Review doi: 10.1111/joim.12338
Complement regulators in human disease: lessons from modern genetics M. K. Liszewski & J. P. Atkinson From the Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
Abstract. Liszewski MK, Atkinson JP (Washington University School of Medicine, St. Louis, MO, USA). Complement regulators in human disease: lessons from modern genetics (Review). J Intern Med 2015; doi: 10.1111/joim.12338. First identified in human serum in the late 19th century as a ‘complement’ to antibodies in mediating bacterial lysis, the complement system emerged more than a billion years ago probably as the first humoral immune system. The contemporary complement system consists of nearly 60 proteins in three activation pathways (classical, alternative and lectin) and a terminal cytolytic pathway common to all. Modern molecular biology
Introduction The system The complement and coagulation systems, two ancient pathways in the circulation, are essential for species with a ‘pumped’ circulation [1, 2]. These systems are characterized by proteolytic cascades that act in seconds with a remarkable ability for amplification. Because of their complexity and extensive biological connections, they are often referred to as ‘the terrible Cs’ by medical students. The major role of both systems is to guard the intravascular space from an infection on the one hand and from haemorrhage on the other. Such powerful cascades also require ongoing homeostatic control and strict regulation regarding what they target; ‘too much’ or ‘not enough’, both scenarios lead to disease [3]. Although there is evidence for their interplay, they are largely two independent systems [1, 4]. The complement system has a key role in innate immunity and is a major effector arm of humoral immunity. It consists of (i) recognition proteins (antibodies and lectins) that trigger the system; (ii) sequentially acting plasma proteins comprising serine proteases and a feedback loop; (iii) terminal membrane-perturbing components that form a
and genetics have not only led to further elucidation of the structure of complement system components, but have also revealed function-altering rare variants and common polymorphisms, particularly in regulators of the alternative pathway, that predispose to human disease by creating ‘hyperinflammatory complement phenotypes’. To treat these ‘complementopathies’, a monoclonal antibody against the initiator of the membrane attack complex, C5, has received approval for use. Additional therapeutic reagents are on the horizon. Keywords: age-related macular degeneration, atypical haemolytic uraemic syndrome, complement regulation, eculizumab, genetics, therapeutics. membrane attack complex (MAC) by nonproteolytic protein–protein interactions; (iv) components that are synthesized primarily in the liver, but also locally by monocytes, macrophages, fibroblasts and many types of epithelial cells; (v) plasma and membrane protein regulators and receptors; and (vi) anaphylatoxins that are liberated by proteolysis to promote the inflammatory response. After engagement of the system by an initiating trigger, the early steps consist of proteolytic cascades grouped into three pathways (classical, alternative and lectin) followed by a terminal membrane attack (cytolytic) pathway common to all. Complement has two major functions: (i) to opsonize and disrupt the membrane integrity of its targets and (ii) to promote the inflammatory response (Fig. 1).
History The complement system was described more than 125 years ago as a relatively unstable and heatlabile lytic substance in blood that ‘complemented’ antibodies (the more stable and nonheat labile fraction of serum) in destroying bacteria. Jules Bordet was awarded the 1919 Nobel Prize in Physiology or Medicine for his discoveries related to the identification of complement and its application in widely employed complement-fixation
ª 2014 The Association for the Publication of the Journal of Internal Medicine
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Review: Complement regulators in human disease
(a) Complement function
Complement
Membrane Perturbation
Inflammation
Opsonins/Lysis
Pathogens
Anaphylatoxins
Cell Debris
Mast Cell Degranulation
Chemotaxis
(b) Complement Activation in Innate Immunity C3 Turnover (AP)
Natural Abs (CP)
Apoptotic cells Tissue debris
Lectins (LP)
Pathogens
Fig. 1 Complement function and activation. (a) The complement system serves two major functions. First, it alters the membrane of pathogens and cellular debris. This coating (i.e. opsonization) promotes removal of particles via complement receptors on host cells. Opsonization also leads to assembly of the membrane attack complex on pathogens and subsequent lysis. A second function of the complement system is to enhance the inflammatory response via release of anaphylatoxins that promote cell activation (e.g. mast cell degranulation) or migration to an inflammatory site (chemotaxis). (b) Complement activation in innate immunity. The complement system becomes activated on a target, such as apoptotic cells, tissue debris, or pathogens. This occurs by at least three mechanisms that are independent of a prior adaptive immune response: (i) natural, spontaneous turnover (i.e. ‘tick over’) of C3 engages the alternative pathway (AP); (ii) binding to the target of naturally occurring antibodies (Abs) engages the classical pathway (CP); and (iii) binding of lectins to carbohydrates on the target engages the lectin pathway (LP). In adaptive immunity, natural Abs are replaced by specific Abs.
