembrane and cytoplasmic domains. The sCR1 bivalently bound dimeric forms of its ligands, C3b and methylamine-treated C4 (C4-ma), and promoted their inactivation by factor I. In nanomolar concentrations, sCR1 blocked complement activation in human serum by the two pathways. The sCR1 had complement inhibitory and anti-inflammatory activities in a rat model of reperfusion injury of ischemic myocardium, reducing myocardial infarction size by 44 percent. These findings identify sCR1 as a potential agent for the suppression of complement-dependent tissue injury in autoimmune and inflammatory diseases.

Modulation of the antitumor immune response by complement

2008-09-28

Maciej M. Markiewski , Robert A. DeAngelis , Fabián Benencia +5 more

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Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria

1993-05-01

Junji Takeda , Toshio Miyata , Kazuyoshi Kawagoe +6 more

Generation of C5a in the absence of C3: a new complement activation pathway

2006-05-21

Markus Huber‐Lang , J. Vidya Sarma , Firas S. Zetoune +7 more

Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome

2006-04-19

Jessica Caprioli , Marina Noris , Simona Brioschi +7 more

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Infectious diseases associated with complement deficiencies

1991-07-01

Julio E. Figueroa , Peter Densen

The complement system consists of both plasma and membrane proteins. The former influence the inflammatory response, immune modulation, and host defense. The latter are complement receptors, which mediate the cellular … The complement system consists of both plasma and membrane proteins. The former influence the inflammatory response, immune modulation, and host defense. The latter are complement receptors, which mediate the cellular effects of complement activation, and regulatory proteins, which protect host cells from complement-mediated injury. Complement activation occurs via either the classical or the alternative pathway, which converge at the level of C3 and share a sequence of terminal components. Four aspects of the complement cascade are critical to its function and regulation: (i) activation of the classical pathway, (ii) activation of the alternative pathway, (iii) C3 convertase formation and C3 deposition, and (iv) membrane attack complex assembly and insertion. In general, mechanisms evolved by pathogenic microbes to resist the effects of complement are targeted to these four steps. Because individual complement proteins subserve unique functional activities and are activated in a sequential manner, complement deficiency states are associated with predictable defects in complement-dependent functions. These deficiency states can be grouped by which of the above four mechanisms they disrupt. They are distinguished by unique epidemiologic, clinical, and microbiologic features and are most prevalent in patients with certain rheumatologic and infectious diseases. Ethnic background and the incidence of infection are important cofactors determining this prevalence. Although complement undoubtedly plays a role in host defense against many microbial pathogens, it appears most important in protection against encapsulated bacteria, especially Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and, to a lesser extent, Neisseria gonorrhoeae. The availability of effective polysaccharide vaccines and antibiotics provides an immunologic and chemotherapeutic rationale for preventing and treating infection in patients with these deficiencies.

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Collectins and Ficolins: Humoral Lectins of the Innate Immune Defense

2003-03-03

Uffe Holmskov , Steffen Thiel , Jens C. Jensenius

Collectins and ficolins, present in plasma and on mucosal surfaces, are humoral molecules of the innate immune systems, which recognize pathogen-associated molecular patterns. The human collectins, mannan-binding lectin (MBL) and … Collectins and ficolins, present in plasma and on mucosal surfaces, are humoral molecules of the innate immune systems, which recognize pathogen-associated molecular patterns. The human collectins, mannan-binding lectin (MBL) and surfactant protein A and D (SP-A and SP-D), are oligomeric proteins composed of carbohydrate-recognition domains (CRDs) attached to collagenous regions and are thus structurally similar to the ficolins, L-ficolin, M-ficolin, and H-ficolin. However, they make use of different CRD structures: C-type lectin domains for the collectins and fibrinogen-like domains for the ficolins. Upon recognition of the infectious agent, MBL and the ficolins initiate the lectin pathway of complement activation through attached serine proteases (MASPs), whereas SP-A and SP-D rely on other effector mechanisms: direct opsonization, neutralization, and agglutination. This limits the infection and concurrently orchestrates the subsequent adaptive immune response. Deficiencies of the proteins may predispose to infections or other complications, e.g., reperfusion injuries or autoimmune diseases. Structure, function, clinical implications, and phylogeny are reviewed.

ROLE OF C5A IN INFLAMMATORY RESPONSES

2005-02-11

Ren-Feng Guo , Peter A. Ward

▪ Abstract The complement system not only represents an effective innate immune mechanism of host defense to eradicate microbial pathogens, but it is also widely involved in many forms of … ▪ Abstract The complement system not only represents an effective innate immune mechanism of host defense to eradicate microbial pathogens, but it is also widely involved in many forms of acute and chronic inflammatory diseases including sepsis, acute lung injury, ischemia-reperfusion injury, and asthma, to give just a few examples. The complement-activated product, C5a, displays powerful biological activities that lead to inflammatory sequelae. C5a is a strong chemoattractant and is involved in the recruitment of inflammatory cells such as neutrophils, eosinophils, monocytes, and T lymphocytes, in activation of phagocytic cells and release of granule-based enzymes and generation of oxidants, all of which may contribute to innate immune functions or tissue damage. Accumulating data suggest that C5a provides a vital bridge between innate and adaptive immune functions, extending the roles of C5a in inflammation. Herein, we review human and animal data describing the cellular and molecular mechanisms of C5a in the development of inflammatory disorders, sepsis, acute lung injury, ischemia-reperfusion injury, and asthma.

Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura

2001-10-04

Gallia G. Levy , William C. Nichols , Eric C.‐Y. Lian +7 more

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Terminal Complement Inhibitor Eculizumab in Atypical Hemolytic–Uremic Syndrome

2013-06-05

Christophe Legendre , Christoph Licht , Petra Muus +7 more

Atypical hemolytic–uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the … Atypical hemolytic–uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease.

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Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

2010-07-02

Marina Noris , Jessica Caprioli , Elena Bresin +7 more

Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Most childhood cases are caused by Shiga toxin-producing bacteria. The other form, atypical HUS (aHUS), accounts … Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Most childhood cases are caused by Shiga toxin-producing bacteria. The other form, atypical HUS (aHUS), accounts for 10% of cases and has a poor prognosis. Genetic complement abnormalities have been found in aHUS.We screened 273 consecutive patients with aHUS for complement abnormalities and studied their role in predicting clinical phenotype and response to treatment. We compared mutation frequencies and localization and clinical outcome in familial (82) and sporadic (191) cases.In >70% of sporadic and familial cases, gene mutations, disease-associated factor H (CFH) polymorphisms, or anti-CFH autoantibodies were found. Either mutations or CFH polymorphisms were also found in the majority of patients with secondary aHUS, suggesting a genetic predisposition. Familial cases showed a higher prevalence of mutations in SCR20 of CFH and more severe disease than sporadic cases. Patients with CFH or THBD (thrombomodulin) mutations had the earliest onset and highest mortality. Membrane-cofactor protein (MCP) mutations were associated with the best prognosis. Plasma therapy induced remission in 55 to 80% of episodes in patients with CFH, C3, or THBD mutations or autoantibodies, whereas patients with CFI (factor I) mutations were poor responders. aHUS recurred frequently after kidney transplantation except for patients with MCP mutations.Results underline the need of genetic screening for all susceptibility factors as part of clinical management of aHUS and for identification of patients who could safely benefit from kidney transplant.

The Association Between Idiopathic Hemolytic Uremic Syndrome and Infection by Verotoxin-Producing Escherichia coli

1985-05-01

Mohamed A. Karmali , M. Petric , Corazon Lim +3 more

Forty pediatric patients with idiopathic hemolytic uremic syndrome (HUS) were investigated for evidence of infection by Verotoxin-producing Escherichia coli (VTEC). Fecal VTEC (belonging to at least six different O serogroups … Forty pediatric patients with idiopathic hemolytic uremic syndrome (HUS) were investigated for evidence of infection by Verotoxin-producing Escherichia coli (VTEC). Fecal VTEC (belonging to at least six different O serogroups including O26, O111, O113, O121, O145, and O157) or specifically neutralizable free-fecal Verotoxin (VT) or both were detected in 24 (60%) patients but were not detected in 40 matched controls. Ten of 15 of the former developed fourfold or greater rises in VT-neutralizing antibody titers, as did six other patients who were negative for both fecal VTEC and VT. A total of 30 (75%) patients had evidence of VTEC infection by one or more criteria. We concluded that a significant association exists between idiopathic HUS and infection by VTEC. The detection of free-fecal VT was the most important procedure for the early diagnosis of this infection because, in our study, VTEC were never isolated in the absence of fecal VT, whereas fecal VT was often present even when VTEC were undetectable.