tests. We now know that the cascades consist of two target-specific initiating arms [the classical pathway (CP) and the lectin pathway (LP)] and one with continuous low-level turnover [the alternative pathway (AP)]. The AP has a huge amplification capacity. The major purpose of this rapid and powerful activation scheme, designed to function on the surface of bacterial pathogens, is to prevent invasion of the circulation. Because of the latter function, the complement system is often termed ‘the guardian of the intravascular space’. Additionally, the powerful activation cascades require tight regulation to maintain appropriate homeostasis and to avoid excessive damage to self. Nearly half of all complement proteins serve as regulators or inhibitors, the expression in body fluids and on cells and the concentrations of which have been 2
ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine
carefully selected and titrated during evolution. Thus, decreased functionality of these regulatory proteins is deleterious. Before the era of modern genetics, our understanding of diseases associated with the complement system was mainly derived from very rare patients (i.e. experiments of nature) who had inherited a complete deficiency of an activation cascade component or an inhibitor [5, 6]. Individuals with a C3 deficiency were particularly predisposed to infections by pyogenic bacteria, whereas those with a deficiency of a membrane attack complex (MAC) component (C5, C6, C7, C8 or C9) presented with infection by meningococcus or gonococcus [5, 6]. Surprisingly, autoimmunity also was found to be associated with deficiencies of complement. A
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complete deficiency of a C1 subcomponent (C1q, C1r or C1s), C4 or C2 predisposed to systemic lupus erythematosus (SLE). These five proteins are all part of the early sequentially acting cascade of the CP. Deficiency of a complement regulatory protein also is associated with disease. For over 50 years, it has been known that haploinsufficiency of the C1-inhibitor causes the autosomal dominant disorder hereditary angioedema. Further, for nearly as long, it has been known that a total deficiency of a regulator [e.g. factor H (FH) or factor I (FI)] at the C3 cleavage step leads to a complete consumption (turnover) of C3. The modern era The advent of modern genetics allowed for the identification of mutations (common and rare variants) in complement proteins. A remarkable finding from modern genetics studies is that a role for the complement system has been defined in unanticipated areas, such as in an acute illness predominantly of childhood, atypical haemolytic uraemic syndrome (aHUS) and a chronic disease of the elderly, age-related macular degeneration (AMD), which is the leading cause of blindness worldwide in this population [7–9]. Previously, there had been only scant and largely overlooked evidence to associate these diseases with the complement system. A breakthrough in understanding aHUS came from studies employing satellite markers that identified causative rare variants in complement inhibitors [10]; progress in the understanding of AMD was based on genome-wide association studies (GWASs) that identified common variants with more modest effects [11–17]. Subsequently, ‘next-generation sequencing’ allowed for identification of causal rare variants in these two diseases. We now know that a number of genetic alterations are associated with increased risk of developing aHUS and AMD. Many of these reside in genes encoding the complement cascade [7, 9, 12–14, 17, 18]. These variants span the allelic spectrum of disease from common variants (frequency ≥1%) that impart relatively low risk of disease to rare variants (frequency 50 million individuals worldwide and is the leading cause of blindness in developed countries [41]. AMD is a slowly progressive, degenerative ophthalmological disease that normally manifests after 60 years of age. Loss of central vision commonly occurs secondary to disruption of photoreceptor cells in the macula (Fig. 5). (a)
(b)
Light
There are two types of AMD: dry (atrophic) and wet (neovascular or exudative). Most cases begin as dry AMD and 10–20% progress to the wet type of disease. Wet AMD accounts for most cases of severe vision loss. This results from growth of abnormal blood vessels from the choroid into the macula that tends to break and leak causing severe macular damage. The involvement of the complement system in AMD was first clearly demonstrated by Hageman and colleagues who identified C3 fragments, MAC components and FH in drusen, the characteristic lipid-/pigment-rich ‘waste’ material found in damaged areas of the eye [22] (Fig 5). They proposed a model for AMD pathogenesis based on a prominent role for inflammation. However, the significance of these observations was not widely appreciated until the genetic connection was established several years later [11–17]. A conceptually straightforward pathophysiological scenario is that drusen accumulate, the AP becomes activated and an excessive (i.e. damaging) inflammatory response ensues to progressively destroy retinal tissue. Further, chronic liberation of proinflammatory C3a and C5a in the retina is likely to be deleterious, especially in light of the role of these proteins as initiators of vascular endothelial growth factor invasion of choroidal vessels (wet AMD) in the macula [42]. Common variants Genetic studies (GWASs) in 2005 by four research teams identified a common single nucleotide
Healthy
Damaged
Photoreceptor cells Drusen RPE Bruch´s membrane Retina Optic nerve
Macula
Choroid
Nutrient uptake
Nutrient uptake
Fig. 5 Cross-sectional diagram of the human eye and pathology of age-related macular degeneration (AMD). (a) Location of the retina and macula in early AMD (dry type). (b) Inset shown in A is amplified to demonstrate healthy versus damaged tissue. Subretinal drusen accumulate, block nutrients (arrows) and damage the photoreceptor cell layer. This leads to subsequent atrophy. Progression to wet-type AMD leads to photoreceptor cell degeneration, abnormal blood vessel growth into the choroid and blindness. Modified from Schramm et al. Molecular Immunology, 2014; 61: 118–125. ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine
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polymorphism (SNP) in the FH gene (rs1061170) that was associated with an increased risk of developing AMD [12, 43–45]. This SNP results in a histidine residue replacing a tyrosine residue at position 402 (i.e. Y402H). FH consists of 1213 amino acids arranged in 20 homologous units termed complement control protein (CCP) modules, each of which is ~60 amino acids long (Fig. 4) [34, 35]. Individuals who are heterozygous for the Y402H polymorphism (also termed Y384H without the 18 amino acid signal peptide) have a two- to fourfold increased risk of developing AMD whilst homozygotes have a five- to 10-fold increased risk [17]. Many ethnic populations carry this polymorphism; for example, approximately 30% of individuals of European descent carry at least one copy of this risk allele. The Y402H polymorphism occurs in the seventh CCP and alters the binding of FH to a number of ligands including charged molecules (such as glycosaminoglycans) that are commonly found on cell surfaces and matrices. A current hypothesis for AMD pathogenesis, which has substantial evidence, is that FH bearing this polymorphism binds less well to drusen and, therefore, there is excessive AP activation leading to further damage. Although this FH polymorphism may not be the primary cause of the disorder, it accelerates the disease process. A possible explanation for the high prevalence of the Y402H polymorphism is that the minor (Hcarrying) allele provides a survival advantage against streptococcal infections early in life and is, therefore, increasing in the population [46, 47]. The FH-binding protein of streptococcus has a much lower affinity for 402H than 402Y and thus would allow for enhanced AP activation on these pathogens. A similar hypothesis to explain positive selection for 402H was suggested by Avery in relation to the bacterium Yersinia pestis [48]. He suggested that less efficient binding of 402H to its membrane would prevent immune evasion (allowing for more AP activation) and thereby confer protection against the Black Death, a disease that is estimated to have killed 30–60% of the European population during the Middle Ages [48]. However, in old age, there is a negative effect of 402H with regard to handling drusen. With advancing age and because this variant also does not bind as well to drusen, it does not control retinal inflammation as efficiently as the more common (402Y) FH allele (reviewed in [11]). Since the important identifica8
ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine
Review: Complement regulators in human disease
tion of this common FH polymorphism predisposing to AMD, much evidence has accumulated to support the notion that AMD is a disease of dysfunctional AP regulation. Common variants in complement proteins may be either ‘protective’ or ‘risk’ alleles (reviewed in [11]). Complete deletion of the genes CFHR1 and CFHR3 was found to protect against AMD, as does the presence of two FB haplotypes [14, 16, 49]. A common SNP in C3 results in an R102G substitution that is associated with an increased risk of AMD due to decreased cofactor function [15, 50]. A common polymorphism near the gene for FI (in the 30 untranslated area) has been described, although its functional defect remains to be elucidated (reviewed in [11]). Rare variants Rare variants that segregate with disease in a Mendelian fashion often have a large effect (highly penetrant). Such a rare variant (1210C) was first identified in FH [11, 51]; subsequently, several other highly penetrant FH variants were recognized [52]. Recently, TDS was used to screen for rare variants in 687 targeted genes including all 59 complement components and regulators in a cohort of 2493 cases and controls [19]. The remarkable finding of this study was that ~8% of patients carried a rare FI variant, representing an enrichment of cases compared to controls. Further, a single uncommon C3 gene, independently identified and investigated by several groups, demonstrates significant reduction in function (reduced cofactor activity) [19, 53, 54]. Three important observations emerge from these studies demonstrating the linkage of complement protein dysfunction to AMD. First, evolution has naturally focused on ensuring that humans reach a reproductive age and not on vision retention in old age. It is proposed that the common allele in FH is protective against AMD but is being replaced in the human population by the minor allele that offers a selective advantage for enhanced survival against infections in early childhood. Secondly, in the last decade, next-generation sequencing studies have demonstrated a link between both common and rare variants in AP proteins and risk of AMD development. Finally, the presence of AP variants establishes a key role of this ancient immune system in the pathogenesis of AMD. The implication is that a balance between activation
Review doi: 10.1111/joim.12338
Complement regulators in human disease: lessons from modern genetics M. K. Liszewski & J. P. Atkinson From the Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
Abstract. Liszewski MK, Atkinson JP (Washington University School of Medicine, St. Louis, MO, USA). Complement regulators in human disease: lessons from modern genetics (Review). J Intern Med 2015; doi: 10.1111/joim.12338. First identified in human serum in the late 19th century as a ‘complement’ to antibodies in mediating bacterial lysis, the complement system emerged more than a billion years ago probably as the first humoral immune system. The contemporary complement system consists of nearly 60 proteins in three activation pathways (classical, alternative and lectin) and a terminal cytolytic pathway common to all. Modern molecular biology
Introduction The system The complement and coagulation systems, two ancient pathways in the circulation, are essential for species with a ‘pumped’ circulation [1, 2]. These systems are characterized by proteolytic cascades that act in seconds with a remarkable ability for amplification. Because of their complexity and extensive biological connections, they are often referred to as ‘the terrible Cs’ by medical students. The major role of both systems is to guard the intravascular space from an infection on the one hand and from haemorrhage on the other. Such powerful cascades also require ongoing homeostatic control and strict regulation regarding what they target; ‘too much’ or ‘not enough’, both scenarios lead to disease [3]. Although there is evidence for their interplay, they are largely two independent systems [1, 4]. The complement system has a key role in innate immunity and is a major effector arm of humoral immunity. It consists of (i) recognition proteins (antibodies and lectins) that trigger the system; (ii) sequentially acting plasma proteins comprising serine proteases and a feedback loop; (iii) terminal membrane-perturbing components that form a
and genetics have not only led to further elucidation of the structure of complement system components, but have also revealed function-altering rare variants and common polymorphisms, particularly in regulators of the alternative pathway, that predispose to human disease by creating ‘hyperinflammatory complement phenotypes’. To treat these ‘complementopathies’, a monoclonal antibody against the initiator of the membrane attack complex, C5, has received approval for use. Additional therapeutic reagents are on the horizon. Keywords: age-related macular degeneration, atypical haemolytic uraemic syndrome, complement regulation, eculizumab, genetics, therapeutics. membrane attack complex (MAC) by nonproteolytic protein–protein interactions; (iv) components that are synthesized primarily in the liver, but also locally by monocytes, macrophages, fibroblasts and many types of epithelial cells; (v) plasma and membrane protein regulators and receptors; and (vi) anaphylatoxins that are liberated by proteolysis to promote the inflammatory response. After engagement of the system by an initiating trigger, the early steps consist of proteolytic cascades grouped into three pathways (classical, alternative and lectin) followed by a terminal membrane attack (cytolytic) pathway common to all. Complement has two major functions: (i) to opsonize and disrupt the membrane integrity of its targets and (ii) to promote the inflammatory response (Fig. 1).