Atypical Hemolytic–Uremic Syndrome

2009-10-21

Marina Noris , Giuseppe Remuzzi

The hemolytic–uremic syndrome, which is characterized by nonimmune hemolytic anemia, thrombocytopenia, and renal impairment, occurs most frequently in young children. Most cases are secondary to infection with Escherichia coli O157:H7 … The hemolytic–uremic syndrome, which is characterized by nonimmune hemolytic anemia, thrombocytopenia, and renal impairment, occurs most frequently in young children. Most cases are secondary to infection with Escherichia coli O157:H7 and other Shiga-toxin–producing strains. However, approximately 10% of cases are atypical and not associated with infection. This article reviews current concepts about the pathobiology of atypical hemolytic–uremic syndrome and its diagnosis and management.

Diagnosis and management of paroxysmal nocturnal hemoglobinuria

2005-07-28

Charles Parker , Mitsuhiro Omine , Stephen J. Richards +7 more

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Complement: a key system for immune surveillance and homeostasis

2010-08-19

Daniel Ricklin , George Hajishengallis , Kun Yang +1 more

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Oxygen radicals mediate endothelial cell damage by complement-stimulated granulocytes. An in vitro model of immune vascular damage.

1978-05-01

T Sacks , Charles F. Moldow , P R Craddock +2 more

During hemodialysis, alternative pathway complement activation leads to pulmonary sequestration of granulocytes, with loss of pulmonary vascular endothelial integrity and, at times, protein-rich pulmonary edema. An in vitro model of … During hemodialysis, alternative pathway complement activation leads to pulmonary sequestration of granulocytes, with loss of pulmonary vascular endothelial integrity and, at times, protein-rich pulmonary edema. An in vitro model of this phenomenon was constructed utilizing 51Cr-labeled human umbilical vein endothelial cell cultures. In this system, granulocytes, when exposed to activated complement (C), induce endothelial damage; this injury is mediated primarily by oxygen radicals produced by the granulocytes. C5a appears to be the C component responsible for granulocyte-induced cytotoxicity; studies with cytochalasin B-treated granulocytes suggest that close approximation of the granulocytes and endothelial cells is necessary for maximal cell injury.

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Schizophrenia risk from complex variation of complement component 4

2016-01-26

Aswin Sekar , Hon‐Cheong So , Heather de Rivera +7 more

Antibodies to von Willebrand Factor–Cleaving Protease in Acute Thrombotic Thrombocytopenic Purpura

1998-11-26

Han‐Mou Tsai , Eric Chun‐Yet Lian

Thrombotic thrombocytopenic purpura is a potentially fatal disease characterized by widespread platelet thrombi in the microcirculation. In the normal circulation, von Willebrand factor is cleaved by a plasma protease. We … Thrombotic thrombocytopenic purpura is a potentially fatal disease characterized by widespread platelet thrombi in the microcirculation. In the normal circulation, von Willebrand factor is cleaved by a plasma protease. We explored the hypothesis that a deficiency of this protease predisposes patients with thrombotic thrombocytopenic purpura to platelet thrombosis.We studied the activity of von Willebrand factor-cleaving protease and sought inhibitors of this protease in plasma from patients with acute thrombotic thrombocytopenic purpura, patients with other diseases, and normal control subjects. We also investigated the effect of shear stress on the ristocetin cofactor activity of purified von Willebrand factor in the cryosupernatant fraction of the plasma samples.Thirty-nine samples of plasma from 37 patients with acute thrombotic thrombocytopenic purpura had severe deficiency of von Willebrand factor-cleaving protease. No deficiency was detected in 16 samples of plasma from patients with thrombotic thrombocytopenic purpura in remission or in 74 plasma samples from normal subjects, randomly selected hospitalized patients or outpatients, or patients with hemolysis, thrombocytopenia, or thrombosis from other causes. Inhibitory activity against the protease was detected in 26 of the 39 plasma samples (67 percent) obtained during the acute phase of the disease. The inhibitors were IgG antibodies. Shear stress increased the ristocetin cofactor activity of von Willebrand factor in the cryosupernatant of plasma samples obtained during the acute phase, but decreased the activity in cryosupernatant of plasma from normal subjects.Inhibitory antibodies against von Willebrand factor-cleaving protease occur in patients with acute thrombotic thrombocytopenic purpura. A deficiency of this protease is likely to have a critical role in the pathogenesis of platelet thrombosis in this disease.

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Disseminated Intravascular Coagulation

1999-08-19

Marcel Levi , Hugo Ten Cate

Disseminated intravascular coagulation is characterized by the widespread activation of coagulation, which results in the intravascular formation of fibrin and ultimately thrombotic occlusion of small and midsize vessels.13 Intravascular coagulation … Disseminated intravascular coagulation is characterized by the widespread activation of coagulation, which results in the intravascular formation of fibrin and ultimately thrombotic occlusion of small and midsize vessels.13 Intravascular coagulation can also compromise the blood supply to organs and, in conjunction with hemodynamic and metabolic derangements, may contribute to the failure of multiple organs. At the same time, the use and subsequent depletion of platelets and coagulation proteins resulting from the ongoing coagulation may induce severe bleeding (Figure 1). Bleeding may be the presenting symptom in a patient with disseminated intravascular coagulation, a factor that can complicate decisions about . . .

Comparison of Plasma Exchange with Plasma Infusion in the Treatment of Thrombotic Thrombocytopenic Purpura

1991-08-08

G. Rock , Kenneth H. Shumak , N Buskard +4 more

Thrombotic thrombocytopenic purpura is an uncommon disease with a high mortality rate even with current treatment. The cause of the syndrome and its optimal treatment are unknown. Although both plasma … Thrombotic thrombocytopenic purpura is an uncommon disease with a high mortality rate even with current treatment. The cause of the syndrome and its optimal treatment are unknown. Although both plasma exchange and plasma infusion have been useful treatments, it is not clear which is superior. In this report we describe a prospective randomized trial comparing plasma exchange with plasma infusion for the treatment of thrombotic thrombocytopenic purpura.

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Natural History of Paroxysmal Nocturnal Hemoglobinuria

1995-11-09

Peter Hillmen , S. M. Lewis , Monica Bessler +2 more

Paroxysmal nocturnal hemoglobinuria (PNH), which is characterized by intravascular hemolysis and venous thrombosis, is an acquired clonal disorder associated with a somatic mutation in a totipotent hematopoietic stem cell. An … Paroxysmal nocturnal hemoglobinuria (PNH), which is characterized by intravascular hemolysis and venous thrombosis, is an acquired clonal disorder associated with a somatic mutation in a totipotent hematopoietic stem cell. An understanding of the natural history of PNH is essential to improve therapy.

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von Willebrand Factor–Cleaving Protease in Thrombotic Thrombocytopenic Purpura and the Hemolytic–Uremic Syndrome

1998-11-26

Miha Furlan , Rodolfo Robles , Miriam Galbusera +7 more

Thrombotic thrombocytopenic purpura and the hemolytic–uremic syndrome are severe microvascular disorders of platelet clumping with similar signs and symptoms. Unusually large multimers of von Willebrand factor, capable of agglutinating circulating … Thrombotic thrombocytopenic purpura and the hemolytic–uremic syndrome are severe microvascular disorders of platelet clumping with similar signs and symptoms. Unusually large multimers of von Willebrand factor, capable of agglutinating circulating platelets under high shear stress, occur in the two conditions. We investigated the prevalence of von Willebrand factor–cleaving protease deficiency in patients with familial and nonfamilial forms of these disorders.

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Keeping It All Going—Complement Meets Metabolism

2017-01-18

Martin Kolev , Claudia Kemper

The complement system is an evolutionary old and crucial component of innate immunity key to the detection and removal of invading pathogens. It was initially discovered as a liver-derived sentinel … The complement system is an evolutionary old and crucial component of innate immunity key to the detection and removal of invading pathogens. It was initially discovered as a liver-derived sentinel system circulating in serum, the lymph and interstitial fluids that mediates the opsonization and lytic killing of bacteria, fungi and viruses and the initiation of the general inflammatory responses. Although work performed specifically in the last five decades identified complement also as a critical instructor of adaptive immunity – indicating that complement's function is likely broader than initially anticipated - the dominant opinion among researchers and clinicians was that the key complement functions were in principle defined. However, there is now a growing realization that complement activity goes well beyond 'classic' immune functions and that this system is also required for normal (neuronal) development and activity and general cell and tissue integrity and homeostasis. Furthermore, the recent discovery that complement activation is not confined to the extracellular space but occurs within cells led to the surprising understanding that complement is involved in the regulation of basic processes of the cell, particularly those of metabolic nature – mostly via novel crosstalks between complement and intracellular sensor, and effector, pathways that had been overlooked because of their spatial separation. These paradigm shifts in the field led to a renaissance in complement research and provide new platforms to now better understand the molecular pathways underlying the wide-reaching effects of complement functions in immunity and beyond. In this review, we will cover the current knowledge about complement's emerging relationship with the cellular metabolism machinery with a focus on the functional differences between serum-circulating versus intracellularly active complement during normal cell survival and induction of effector functions. We will also discuss how taking a closer look into the evolution of key complement components not only made the functional connection between complement and metabolism rather 'predictable' but how it may also give clues for the discovery of additional roles for complement in basic cellular processes.

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A second serine protease associated with mannan-binding lectin that activates complement

1997-04-01

Steffen Thiel , Thomas Vorup‐Jensen , Cordula Stover +7 more

Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura

2019-01-09

Marie Scully , Spero R. Cataland , Flora Peyvandi +7 more

In acquired thrombotic thrombocytopenic purpura (TTP), an immune-mediated deficiency of the von Willebrand factor–cleaving protease ADAMTS13 allows unrestrained adhesion of von Willebrand factor multimers to platelets and microthrombosis, which result … In acquired thrombotic thrombocytopenic purpura (TTP), an immune-mediated deficiency of the von Willebrand factor–cleaving protease ADAMTS13 allows unrestrained adhesion of von Willebrand factor multimers to platelets and microthrombosis, which result in thrombocytopenia, hemolytic anemia, and tissue ischemia. Caplacizumab, an anti–von Willebrand factor humanized, bivalent variable-domain-only immunoglobulin fragment, inhibits interaction between von Willebrand factor multimers and platelets.

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THROMBOTIC THROMBOCYTOPENIC PURPURA

1966-03-01

Edward L. Amorosi , John E. Ultmann

Department of Medicine, Presbyterian Hospital and the Institute of Cancer Research, Columbia University College of Physicians and Surgeons, New York City 10032. Department of Medicine, Presbyterian Hospital and the Institute of Cancer Research, Columbia University College of Physicians and Surgeons, New York City 10032.

Complement

2001-04-05

Mark Walport

Complement is part of the innate immune system and underlies one of the main effector mechanisms of antibody-mediated immunity. It has three overarching physiologic activities (Table 1): defending against pyogenic … Complement is part of the innate immune system and underlies one of the main effector mechanisms of antibody-mediated immunity. It has three overarching physiologic activities (Table 1): defending against pyogenic bacterial infection, bridging innate and adaptive immunity, and disposing of immune complexes and the products of inflammatory injury. In this review, each of these activities will be placed in a clinical context.Complement was first identified as a heat-labile principle in serum that “complemented” antibodies in the killing of bacteria. We now know that complement is a system of more than 30 proteins in plasma and on cell surfaces. Complement . . .

Thrombotic Microangiopathies

2002-08-22

Joel L. Moake

This article reviews the substantial progress made in understanding the thrombotic microangiopathies. The mechanisms of both thrombotic thrombocytopenic purpura and the hemolytic–uremic syndrome are considered. This article reviews the substantial progress made in understanding the thrombotic microangiopathies. The mechanisms of both thrombotic thrombocytopenic purpura and the hemolytic–uremic syndrome are considered.

THE C3-ACTIVATOR SYSTEM: AN ALTERNATE PATHWAY OF COMPLEMENT ACTIVATION

1971-09-01

Otto Götze , Hans J. Müller‐Eberhard

Evidence has accumulated indicating the existence of a second complement activation mechanism which is functionally analogous to C1, C2, and C4. The noncomplement protein C3PA, previously recognized through its ability … Evidence has accumulated indicating the existence of a second complement activation mechanism which is functionally analogous to C1, C2, and C4. The noncomplement protein C3PA, previously recognized through its ability to form a complex enzyme with a protein from cobra venom, appears to be the precursor of the C4,2 analogue. It is a thermolabile ß-globulin with a molecular weight of 80,000. When serum is treated with naturally occurring plant or bacterial polysaccharides, the C3PA is cleaved into at least two fragments, one having the electrophoretic mobility of a γ-globulin and a molecular weight of 60,000, and the other being an acidic peptide with a molecular weight of 20,000. The larger fragment has the ability to cleave C3 into C3a and C3b and is therefore called C3 activator. It arises from the action of an as yet unidentified serum enzyme upon the C3PA, which is tentatively called C3PA convertase. In addition to endotoxins, yeast cell walls, inulin, and agar, aggregates of immunoglobulins were found to be activating substances, including human IgA, guinea pig γ1, and duck antibody. Serum depleted of C3PA had reduced E. coli bactericidal and increased hemolytic activity. The relationship of the C3-activator system to experimental and clinical observations has been discussed.

Case 6-2025: A 62-Year-Old Man with Abdominal Pain

2025-06-25

Gabrielle Kis Bromberg , Katayoon Goodarzi | New England Journal of Medicine

Clinical cases of hemolytic-uremic syndrome in children with E. coli infection

2025-06-25

Yu. B. Belan , Е. А. Гашина , Е. Ф. Лобова +2 more | CHILDREN INFECTIONS

Among other children infectious diseases hemolytic-uremic syndrome (HUS) remains a significant issue since it can lead to death or chronic kidney pathology. The most vulnerable group are children under the … Among other children infectious diseases hemolytic-uremic syndrome (HUS) remains a significant issue since it can lead to death or chronic kidney pathology. The most vulnerable group are children under the age of 5. The progression of HUS triggered by bacterial intestinal infections is more likely to occur as a sporadic disease in the summer-autumn period. Materials and methods . The article describes clinical observations of patients undergoing treatment at the children infectious hospital at the Budgetary Healthcare Institution of Omsk Oblast City Clinical Hospital №1 named after A.N. Kabanov in Omsk. In each case the development of HUS was preceded by symptoms of acute intestinal infections of medium severity. Сlinical and laboratory manifestations matched the classic version of HUS development. When conducting bacteriological research of stool, causative agents of intestinal infections were not identified. Only in two cases etiological agent was identified using PCR.

Local and Cell-intrinsic complement: The new player in cancer progression

2025-06-24

Messika Revel , Nicolas S. Merle | Seminars in Immunology

Danicopan in paroxysmal nocturnal haemoglobinuria: a profile of its use

2025-06-24

Nicole L. France , Hannah A. Blair | Drugs & Therapy Perspectives

Post-translationally modified proteins bind and activate complement with implications for cellular uptake and autoantibody formation

2025-06-23

Michelle D van den Beukel , Lu Zhang , Stef van der Meulen +7 more | Journal of Autoimmunity

Autoimmune diseases, such as rheumatoid arthritis (RA), are characterized by the presence of autoantibodies including those targeting self-proteins modified by post-translational modifications (PTMs). The complement system is known for its … Autoimmune diseases, such as rheumatoid arthritis (RA), are characterized by the presence of autoantibodies including those targeting self-proteins modified by post-translational modifications (PTMs). The complement system is known for its role in innate immune defense, but also in clearing debris and induction of antibody responses. We therefore hypothesized that complement could directly bind to PTMs and target PTM-modified proteins for clearance, or stimulate (chronic) inflammation and development of anti-PTM autoimmunity. Six PTMs were investigated: nitration (Nt), citrullination (Cit), carbamylation (Ca), acetylation (Ac), malondialdehyde-acetaldehyde adducts (MAA) and advanced glycation end-products (AGE). We used mass spectrometry and plate-bound assays to analyze binding of serum proteins to PTM-modified proteins. The impact of complement activation on cellular uptake was studied in phagocytosis assays. The relationship between complement SNPs, and presence of anti-PTM autoantibodies was analyzed in 587 RA patients. Mass spectrometry analysis revealed a strong binding of complement to proteins modified with Ca, Ac, MAA and AGE but not to Nt and Cit. These observations were confirmed by plate-bound assays revealing that Ca-, MAA- and AGE-modified proteins activated the classical pathway, without involving antibodies. Ac activated the lectin pathway through ficolin-3. Complement activation on Ca-, Ac-, MAA- and AGE-coupled beads enhanced phagocytosis. SNPs in complement genes, associated with higher complement activity, were strongly associated with the presence of anti-PTM antibodies in RA patients. Proteins containing the PTMs Ca, Ac, MAA or AGE activate complement. These complement opsonized PTMs increase phagocytosis and may lead to the development of anti-PTM antibodies.