History The complement system was described more than 125 years ago as a relatively unstable and heatlabile lytic substance in blood that ‘complemented’ antibodies (the more stable and nonheat labile fraction of serum) in destroying bacteria. Jules Bordet was awarded the 1919 Nobel Prize in Physiology or Medicine for his discoveries related to the identification of complement and its application in widely employed complement-fixation
ª 2014 The Association for the Publication of the Journal of Internal Medicine
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appreciation of its roles in innate immunity and by new understandings derived from modern genetics. The past decade has witnessed a rapid growth in interest in complement-targeted therapeutics. The future emergence of additional complement inhibitors is much anticipated. Conflict of interest statement MKL has no conflict of interests. JPA has received research funding from Alexion Pharmaceuticals and honoraria or consultancy fees from Compliment Corporation, Celldex Therapeutics, Alnylam Pharmaceuticals, Biothera, Clinical Pharmacy Services, Kypha, iPierian, Allergan and Achillion Pharmaceuticals.
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11 Schramm EC, Clark SJ, Triebwasser MP, Raychaudhuri S, Seddon J, Atkinson JP. Genetic variants in the complement system predisposing to age-related macular degeneration: A review. Mol Immunol 2014; 61: 118–25. 12 Klein RJ, Zeiss C, Chew EY et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005; 308: 385–9. 13 Maller J, George S, Purcell S et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet 2006; 38: 1055–9. 14 Hughes AE, Orr N, Esfandiary H, Diaz-Torres M, Goodship T, Chakravarthy U. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet 2006; 38: 1173–7. 15 Maller JB, Fagerness JA, Reynolds RC, Neale BM, Daly MJ, Seddon JM. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet 2007; 39: 1200–1. 16 Fritsche LG, Chen W, Schu M et al. Seven new loci associated with age-related macular degeneration. Nat Genet 2013; 45: 433–9, 9e1-2. 17 Sofat R, Casas JP, Webster AR et al. Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype. Int J Epidemiol 2012; 41: 250–62. 18 Riedl M, Fakhouri F, Le Quintrec M et al. Spectrum of complement-mediated thrombotic microangiopathies: pathogenetic insights identifying novel treatment approaches. Semin Thromb Hemost 2014; 40: 444–64. 19 Seddon JM, Yu Y, Miller EC et al. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat Genet 2013; 45: 1366–70. 20 Liszewski MK, Atkinson JP. Novel disease associations revealed by whole genome screens. The Rheumatologist 2010; 4: 16–23. 21 Kavanagh D, Richards A, Atkinson JP. Complement regulatory genes and hemolytic uremic syndromes. Annu Rev Med 2008; 59: 293–309. 22 Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 2001; 20: 705–32. 23 Ariki S, Takahara S, Shibata T et al. Factor C acts as a lipopolysaccharide-responsive C3 convertase in horseshoe crab complement activation. J Immunol 2008; 181: 7994– 8001. 24 Zhu Y, Thangamani S, Ho B, Ding JL. The ancient origin of the complement system. EMBO J 2005; 24: 382–94. 25 Nonaka M, Kimura A. Genomic view of the evolution of the complement system. Immunogenetics 2006; 58: 701–13. 26 Smith LC, Azumi K, Nonaka M. Complement systems in invertebrates. The ancient alternative and lectin pathways. Immunopharmacology 1999; 42: 107–20. 27 Lachmann PJ. The amplification loop of the complement pathways. Adv Immunol 2009; 104: 115–49. 28 Liszewski MK, Post TW, Atkinson JP. Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster. Annu Rev Immunol 1991; 9: 431–55.