A Rare Case of Atypical Haemolytic Syndrome Following Right Retrograde Intrarenal Surgery (RIRS)

2025-06-23

Antonio Cretì , Francesco Pinto , Maria Chiara Sighinolfi +3 more | Cureus

A predictive algorithm involving lactate dehydrogenase to serum creatinine ratio may assist in identifying patients with thrombotic thrombocytopenic purpura

2025-06-21

Xuduan Chen , Jiexi Zhang , Jingjing Fu +6 more | Annals of Hematology

Thrombotic thrombocytopenic purpura (TTP) is a rare but fatal disease requiring urgent diagnosis. The PLASMIC scoring model has been reported to be a valuable model for identifying TTP. This study … Thrombotic thrombocytopenic purpura (TTP) is a rare but fatal disease requiring urgent diagnosis. The PLASMIC scoring model has been reported to be a valuable model for identifying TTP. This study aimed to investigate the diagnostic accuracy of this model and the diagnostic utility of lactate dehydrogenase (LDH)-to-serum creatinine (sCr) ratio in identifying TTP in Chinese patients. The records of 61 patients with suspected TTP tested for ADAMTS13 activity in our hospital between June 2016 and April 2024 were retrospectively analyzed. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic accuracy of LDH, sCr, and the LDH-to-sCr (LDH/sCr) in predicting TTP. Multivariate logistic regression analysis was used to screen for independent risk factors of TTP, and a combined predictive algorithm was established. The AUC for the PLASMIC scoring model distinguishing TTP from non-TTP was 0.850 (optimal cutoff: 5), with 92.8% sensitivity, 76.5% specificity, 75.8% positive predictive value (PPV), and 92.9% negative predictive value (NPV). The AUC derived from the LDH/sCr ratio was higher than that derived from LDH or sCr (P < 0.05). A combined predictive algorithm, termed the LCRP algorithm (including the LDH/sCr ratio, reticulocyte percentage, and platelet count), was developed for TTP. The AUC (0.955) derived from the LCRP algorithm, with 96.3% sensitivity, 88.2% specificity, 86.7% PPV, and 96.8% NPV, was higher than that of the PLASMIC scoring model (P < 0.05). The LDH/sCr ratio is more effective than isolated LDH or sCr measurements for predicting TTP. The LCRP algorithm involving the LDH/sCr ratio showed superior predictive performance and may hold significant potential for early identification of Chinese patients with TTP.

C3d-targeted complement inhibitors to correct complement dysregulation in aHUS patients

2025-06-20

Valeria Guaschino , Donata Santarsiero , Sara Gastoldi +7 more | Frontiers in Immunology

Atypical hemolytic uremic syndrome (aHUS) is a rare and severe thrombotic microangiopathy caused by genetic or acquired abnormalities leading to activation of the complement alternative pathway on cell surfaces. This … Atypical hemolytic uremic syndrome (aHUS) is a rare and severe thrombotic microangiopathy caused by genetic or acquired abnormalities leading to activation of the complement alternative pathway on cell surfaces. This process leads to endothelial dysfunction and microvascular thrombosis. The introduction of anti-C5 antibodies has dramatically improved aHUS prognosis; however, these treatments require regular intravenous infusions and block systemic complement activity, exposing the patient to risk of infections. Recently complement inhibitors have been developed to selectively bind injury-associated target molecules, thereby concentrating the drug at specific cellular or tissue sites while preserving systemic complement function. This study evaluated the local complement inhibitory activity of new molecules that exploit the natural localization of C3d at complement activation sites on cells: namely the anti-C3d monoclonal antibody 3d8b conjugated with the first 10 or 17 short consensus repeats (SCRs) of complement receptor 1 (CR1 1–10 and CR1 1-17 , respectively) or the first 5 SCRs of complement factor H (FH 1-5 ). To this purpose we tested their capability to block C3 deposition and C5b-9 formation on microvascular endothelial cells (HMEC-1) exposed to serum from patients with aHUS. We also assessed their ability to prevent loss of anti-thrombogenic properties in HMEC-1 pre-exposed to aHUS serum and then perfused with control blood. We demonstrate that anti-C3d-antibody conjugated with CR1 1-10 , or CR1 1-17 , or FH 1–5 effectively prevented aHUS serum-induced complement activation on HMEC-1, outperforming their non-targeted soluble counterparts. The efficacy of C3 convertase inhibition varied depending on the complement inhibitory component (CR1 1-17 &gt; CR1 1-10 &gt; FH 1-5 ). However, all the inhibitors successfully blocked C5 convertase activity and eliminated the pro-thrombogenic effects of aHUS patients’ serum. These findings support the potential of tissue-targeted complement inhibition as a novel, non-systemic therapeutic strategy for aHUS and other diseases characterized by localized complement dysregulation.

Chemotherapy of breast cancer cells alters susceptibility to complement-mediated opsonization and killing

2025-06-19

Mohamed H. Nasraa , Mahmoud Mohamed Bahgat , Michael Kirschfink | Medical Oncology

Impact of smoking on the complement system: a narrative review

2025-06-19

Ahmed B. Alarabi , Fatima Z. Alshbool , Fadi T. Khasawneh | Frontiers in Immunology

Smoking is a major cause of morbidity and mortality, resulting in an increased risk of cardiovascular, respiratory, inflammatory, and degenerative diseases. In this review, we highlight the complex interactions between … Smoking is a major cause of morbidity and mortality, resulting in an increased risk of cardiovascular, respiratory, inflammatory, and degenerative diseases. In this review, we highlight the complex interactions between smoking and activation of different components of the complement system, in order to underscore the notion that its dysregulation underlies—mechanistically—as well as exacerbates the progression of a host of disease processes. Moreover, we also briefly delve into components of tobacco smoke—including chemical constituents like tobacco glycoprotein (TGP) and particulate matter (PM), toxic metals, and other mainstream cigarette smoke chemicals—that have been identified as possible culprits in complement activation. In doing so, this review makes important and meaningful contributions to the ongoing efforts of combating the global health crisis posed by tobacco use, all while emphasizing the need for multifaceted strategies that include not only public health measures and educational efforts, but also innovative research that focuses on understanding and mitigating the biological mechanisms underlying smoking-related health conditions.

Concurrent Immune Thrombocytopenic Purpura (ITP) and Thrombotic Thrombocytopenic Purpura (TTP) with Underlying Antiphospholipid Syndrome

2025-06-19

S. J. Carlan | Journal of Clinical Medical Research

Background: Immune Thrombocytopenic Purpura (ITP) and Thrombotic Thrombocytopenic Purpura (TTP) are both conditions that lead to thrombocytopenia. It is crucial to recognize TTP because it significantly impacts the treatment options … Background: Immune Thrombocytopenic Purpura (ITP) and Thrombotic Thrombocytopenic Purpura (TTP) are both conditions that lead to thrombocytopenia. It is crucial to recognize TTP because it significantly impacts the treatment options and the prognosis. In clinical practice, both corticosteroids and rituximab can be utilized to treat ITP and TTP. However, plasma exchange therapy is the first-line treatment specifically for TTP, while corticosteroids are strongly recommended as the first-line treatment for ITP. Antiphospholipid syndrome is an autoimmune disorder resulting in a hypercoagulable state and is rarely reported with TTP. Case Report: A 33-year-old woman with a history of chronic primary ITP presented in the second-trimester of pregnancy with HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome requiring an emergency cesarean delivery. Following the delivery, she required continued prednisone for treatment. Four years later, she presented with acute neurological deficits and a platelet count of 5,000 per microliter. A critically low activity of ADAMTS13 and the presence of autoantibodies targeting ADAMTS13 led to a definitive diagnosis of TTP. Despite her neurological deficits resolving within 45 minutes, a magnetic resonance imaging of her brain showed small subacute punctate ischemic strokes. Her labs were positive for antiphospholipid syndrome. She was treated with dexamethasone, intravenous immunoglobulin, plasmapheresis, rituximab, prednisone, low molecular weight heparin and caplacizumab-yhdp. She was discharged on warfarin for life. Conclusion: Conducting systematic testing for ADAMTS13 activity and anti-ADAMTS13 antibodies in patients who exhibit neurological symptoms alongside thrombocytopenia while also screening for antiphospholipid antibodies may significantly enhance the diagnosis and management of this rare but serious combination of thrombotic conditions.

Complement System Inhibitors in Nephrology: An Update—Narrative Review

2025-06-19

Mugurel Apetrii , Alexandru Dan Costache , Irina Enache +4 more | International Journal of Molecular Sciences

Complement system inhibitors are emerging as promising therapies in nephrology, particularly for diseases where complement dysregulation is central to pathogenesis. This review summarizes the role of complement activation in kidney … Complement system inhibitors are emerging as promising therapies in nephrology, particularly for diseases where complement dysregulation is central to pathogenesis. This review summarizes the role of complement activation in kidney diseases and current evidence supporting complement-targeted treatments. As the complement system can be involved in the pathogenesis of different diseases to varying degrees, several research works have been conducted. These research efforts aim, firstly, to understand the mechanisms and role of complement cascade components in the most prevalent nephrological diseases and, secondly, to explore the potential of complement system inhibitors in these conditions and their possible clinical applications. Clinical trials demonstrate that complement inhibitors are most effective in conditions with significant complement involvement, such as C3 glomerulopathy (C3G), atypical hemolytic uremic syndrome (aHUS), and immune complex membranoproliferative glomerulonephritis (IC-MPGN). These agents show variable benefits in diseases with partial complement activation, including lupus nephritis and ANCA-associated vasculitis, while their role in disorders like diabetic nephropathy and focal-segmental glomerulosclerosis remains limited. Complement inhibition offers a targeted strategy to prevent disease progression and improve outcomes in selected nephrological disorders.

Clinical skills in therapeutic plasmapheresis in intensive care: A scoping review

2025-06-19

Pedro Ramos-Figueiras , Maria Pinto-Marques , Margarida Palma-Goes +1 more | Enfermería Intensiva

Case Report: Failure of eculizumab to block complement to prevent relapse of anti-phospholipid syndrome in kidney transplant recipient

2025-06-18

Thibault Laban , F. Pigneur , Constance Guillaud +7 more | Frontiers in Nephrology

Catastrophic antiphospholipid syndrome (CAPS) leads to organ dysfunction due to thrombotic microangiopathy (TMA). Complement may play a role in CAPS, and its blockade could prevent antiphospholipid syndrome (APS) complications after … Catastrophic antiphospholipid syndrome (CAPS) leads to organ dysfunction due to thrombotic microangiopathy (TMA). Complement may play a role in CAPS, and its blockade could prevent antiphospholipid syndrome (APS) complications after kidney transplantation (KT). Here, we report a case of APS recurrence after KT in a 38-year-old woman with early acute cortical kidney allograft necrosis despite preventive eculizumab treatment, probably because of insufficient complement blockade. The patient had recurrent but controlled CAPS for years with renal dysfunction, leading to preemptive KT. Anticoagulation and eculizumab were administered to prevent thrombosis and TMA after KT. She developed acute kidney injury (AKI) with incomplete biological TMA. Imaging revealed cortical necrosis in the renal allograft. In the absence of donor-specific anti-HLA antibodies, we concluded a relapse. Additional doses of eculizumab and plasma exchange allowed the normalization of biological tests and improvement of kidney allograft function. A retrospective complement analysis showed an incomplete blockade at the time of AKI. One year after KT, the renal allograft function was impaired. This suggests that inadequate complement blockade leads to a relapse of APS in the renal allograft with cortical necrosis and dysfunction. Our case highlights the importance of monitoring complement activity and adjusting the dose of eculizumab or ravulizumab.

Complete recovery after complement factor I deficiency associated fulminant acute hemorrhagic leukoencephalitis: a case report

2025-06-18

Fanni Szumutku , L Szabó , Zoltán Liptai +7 more | Frontiers in Immunology

Introduction Acute hemorrhagic leukoencephalitis (AHLE) is a rare, fulminant neuroinflammatory disease with high mortality rate. It most often occurs after infections; however, the exact etiology of the disease remains unclear. … Introduction Acute hemorrhagic leukoencephalitis (AHLE) is a rare, fulminant neuroinflammatory disease with high mortality rate. It most often occurs after infections; however, the exact etiology of the disease remains unclear. We highlight that complement factor I (FI) deficiency may be a possible cause of AHLE. Case report We describe a 9-year-old patient presenting with fever, headache, dizziness, ataxia, and diplopia, who developed rapid neurologic decline and refractory intracranial pressure elevation. Based on clinical, laboratory, and MRI findings, AHLE was diagnosed. Successful treatment included therapeutic plasma exchange (PEX) and early decompressive craniectomy. At one year of follow-up, the patient showed complete recovery. Complement testing of the patient revealed complete FI deficiency. Genetic workup uncovered a germline pathogenic variant in the CFI gene. Discussion As AHLE is an emerging phenotype of complement FI deficiency, with only a few previously reported cases in the literature, high clinical suspicion and awareness among clinicians are needed. To control the complement system, prompt blockade with complement FI substitution via PEX and early decompressive craniectomy may be life-saving. In neuroinflammatory diseases with unknown etiology, complement testing is recommended.

Short-Term Efficacy of Eculizumab Therapy in Atypical Hemolytic Uremic Syndrome

2025-06-18

Tanvi Bindal , Aditi Sinha , Anand Narain Tiwari +2 more | The Indian Journal of Pediatrics

Thrombotic thrombocytopenic purpura as a rare stroke mimic

2025-06-18

Jürgen Mattern , Björn Jacobi , Markus Munder | Deutsches Ärzteblatt international

ATP synthase epsilon subunit: An unconventional adaptor of clathrin-mediated endocytosis of hemoglobin in Leishmania

2025-06-18

Anjali Kapoor , Jitender Verma , D. P. Goyal +3 more | Journal of Cell Science

In clathrin-mediated endocytosis, cytoplasmic domain of the receptor binds with AP2-adaptor which recruits clathrin to mediate endocytosis. Classical AP2-adaptor Leishmania is not yet characterized. Here, we have identified ATP Synthase … In clathrin-mediated endocytosis, cytoplasmic domain of the receptor binds with AP2-adaptor which recruits clathrin to mediate endocytosis. Classical AP2-adaptor Leishmania is not yet characterized. Here, we have identified ATP Synthase epsilon (LdATPSɛ) subunit as a novel adaptor in Leishmania using yeast two-hybrid screening. Subsequently, we have cloned and expressed LdATPSɛ from Leishmania and have shown that LdATPSɛ co-localizes with LdClathrin and hemoglobin receptor in Leishmania. We have found that LdATPSɛ directly binds with cargo-binding motif ‘YLAP’ in the cytoplasmic domain of LdHbR, whereas it interacts with LdClathrin terminal domain via clathrin-binding motif ‘LSELD’. Consequently, we have shown that mutated clathrin-binding box LdATPSɛL133A/L136A/D137A does not bind with clathrin, fails to localize in the flagellar pocket and its overexpression completely blocks the hemoglobin internalization in Leishmania. LdATPSɛ−/- knock out parasites are not viable indicating its essential function. However, hemoglobin internalization in LdATPSɛ+/- parasites is significantly blocked and LdATPSɛ+/- parasites fails to grow in macrophages as parasite in unable internalize hemoglobin. Our results have demonstrated that LdATPSɛ is a novel adaptor for clathrin in hemoglobin endocytosis in Leishmania.