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29 Zipfel PF, Skerka C. Complement regulators and inhibitory proteins. Nat Rev Immunol 2009; 9: 729–40. 30 Lambris JD, Ricklin D, Geisbrecht BV. Complement evasion by human pathogens. Nat Rev Microbiol 2008; 6: 132– 42. 31 Thurman JM, Holers VM. The central role of the alternative complement pathway in human disease. J Immunol 2006; 176: 1305–10. 32 Holers VM. The spectrum of complement alternative pathway-mediated diseases. Immunol Rev 2008; 223: 300– 16. 33 Fang C, Richards A, Liszewski MK, Kavanagh D, Atkinson JP. Advances in understanding of pathogenesis of aHUS and HELLP. Br J Haematol 2008; 143: 336–48. 34 Makou E, Herbert AP, Barlow PN. Functional anatomy of complement factor H. Biochemistry (Mosc) 2013; 52: 3949– 62. 35 Kopp A, Hebecker M, Svobodova E, Jozsi M. Factor h: a complement regulator in health and disease, and a mediator of cellular interactions. Biomolecules 2012; 2: 46–75. 36 Cardone J, Le Friec G, Kemper C. CD46 in innate and adaptive immunity: an update. Clin Exp Immunol 2011; 164: 301–11. 37 Liszewski MK, Kemper C, Price JD, Atkinson JP. Emerging roles and new functions of CD46. Springer Semin Immunopathol 2005; 27: 345–58. 38 Fremeaux-Bacchi V, Goodship T, Regnier CH, Dragon-Durey MA, Janssen B, Atkinson J. Mutations in complement C3 predispose to development of atypical haemolytic uraemic syndrome. Mol Immunol 2007; 44: 3923. 39 Dragon-Durey MA, Blanc C, Garnier A, Hofer J, Sethi SK, Zimmerhackl LB. Anti-factor H autoantibody-associated hemolytic uremic syndrome: review of literature of the autoimmune form of HUS. Semin Thromb Hemost 2010; 36: 633– 40. 40 Loirat C, Fremeaux-Bacchi V. Anti-factor H autoantibody-associated hemolytic uremic syndrome: the earlier diagnosed and treated, the better. Kidney Int 2014; 85: 1019–22. 41 Khandhadia S, Cipriani V, Yates JR, Lotery AJ. Age-related macular degeneration and the complement system. Immunobiology 2012; 217: 127–46. 42 Gehrs KM, Anderson DH, Johnson LV, Hageman GS. Age-related macular degeneration-emerging pathogenetic and therapeutic concepts. Ann Med 2006; 38: 450–71. 43 Hageman GS, Anderson DH, Johnson LV et al. A common haplotype in the complement regulatory gene factor H (HF1/ CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 2005; 102: 7227–32. 44 Edwards AO, Ritter R III, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science 2005; 308: 421–4. 45 Haines JL, Hauser MA, Schmidt S et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005; 308: 419–21. 46 Haapasalo K, Vuopio J, Syrjanen J et al. Acquisition of complement factor H is important for pathogenesis of Streptococcus pyogenes infections: evidence from bacterial in vitro survival and human genetic association. J Immunol 2012; 188: 426–35. 47 Haapasalo K, Jarva H, Siljander T, Tewodros W, Vuopio-Varkila J, Jokiranta TS. Complement factor H allotype 402H is
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associated with increased C3b opsonization and phagocytosis of Streptococcus pyogenes. Mol Microbiol 2008; 70: 583–94. Avery RL. The plague and macular degeneration. Ophthalmology 2010; 117: 2442. Hageman GS, Hancox LS, Taiber AJ et al. Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann Med 2006; 38: 592–604. Yates JR, Sepp T, Matharu BK et al. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 2007; 357: 553–61. Raychaudhuri S, Iartchouk O, Chin K et al. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat Genet 2011; 43: 1232–6. Yu Y, Triebwasser MP, Wong KS, et al. Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration. Hum Mol Gen 2014; 23: 5283–93. Zhan X, Larson DE, Wang C et al. Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. Nat Genet 2013; 45: 1375–9. Helgason H, Sulem P, Duvvari MR et al. A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration. Nat Genet 2013; 45: 1371–4. Salmon JE, Heuser C, Triebwasser M et al. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med 2011; 8: e1001013. Fang CJ, Fremeaux-Bacchi V, Liszewski MK et al. Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood 2008; 111: 624– 32. Fakhouri F, Jablonski M, Lepercq J et al. Factor H, membrane cofactor protein and Factor I mutations in patients with HELLP syndrome. Blood 2008; 112: 4542–5. Wagner E, Frank MM. Therapeutic potential of complement modulation. Nat Rev Drug Discov 2010; 9: 43–56. Ricklin D, Lambris JD. Complement-targeted therapeutics. Nat Biotechnol 2007; 25: 1265–75. Legendre CM, Licht C, Muus P et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013; 368: 2169–81. Keating GM. Eculizumab: a review of its use in atypical haemolytic uraemic syndrome. Drugs 2013; 73: 2053–66. Kavanagh D, Goodship TH, Richards A. Atypical hemolytic uremic syndrome. Semin Nephrol 2013; 33: 508–30. Java A, Atkinson J, Salmon J. Defective complement inhibitory function predisposes to renal disease. Annu Rev Med 2013; 64: 307–24. Kavanagh D, Richards A, Fremeaux-Bacchi V et al. Screening for complement system abnormalities in patients with atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 2007; 2: 591–6. Wehling C, Kirschfink M. Tailored eculizumab regimen for patients with atypical hemolytic uremic syndrome: requirement for comprehensive complement analysis. J Thromb Haemost 2014; 12: 1437–9. Cugno M, Gualtierotti R, Possenti I et al. Complement functional tests for monitoring eculizumab treatment in patients
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with atypical hemolytic uremic syndrome. J Thromb Haemost 2014; 12: 1440–8. 67 Noris M, Galbusera M, Gastoldi S et al. Dynamics of complement activation in atypical HUS and how to monitor eculizumab therapy. Blood 2014; 124: 1715–26. 68 Cataland SR, Wu HM. How I treat: the clinical differentiation and initial treatment of adult patients with atypical hemolytic uremic syndrome. Blood 2014; 123: 2478–84.
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69 Cataland SR, Wu HM. Diagnosis and management of complement mediated thrombotic microangiopathies. Blood Rev 2014; 28: 67–74. Correspondence: John P. Atkinson, MD, Division of Rheumatology, Washington University School of Medicine, 660 S Euclid, Box 8045, St. Louis, MO 63110, USA. (fax: 314-362-9257; e-mail: [email protected]).