Adverse functions of Neutrophils are regulated by Neutrophilic Angiotensin-Converting Enzyme in Immune Complex-Medicated Crescentic Glomerulonephritis

2025-06-17

Suguru Saito , Satoshi Kumakura , Zakir Khan +4 more | AJP Renal Physiology

Neutrophils play a pathogenic role in immune complex (IC)-mediated crescentic glomerulonephritis (GN). Angiotensin-converting enzyme (ACE) plays a crucial role in regulating blood pressure and inflammation via angiotensin II. We recently … Neutrophils play a pathogenic role in immune complex (IC)-mediated crescentic glomerulonephritis (GN). Angiotensin-converting enzyme (ACE) plays a crucial role in regulating blood pressure and inflammation via angiotensin II. We recently reported that ACE-overexpressing neutrophils have the reno-protective role in IC-mediated crescentic GN by the complement C3b-complement receptor1/2 axis. Here, we further investigate the precise mechanism of the adverse, pathogenic and reno-protective, functions of neutrophils in GN. Nephrotoxic serum nephritis (NTN) was induced in the mice with four different conditions and analyzed: 1) Neutrophil depletion in WT and NeuACE mice that overexpress ACE specifically in neutrophils; 2) Adoptive transfer of ACE-overexpressing neutrophils into WT mice; 3) Analysis of ACE’s catalytic C and N domains using each domain-knockout (Tg-CKO, Tg-NKO) and WT-ACE transgenic (Tg-ACE) mice; and 4) Comparison between C3KO and C3KO-NeuACE mice that overexpress ACE in neutrophils but lack complement C3. The results were as follows: 1) WT mice without neutrophils showed ameliorated glomerular injury, while neutrophil-depleted NeuACE mice lost the reno-protective effect. 2) WT mice with ACE-overexpressing neutrophils exhibited less severe glomerular injury. 3) Tg-CKO or Tg-NKO mice showed a partial loss of the reno-protective effects compared with Tg-ACE mice, suggesting both C and N domains are needed for full reno-protection. 4) C3KO-NeuACE mice lost the reno-protective effects. Complement C3 is essential for the reno-protection of overexpressed neutrophilic ACE in NeuACE mice. The present study demonstrated that canonical pathogenic effects of neutrophils were overcome by the non-canonical reno-protection by neutrophils through both C- and N-domains of ACE and complement C3.

Gleiche Antikörper, neue Fragen – interdisziplinäre Diagnostik bei einer 72-jährigen Patientin mit Enzephalitis

2025-06-16

Christiane Kellner , Mihai Ceangă , Jakob Leicht +5 more | Deleted Journal

At 1.5 years after the diagnosis of glutamate decarboxylase(GAD)-associated encephalitis (highly positive GAD antibodies in cerebrospinal fluid and serum) in a 72-year-old patient, hyperglycemia above 40 mmol/l was the cause … At 1.5 years after the diagnosis of glutamate decarboxylase(GAD)-associated encephalitis (highly positive GAD antibodies in cerebrospinal fluid and serum) in a 72-year-old patient, hyperglycemia above 40 mmol/l was the cause of progressive neurological symptoms. GAD is an important enzyme in the central nervous system and pancreatic β‑cells that convert L‑glutamate into γ‑aminobutyric acid (GABA). High GAD antibodies are associated with autoimmune diseases such as encephalitis and diabetes mellitus type 1, requiring interdisciplinary diagnostics and therapy.

Role for Complement <scp>C5</scp> in Eosinophilic Inflammation of Severe Asthma

2025-06-16

Cong Dong , Shaohua Lu , Zhenan Deng +7 more | Allergy

ABSTRACT Background We investigated the role of the complement system, particularly complement C5, in severe asthma defined from an analysis of sputum proteomics. Although there has been evidence of complement … ABSTRACT Background We investigated the role of the complement system, particularly complement C5, in severe asthma defined from an analysis of sputum proteomics. Although there has been evidence of complement activation in asthma, its role in severe asthma remains unclear. Method Sputum protein expression profiles were analyzed from healthy controls and severe asthma patients using data‐dependent acquisition mass spectrometry. Weighted correlation network analysis (WGCNA) was used to define the unique modules that were highly correlated with clinical, physiologic, and inflammatory traits. Differential analysis was performed for the complement C5 pathway protein levels and eosinophilic protein expression as influenced by C5. Asthmatic mouse models were used to verify the effect of complement C5 administration and inhibition. Results The WGCNA “brown” module related to the complement system activation was positively correlated with eosinophilic inflammation. Specifically, C5 and downstream complement proteins were up‐regulated in patients with high sputum eosinophil levels (≥ 3%) compared to low sputum eosinophils (< 3%). Patients with reduced C5 expression had less eosinophilic inflammation and better lung function. Using single‐cell RNA sequencing and immunofluorescence staining led to identification of macrophages as the main source of C5. In vivo experiments confirmed that inhibiting C5 reduced inflammation in allergic mouse models, while direct stimulation with recombinant C5 in IL‐5 transgenic mice increased eosinophilic inflammation. Conclusion We demonstrate a direct role for complement C5 in exacerbating eosinophilic inflammation in severe asthma.

Role of local complement activation in kidney fibrosis and repair

2025-06-15

Didier Portilla , Vikram Sabapathy , Daniel Chauss | Journal of Clinical Investigation

The complement system is an important component of the innate immune system involved in host defense and maintaining homeostasis. While the liver is the main source of complement proteins in … The complement system is an important component of the innate immune system involved in host defense and maintaining homeostasis. While the liver is the main source of complement proteins in the bloodstream, recent research has shown that various tissues, including the kidneys, can produce complement components locally in response to both acute and chronic inflammation. This Review highlights evidence from animal models of glomerular and tubulointerstitial kidney disease showing increased expression of intracellular complement in the kidneys. Studies using knockout mice for complement and complement receptors, along with complement inhibitors, have demonstrated that reduced complement activation in animal models of kidney fibrosis led to reduced inflammation and fibrosis, thereby supporting the pathogenic role of complement activation. Data from single-cell RNA-sequencing, spatial transcriptomics, and proteomics studies further demonstrate that alterations in local complement levels contribute to the fibrotic microenvironment observed in these models. Additionally, kidney biopsy results from patients with acute kidney injury and chronic kidney disease (CKD) indicate an increased expression of intracellular complement components as disease progresses. Developing drugs aimed at diminishing the expression and activation of local complement in glomerular and tubulointerstitial kidney disease could provide a novel approach to managing CKD.

The secret life of complement: challenges and opportunities in exploring functions of the complosome in disease

2025-06-15

Tilo Freiwald , Behdad Afzali | Journal of Clinical Investigation

The complement system is a highly conserved and essential immune component with pivotal roles in innate and adaptive immunity. It is increasingly recognized that the complement system has a profound … The complement system is a highly conserved and essential immune component with pivotal roles in innate and adaptive immunity. It is increasingly recognized that the complement system has a profound impact on disease. Current complement-targeting therapeutics for clinical use almost exclusively target the complement system in circulation. However, recent discoveries have demonstrated that complement is not only liver derived and plasma operative, but also synthesized and activated inside many cells locally within tissues, performing noncanonical, cell-autonomous intracellular functions, collectively referred to as the complosome. These intracellular complement pathways are distinct from the classical plasma-based system and critical for regulating fundamental cellular processes, including metabolism, gene transcription, autophagy, and the activation and resolution of inflammation. This Review explores the emerging roles of the complosome and current knowledge regarding its relation to human diseases, highlighting evidence across organ systems and disease states, including the kidneys, digestive tract, lungs, heart, CNS, musculoskeletal system, skin, and cancer. We also review current scientific approaches for detecting and functionally investigating the complosome, addressing challenges such as technological limitations and the need for advanced experimental models to delineate its tissue-specific roles. Finally, we discuss central unanswered questions critical for developing innovative therapeutic strategies targeting intracellular complement pathways. These strategies hold potential to modulate disease-specific mechanisms while preserving systemic complement activity.

Friend or foe: assessing the value of animal models for facilitating clinical breakthroughs in complement research

2025-06-15

Felix Poppelaars , V. Michael Holers , Joshua M. Thurman | Journal of Clinical Investigation

Animal experiments have long been a cornerstone of advancements in biomedical research, particularly in developing novel therapeutic strategies for inflammatory and autoimmune diseases. However, these historically important approaches are now … Animal experiments have long been a cornerstone of advancements in biomedical research, particularly in developing novel therapeutic strategies for inflammatory and autoimmune diseases. However, these historically important approaches are now facing growing scrutiny for ethical reasons, concerns about translational limitations to human biology, and the rising availability of animal-free research methods. This shift raises a critical question: How relevant and effective are animal models for driving future advancements in today's research landscape? This Review aims to explore this question within the field of biomedical research on the complement system, critically evaluating the contribution of animal models to the recent advancements and clinical successes of complement-targeted therapies. Specifically, we assess areas where animal studies have been indispensable for elucidating disease mechanisms and conducting preclinical evaluations, alongside instances where findings from animal models failed to translate successfully to human trials. Furthermore, we discuss similarities and differences in the complement system between animals and humans and explore innovations in animal research designed to improve translatability to human biology. By assessing the contributions of animal studies to complement therapeutics, this Review aims to provide insights into animal models' strengths, limitations, and evolving role in complement research.

A piperidinyl indole derivative, potential complement factor B inhibitor, plays a renoprotective role in diabetic nephropathy

2025-06-15

Zandong Li , Zi‐Jun Sun , Dong‐Yuan Chang +3 more | Diabetic Medicine

Abstract Aims Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus (DM) and the main cause of end‐stage kidney disease (ESKD) worldwide. The pathogenesis of DN … Abstract Aims Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus (DM) and the main cause of end‐stage kidney disease (ESKD) worldwide. The pathogenesis of DN is complex, and cumulating evidence demonstrated that over‐activation of the complement system is involved. Complement factor B (CFB), a serine protease, drives the central amplification loop of the alternative pathway (AP) of the complement, making it a potential therapeutic target. In this study, we investigated the therapeutic potential of a piperidinyl indole derivative in db / db mice. Methods A highly potent CFB‐targeting compound, (+)‐4‐((2 S ,4 R )‐1‐((5‐methoxy‐7‐methyl‐1 H ‐indol‐4‐yl) methyl)‐4‐methylpiperidin‐2‐yl) benzoic acid (hereafter referred as the “compound”), was orally administered to the db / db mice model. Bioinformatics and network pharmacology analyses were applied in our research. Results Oral administration of the compound attenuated established DN in db / db mice, as evidenced by reduced urine albumin‐to‐creatine ratio (uACR), tubulointerstitial inflammation and fibrosis, and thickening of glomerular basement membrane. Besides binding to the active site of Bb, the enzyme‐cleaved activated fragment of CFB, and inhibiting the activity of complement component 3 (C3) convertase of the AP, the compound could regulate the expression of cysteinyl aspartate specific proteinase 3 (CASP3, a key executor of renal tubular apoptosis) and dipeptidyl peptidase 4 (DPP4, a pro‐fibrotic driver in tubulointerstitium) by bioinformatics and network pharmacology analysis. These complementary mechanisms cooperated to inhibit the over‐activation of complements and the apoptosis/fibrosis cascade and together alleviated DN progression. Conclusions Our data revealed the potential therapeutic strategy of using the piperidinyl indole derivative for the treatment of DN and provided a basis for its clinical development.

Proof-of-Concept in a Murine Model of Treatment of Thrombotic Thrombocytopenic Purpura Using Engineered Red Blood Cells

2025-06-15

Karl Roberts , Shouping Zhang , Batbayar Khulan +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Thrombotic Thrombocytopenic Purpura (TTP) is caused by congenital or acquired deficiency of ADAMTS13, a metalloproteinase that cleaves von Willebrand Factor (vWF) multimers. Current treatments, plasma exchange and immunosuppression, are costly … Thrombotic Thrombocytopenic Purpura (TTP) is caused by congenital or acquired deficiency of ADAMTS13, a metalloproteinase that cleaves von Willebrand Factor (vWF) multimers. Current treatments, plasma exchange and immunosuppression, are costly and associated with significant morbidity therefore, alternative strategies are needed.We developed the kitJak2 platform for producing genetically engineered lab-grown red blood cells (lgRBCs) as drug delivery vectors. We hypothesized that membrane-bound ADAMTS13 displayed on lgRBCs could provide a durable treatment for TTP. To test this, we engineered erythroid cells expressing both wild-type and mutant variants MDTCS fragments of ADAMTS13, conferring resistance to autoantibodies. Flow cytometry and FRET-based assays confirmed robust membrane expression and enzymatic activity. Importantly, mutant MDTCS variants retained catalytic activity in the presence of plasma from TTP patients, whereas wild-type variants were inhibited.For in vivo evaluation, we generated transgenic mice expressing MDTCS ADAMTS13 on their RBC membranes. These mice exhibited normal RBC half-lives and stable, catalytically active ADAMTS13 expression. Using a murine model of TTP, where ADAMTS13 knockout mice challenged with recombinant human vWF (rhvWF) develop thrombocytopenia and schistocytes, we demonstrated that transfusion of ADAMTS13-expressing RBCs significantly mitigated disease, preventing platelet loss and schistocyte formation. This confirms that membrane-bound MDTCS ADAMTS13 cleaves circulating rhvWF under physiological flow conditions in vivo.Finally, employing our KitJak2 platform, we generated human enucleated lgRBCs expressing high levels of catalytically active ADAMTS13.This novel work establishes proof-of-concept that membrane-anchored ADAMTS13-expressing lab-grown RBCs may offer a feasible and effective therapeutic approach for both congenital and acquired TTP.

Effectiveness and safety of ravulizumab for Japanese patients with atypical hemolytic uremic syndrome switched from eculizumab: an analysis of a post-marketing surveillance

2025-06-14

Shuichi Ito , Hiroshi Hataya , Masanori Matsumoto +5 more | Clinical and Experimental Nephrology

Patient-reported outcomes in patients with paroxysmal nocturnal hemoglobinuria treated with crovalimab and approved C5 inhibitors in the phase III COMMODORE 2 and 1 studies

2025-06-14

Jens Panse , Bing Han , Jaroslav Čermák +7 more | Annals of Hematology

Advances in Complement Inhibitory Strategies for the Treatment of Glomerular Disease: A Rapidly Evolving Field

2025-06-13

Ester Conversano , Marina Vivarelli | Journal of Clinical Medicine

There is rapidly increasing evidence of the role of complement in different forms of kidney disease and this has broadened the field to involve not only atypical hemolytic uremic syndrome … There is rapidly increasing evidence of the role of complement in different forms of kidney disease and this has broadened the field to involve not only atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G), but also a number of other glomerular diseases, mainly ANCA-associated renal vasculitis, immune-complex glomerulonephritis, membranous nephropathy, and IgA nephropathy (IgAN). In parallel, the field of therapeutic agents able to target the three complement pathways at different levels, both proximally and terminally, has grown tremendously in recent years. This has led to the approval of agents targeting complement for ANCA-associated vasculitis, IgA nephropathy, and, very recently, C3 glomerulopathy. The real-world implementation of these agents remains a challenge. This review will attempt, through the presentation of representative clinical vignettes, to provide some practical guidance for the nephrologist in how to navigate these new therapeutic opportunities, focusing on aHUS, C3G, and IgAN.

<scp>RBPJ</scp>/<scp>PAF1</scp> Signaling Axis Promotes Cloning Expansion in Paroxysmal Nocturnal Hemoglobinuria Through <scp>NOTCH</scp> Signaling

2025-06-12

Liyan Li , Junshu Wu , Zewei Chen +5 more | International Journal of Laboratory Hematology

ABSTRACT Background The pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH) is closely related to additional somatic mutations besides PIG‐A. Our previous research showed that some PNH patients had a high frequency … ABSTRACT Background The pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH) is closely related to additional somatic mutations besides PIG‐A. Our previous research showed that some PNH patients had a high frequency mutation of RBPJ through whole genome exon sequencing, which played an important role in the pathogenesis of PNH, but its molecular mechanism is still unclear. Methods SiRNA transfection was employed to generate RBPJ‐knockdown K562 and PNH cell lines. Cell proliferation and apoptosis were assessed via EDU and flow cytometry, respectively. LC–MS following silver staining identified RBPJ‐interacting proteins, which were subsequently validated using CO‐IP and gradient expression analysis. Western blot examined the relationship between RBPJ, PAF1, and the NOTCH signaling pathway in low‐RBPJ‐expressing PNH cell lines. The correlation between PAF1 expression, clonal PNH, and RBPJ expression was also analyzed. Results Knocking Out RBPJ Leads to Reduced Cell Proliferation and Increased Apoptosis in PNH Cells. We Identified PAF1 as an Interacting Protein of RBPJ and Confirmed the Interaction Domain to Be the BTD Domain of RBPJ . Knocking Out RBPJ Resulted in a Decrease of PAF1 Protein in KO Cell Lines, While the NOTCH1 and HEY1 Protein Expression Related to the NOTCH Signaling Decreased. GSEA Demonstrated That the KO Cell Lines Exhibited a Decreased NOTCH Signaling Pathway Upon PAF1 Downregulation. Knocking Down PAF1 Results in Reduced Protein Levels of NOTCH1 and NOTCH2 . Subsequently, After Knocking Out RBPJ With PAF1 Overexpression, NOTCH1 Expression Was Restored, Cell Apoptosis Rate Decreased, and Cell Proliferation Increased. Subsequently, we Observed Elevated PAF1 Expression in PNH Patients, Which Positively Correlated With the FLAER ‐CD14, FLAER‐ CD24 and RBPJ mRNA Expression in PNH Patients. Conclusion RBPJ/PAF1 may promote PNH clone proliferation by regulating the NOTCH signaling pathway.