Complement regulators in human disease: lessons from modern genetics M. K. Liszewski & J. P. Atkinson From the Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
Abstract. Liszewski MK, Atkinson JP (Washington University School of Medicine, St. Louis, MO, USA). Complement regulators in human disease: lessons from modern genetics (Review). J Intern Med 2015; doi: 10.1111/joim.12338. First identified in human serum in the late 19th century as a ‘complement’ to antibodies in mediating bacterial lysis, the complement system emerged more than a billion years ago probably as the first humoral immune system. The contemporary complement system consists of nearly 60 proteins in three activation pathways (classical, alternative and lectin) and a terminal cytolytic pathway common to all. Modern molecular biology
Introduction The system The complement and coagulation systems, two ancient pathways in the circulation, are essential for species with a ‘pumped’ circulation [1, 2]. These systems are characterized by proteolytic cascades that act in seconds with a remarkable ability for amplification. Because of their complexity and extensive biological connections, they are often referred to as ‘the terrible Cs’ by medical students. The major role of both systems is to guard the intravascular space from an infection on the one hand and from haemorrhage on the other. Such powerful cascades also require ongoing homeostatic control and strict regulation regarding what they target; ‘too much’ or ‘not enough’, both scenarios lead to disease [3]. Although there is evidence for their interplay, they are largely two independent systems [1, 4]. The complement system has a key role in innate immunity and is a major effector arm of humoral immunity. It consists of (i) recognition proteins (antibodies and lectins) that trigger the system; (ii) sequentially acting plasma proteins comprising serine proteases and a feedback loop; (iii) terminal membrane-perturbing components that form a
and genetics have not only led to further elucidation of the structure of complement system components, but have also revealed function-altering rare variants and common polymorphisms, particularly in regulators of the alternative pathway, that predispose to human disease by creating ‘hyperinflammatory complement phenotypes’. To treat these ‘complementopathies’, a monoclonal antibody against the initiator of the membrane attack complex, C5, has received approval for use. Additional therapeutic reagents are on the horizon. Keywords: age-related macular degeneration, atypical haemolytic uraemic syndrome, complement regulation, eculizumab, genetics, therapeutics. membrane attack complex (MAC) by nonproteolytic protein–protein interactions; (iv) components that are synthesized primarily in the liver, but also locally by monocytes, macrophages, fibroblasts and many types of epithelial cells; (v) plasma and membrane protein regulators and receptors; and (vi) anaphylatoxins that are liberated by proteolysis to promote the inflammatory response. After engagement of the system by an initiating trigger, the early steps consist of proteolytic cascades grouped into three pathways (classical, alternative and lectin) followed by a terminal membrane attack (cytolytic) pathway common to all. Complement has two major functions: (i) to opsonize and disrupt the membrane integrity of its targets and (ii) to promote the inflammatory response (Fig. 1).
History The complement system was described more than 125 years ago as a relatively unstable and heatlabile lytic substance in blood that ‘complemented’ antibodies (the more stable and nonheat labile fraction of serum) in destroying bacteria. Jules Bordet was awarded the 1919 Nobel Prize in Physiology or Medicine for his discoveries related to the identification of complement and its application in widely employed complement-fixation
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Review: Complement regulators in human disease
(a) Complement function
Complement
Membrane Perturbation
Inflammation
Opsonins/Lysis
Pathogens
Anaphylatoxins
Cell Debris
Mast Cell Degranulation
Chemotaxis
(b) Complement Activation in Innate Immunity C3 Turnover (AP)
Natural Abs (CP)
Apoptotic cells Tissue debris
Lectins (LP)
Pathogens
Fig. 1 Complement function and activation. (a) The complement system serves two major functions. First, it alters the membrane of pathogens and cellular debris. This coating (i.e. opsonization) promotes removal of particles via complement receptors on host cells. Opsonization also leads to assembly of the membrane attack complex on pathogens and subsequent lysis. A second function of the complement system is to enhance the inflammatory response via release of anaphylatoxins that promote cell activation (e.g. mast cell degranulation) or migration to an inflammatory site (chemotaxis). (b) Complement activation in innate immunity. The complement system becomes activated on a target, such as apoptotic cells, tissue debris, or pathogens. This occurs by at least three mechanisms that are independent of a prior adaptive immune response: (i) natural, spontaneous turnover (i.e. ‘tick over’) of C3 engages the alternative pathway (AP); (ii) binding to the target of naturally occurring antibodies (Abs) engages the classical pathway (CP); and (iii) binding of lectins to carbohydrates on the target engages the lectin pathway (LP). In adaptive immunity, natural Abs are replaced by specific Abs.