Identification of a Novel Homozygous C1QB Mutation in an Iranian Girl: Expanding the Clinical Spectrum of C1q Deficiency

2025-06-12

Nassim Gorjizadeh , Negar Gorjizadeh , Fatemeh Bitarafan +2 more | International Journal of Immunogenetics

ABSTRACT C1q deficiency is a rare autosomal recessive disease associated with recurrent skin lesions, chronic infections and an increased risk of autoimmune disorders, particularly systemic lupus erythematosus (SLE) or SLE‐like … ABSTRACT C1q deficiency is a rare autosomal recessive disease associated with recurrent skin lesions, chronic infections and an increased risk of autoimmune disorders, particularly systemic lupus erythematosus (SLE) or SLE‐like disorders. Additionally, it has been linked to chronic glomerulonephritis and renal failure. C1q is the initial subcomponent of the classical pathway of the complement system and serves as a crucial linking factor between innate and acquired immunity. The C1 complex comprises three proteins: C1q, C1r and C1s. C1q comprises three chains: the A, B and C. The C1QB gene encodes the B‐chain polypeptide of the serum complement subcomponent C1q. We report the case of an Iranian girl from a consanguineous family who suffers from C1q deficiency, presenting with some SLE symptoms that have not previously been described in the literature. She presented with progressive weakness in walking, tissue injury, skin lesions and subjective cognitive complaints regarding concentration and memory. The proband exhibited mild asymmetric uptake in the pelvic region, resulting in a waddling gait. Additionally, she showed abnormal circulating homocysteine levels, skin abnormalities and early inflammatory arthritis symptoms associated with SLE. Whole‐exome sequencing (WES) was performed on the proband. A novel homozygous likely pathogenic missense variant in the C1QB gene, NM_001378156.1:c.263G>A, was identified. The variant was confirmed by Sanger sequencing in the proband, her parents and her healthy sister. This case highlights the significance of identifying a novel mutation in the C1QB gene, which expands the clinical spectrum of C1q deficiency. This finding contributes to the broader understanding of the disease's phenotype, helping to refine diagnostic criteria, particularly in cases with atypical manifestations. Furthermore, identifying such mutations in consanguineous families aids in genetic counselling and early diagnosis, allowing for better clinical management and prevention strategies.

Thrombotic Microangiopathy After Kidney Pancreas Transplant Managed With Eculizumab and a Calcineurin Inhibitor-free Basiliximab/Belatacept Maintenance Regimen: Between a Rock and a Hard Place

2025-06-12

Jeanne Chen , Muhammad S. Yaqub , Muhammad Y. Jan +5 more | Transplantation Direct

Reduced hemolytic complement activity in the classical pathway (CH50) is a risk factor for poor clinical outcomes of patients with infections: a retrospective analysis of health insurance claims in Japan

2025-06-05

Hiroyuki Koami , Yutaro Furukawa , Yuri Hirota +7 more | Frontiers in Immunology

Purpose To evaluate whether low CH50 (a comprehensive measure of hemolytic activity of the classical complement pathway) is associated with infection-related coagulopathy, organ dysfunction, and poor clinical outcomes. Methods This … Purpose To evaluate whether low CH50 (a comprehensive measure of hemolytic activity of the classical complement pathway) is associated with infection-related coagulopathy, organ dysfunction, and poor clinical outcomes. Methods This was a retrospective study using Japanese health insurance claim data (2014-2023). Adult patients whose CH50 values were measured within one week of admission were included. We divided the patients into three groups based on the normal CH50 range: Low CH50 (&lt; 25 U/mL; n=168), Normal CH50 (25 ≤, &lt; 48 U/mL; n=1273), and High CH50 (48 ≤ U/mL; n=1285). Results Of 2,726 patients who met the inclusion criteria, logistic regression models demonstrated that decreased CH50 is a significant predictor of 180-day mortality (OR: 0.98-0.99). Cumulative survival rates in the Low CH50 group at 28 days and 180 days were both unfavorable (both p &lt; 0.0001, Log-rank test). CH50 was significantly inversely correlated with SOFA, SIC, ISTH-overt DIC, and JAAM-2 DIC scores, and was also correlated with C3 and C4 levels. Diminished CH50 may be particularly useful in diagnosing SIC (specificity; 79.2%) and excluding ISTH-overt DIC (sensitivity; 90.5%). Moreover, patients with low levels of both CH50 and C3 had an extremely high mortality rate (25.0%). Conclusion Low CH50 after infection is not only significantly associated with multiple organ failure and coagulopathy but is also an independent risk factor for poor prognosis. Complement activation after infection may help to avert organ damage and to improve clinical outcomes.

Two Siblings with Missense Homozygous ABCA3 R43H Mutation Showing Good Response to Glucocorticoid

2025-06-04

Yasemin Mocan Çağlar , Özge Ülgen , Sinem Can Oksay +4 more | The Indian Journal of Pediatrics

Myocarditis and right atrial thrombus in a patient with Thrombotic thrombocytopenic purpura- CASE REPORT

2025-06-03

Jaideep Dey , Ashok Garg , Arif Mustaqueem +2 more | Research Square (Research Square)

<title>Abstract</title> <bold>Background: </bold>Thrombotic thrombocytopenic purpura is a very rare form of thrombotic microangiopathy with an annual incidence ranging between 1.5-6 cases per million adult individuals. Cardiac involvement in thrombotic thrombocytopenic … <title>Abstract</title> <bold>Background: </bold>Thrombotic thrombocytopenic purpura is a very rare form of thrombotic microangiopathy with an annual incidence ranging between 1.5-6 cases per million adult individuals. Cardiac involvement in thrombotic thrombocytopenic purpura may be diagnosed in up to a quarter of these patients, often associated with an adverse prognosis. Though cardiac microvascular thrombosis is most commonly noted, macrovascular thrombosis may also occur. <bold>Case Presentation:</bold> We report about a young male patient with obesity and hypertension who presented with recurrent ischemic strokes. He was found to be having severe hemolytic anemia along with severe thrombocytopenia. A diagnosis of thrombotic thrombocytopenic purpura was confirmed due to almost undetectable levels of a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 levels. His troponin I level was also elevated while having no cardiac symptoms. He was diagnosed with asymptomatic myocarditis along with right atrial thrombosis which was confirmed with transesophageal echocardiography and cardiac magnetic resonance imaging. This is probably the first reported case of concomitant myocarditis with intracardiac thrombosis in a patient of thrombotic thrombocytopenic purpura. Prompt initiation of plasma exchange therapy followed by corticosteroids, rituximab and aspirin led to disease remission. <bold>Conclusion: </bold>Intensivists and cardiologists must be aware of the varied presentations associated with thrombotic thrombocytopenic purpura. Early diagnosis and cardiac evaluation is essential for ensuring a favorable outcome in these critically ill patients.

Thrombotic thrombocytopenic purpura in pregnancy: A case report and literature review

2025-06-03

Brielle Andreatidis , N Weber , Ann‐Maree Craven +3 more | Obstetric Medicine

Thrombotic thrombocytopenic purpura (TTP) is a serious but rare cause of thrombocytopenia in pregnancy which poses a significant morbidity and mortality burden to the maternofetal dyad. Diagnosing TTP in pregnancy … Thrombotic thrombocytopenic purpura (TTP) is a serious but rare cause of thrombocytopenia in pregnancy which poses a significant morbidity and mortality burden to the maternofetal dyad. Diagnosing TTP in pregnancy is challenging due to its non-specific clinical presentation, and the potential for similar or concomitant presentation with other thrombotic microangiopathies. We present an atypical case of TTP diagnosed in an asymptomatic 28-year-old female, at 35 weeks' gestation. TTP must be considered a differential for thrombocytopenia, especially in the context of autoimmune disease and even in the absence of typical signs or symptoms. Increasingly available diagnostic tools may help redefine our understanding of TTP presentations in pregnancy.

New insights into renal involvement during immune-mediated thrombotic thrombocytopenic purpura

2025-06-01

M Robert , Valentin Maisons , Marion Rabant +7 more | Kidney International Reports