tests. We now know that the cascades consist of two target-specific initiating arms [the classical pathway (CP) and the lectin pathway (LP)] and one with continuous low-level turnover [the alternative pathway (AP)]. The AP has a huge amplification capacity. The major purpose of this rapid and powerful activation scheme, designed to function on the surface of bacterial pathogens, is to prevent invasion of the circulation. Because of the latter function, the complement system is often termed ‘the guardian of the intravascular space’. Additionally, the powerful activation cascades require tight regulation to maintain appropriate homeostasis and to avoid excessive damage to self. Nearly half of all complement proteins serve as regulators or inhibitors, the expression in body fluids and on cells and the concentrations of which have been 2
ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine
carefully selected and titrated during evolution. Thus, decreased functionality of these regulatory proteins is deleterious. Before the era of modern genetics, our understanding of diseases associated with the complement system was mainly derived from very rare patients (i.e. experiments of nature) who had inherited a complete deficiency of an activation cascade component or an inhibitor [5, 6]. Individuals with a C3 deficiency were particularly predisposed to infections by pyogenic bacteria, whereas those with a deficiency of a membrane attack complex (MAC) component (C5, C6, C7, C8 or C9) presented with infection by meningococcus or gonococcus [5, 6]. Surprisingly, autoimmunity also was found to be associated with deficiencies of complement. A
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complete deficiency of a C1 subcomponent (C1q, C1r or C1s), C4 or C2 predisposed to systemic lupus erythematosus (SLE). These five proteins are all part of the early sequentially acting cascade of the CP. Deficiency of a complement regulatory protein also is associated with disease. For over 50 years, it has been known that haploinsufficiency of the C1-inhibitor causes the autosomal dominant disorder hereditary angioedema. Further, for nearly as long, it has been known that a total deficiency of a regulator [e.g. factor H (FH) or factor I (FI)] at the C3 cleavage step leads to a complete consumption (turnover) of C3. The modern era The advent of modern genetics allowed for the identification of mutations (common and rare variants) in complement proteins. A remarkable finding from modern genetics studies is that a role for the complement system has been defined in unanticipated areas, such as in an acute illness predominantly of childhood, atypical haemolytic uraemic syndrome (aHUS) and a chronic disease of the elderly, age-related macular degeneration (AMD), which is the leading cause of blindness worldwide in this population [7–9]. Previously, there had been only scant and largely overlooked evidence to associate these diseases with the complement system. A breakthrough in understanding aHUS came from studies employing satellite markers that identified causative rare variants in complement inhibitors [10]; progress in the understanding of AMD was based on genome-wide association studies (GWASs) that identified common variants with more modest effects [11–17]. Subsequently, ‘next-generation sequencing’ allowed for identification of causal rare variants in these two diseases. We now know that a number of genetic alterations are associated with increased risk of developing aHUS and AMD. Many of these reside in genes encoding the complement cascade [7, 9, 12–14, 17, 18]. These variants span the allelic spectrum of disease from common variants (frequency ≥1%) that impart relatively low risk of disease to rare variants (frequency 50 million individuals worldwide and is the leading cause of blindness in developed countries [41]. AMD is a slowly progressive, degenerative ophthalmological disease that normally manifests after 60 years of age. Loss of central vision commonly occurs secondary to disruption of photoreceptor cells in the macula (Fig. 5). (a)
(b)
Light
There are two types of AMD: dry (atrophic) and wet (neovascular or exudative). Most cases begin as dry AMD and 10–20% progress to the wet type of disease. Wet AMD accounts for most cases of severe vision loss. This results from growth of abnormal blood vessels from the choroid into the macula that tends to break and leak causing severe macular damage. The involvement of the complement system in AMD was first clearly demonstrated by Hageman and colleagues who identified C3 fragments, MAC components and FH in drusen, the characteristic lipid-/pigment-rich ‘waste’ material found in damaged areas of the eye [22] (Fig 5). They proposed a model for AMD pathogenesis based on a prominent role for inflammation. However, the significance of these observations was not widely appreciated until the genetic connection was established several years later [11–17]. A conceptually straightforward pathophysiological scenario is that drusen accumulate, the AP becomes activated and an excessive (i.e. damaging) inflammatory response ensues to progressively destroy retinal tissue. Further, chronic liberation of proinflammatory C3a and C5a in the retina is likely to be deleterious, especially in light of the role of these proteins as initiators of vascular endothelial growth factor invasion of choroidal vessels (wet AMD) in the macula [42]. Common variants Genetic studies (GWASs) in 2005 by four research teams identified a common single nucleotide
Healthy
Damaged
Photoreceptor cells Drusen RPE Bruch´s membrane Retina Optic nerve
Macula
Choroid
Nutrient uptake
Nutrient uptake
Fig. 5 Cross-sectional diagram of the human eye and pathology of age-related macular degeneration (AMD). (a) Location of the retina and macula in early AMD (dry type). (b) Inset shown in A is amplified to demonstrate healthy versus damaged tissue. Subretinal drusen accumulate, block nutrients (arrows) and damage the photoreceptor cell layer. This leads to subsequent atrophy. Progression to wet-type AMD leads to photoreceptor cell degeneration, abnormal blood vessel growth into the choroid and blindness. Modified from Schramm et al. Molecular Immunology, 2014; 61: 118–125. ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine
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polymorphism (SNP) in the FH gene (rs1061170) that was associated with an increased risk of developing AMD [12, 43–45]. This SNP results in a histidine residue replacing a tyrosine residue at position 402 (i.e. Y402H). FH consists of 1213 amino acids arranged in 20 homologous units termed complement control protein (CCP) modules, each of which is ~60 amino acids long (Fig. 4) [34, 35]. Individuals who are heterozygous for the Y402H polymorphism (also termed Y384H without the 18 amino acid signal peptide) have a two- to fourfold increased risk of developing AMD whilst homozygotes have a five- to 10-fold increased risk [17]. Many ethnic populations carry this polymorphism; for example, approximately 30% of individuals of European descent carry at least one copy of this risk allele. The Y402H polymorphism occurs in the seventh CCP and alters the binding of FH to a number of ligands including charged molecules (such as glycosaminoglycans) that are commonly found on cell surfaces and matrices. A current hypothesis for AMD pathogenesis, which has substantial evidence, is that FH bearing this polymorphism binds less well to drusen and, therefore, there is excessive AP activation leading to further damage. Although this FH polymorphism may not be the primary cause of the disorder, it accelerates the disease process. A possible explanation for the high prevalence of the Y402H polymorphism is that the minor (Hcarrying) allele provides a survival advantage against streptococcal infections early in life and is, therefore, increasing in the population [46, 47]. The FH-binding protein of streptococcus has a much lower affinity for 402H than 402Y and thus would allow for enhanced AP activation on these pathogens. A similar hypothesis to explain positive selection for 402H was suggested by Avery in relation to the bacterium Yersinia pestis [48]. He suggested that less efficient binding of 402H to its membrane would prevent immune evasion (allowing for more AP activation) and thereby confer protection against the Black Death, a disease that is estimated to have killed 30–60% of the European population during the Middle Ages [48]. However, in old age, there is a negative effect of 402H with regard to handling drusen. With advancing age and because this variant also does not bind as well to drusen, it does not control retinal inflammation as efficiently as the more common (402Y) FH allele (reviewed in [11]). Since the important identifica8
ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine
Review: Complement regulators in human disease
tion of this common FH polymorphism predisposing to AMD, much evidence has accumulated to support the notion that AMD is a disease of dysfunctional AP regulation. Common variants in complement proteins may be either ‘protective’ or ‘risk’ alleles (reviewed in [11]). Complete deletion of the genes CFHR1 and CFHR3 was found to protect against AMD, as does the presence of two FB haplotypes [14, 16, 49]. A common SNP in C3 results in an R102G substitution that is associated with an increased risk of AMD due to decreased cofactor function [15, 50]. A common polymorphism near the gene for FI (in the 30 untranslated area) has been described, although its functional defect remains to be elucidated (reviewed in [11]). Rare variants Rare variants that segregate with disease in a Mendelian fashion often have a large effect (highly penetrant). Such a rare variant (1210C) was first identified in FH [11, 51]; subsequently, several other highly penetrant FH variants were recognized [52]. Recently, TDS was used to screen for rare variants in 687 targeted genes including all 59 complement components and regulators in a cohort of 2493 cases and controls [19]. The remarkable finding of this study was that ~8% of patients carried a rare FI variant, representing an enrichment of cases compared to controls. Further, a single uncommon C3 gene, independently identified and investigated by several groups, demonstrates significant reduction in function (reduced cofactor activity) [19, 53, 54]. Three important observations emerge from these studies demonstrating the linkage of complement protein dysfunction to AMD. First, evolution has naturally focused on ensuring that humans reach a reproductive age and not on vision retention in old age. It is proposed that the common allele in FH is protective against AMD but is being replaced in the human population by the minor allele that offers a selective advantage for enhanced survival against infections in early childhood. Secondly, in the last decade, next-generation sequencing studies have demonstrated a link between both common and rare variants in AP proteins and risk of AMD development. Finally, the presence of AP variants establishes a key role of this ancient immune system in the pathogenesis of AMD. The implication is that a balance between activation
Review doi: 10.1111/joim.12338
Complement regulators in human disease: lessons from modern genetics M. K. Liszewski & J. P. Atkinson From the Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
Abstract. Liszewski MK, Atkinson JP (Washington University School of Medicine, St. Louis, MO, USA). Complement regulators in human disease: lessons from modern genetics (Review). J Intern Med 2015; doi: 10.1111/joim.12338. First identified in human serum in the late 19th century as a ‘complement’ to antibodies in mediating bacterial lysis, the complement system emerged more than a billion years ago probably as the first humoral immune system. The contemporary complement system consists of nearly 60 proteins in three activation pathways (classical, alternative and lectin) and a terminal cytolytic pathway common to all. Modern molecular biology
Introduction The system The complement and coagulation systems, two ancient pathways in the circulation, are essential for species with a ‘pumped’ circulation [1, 2]. These systems are characterized by proteolytic cascades that act in seconds with a remarkable ability for amplification. Because of their complexity and extensive biological connections, they are often referred to as ‘the terrible Cs’ by medical students. The major role of both systems is to guard the intravascular space from an infection on the one hand and from haemorrhage on the other. Such powerful cascades also require ongoing homeostatic control and strict regulation regarding what they target; ‘too much’ or ‘not enough’, both scenarios lead to disease [3]. Although there is evidence for their interplay, they are largely two independent systems [1, 4]. The complement system has a key role in innate immunity and is a major effector arm of humoral immunity. It consists of (i) recognition proteins (antibodies and lectins) that trigger the system; (ii) sequentially acting plasma proteins comprising serine proteases and a feedback loop; (iii) terminal membrane-perturbing components that form a
and genetics have not only led to further elucidation of the structure of complement system components, but have also revealed function-altering rare variants and common polymorphisms, particularly in regulators of the alternative pathway, that predispose to human disease by creating ‘hyperinflammatory complement phenotypes’. To treat these ‘complementopathies’, a monoclonal antibody against the initiator of the membrane attack complex, C5, has received approval for use. Additional therapeutic reagents are on the horizon. Keywords: age-related macular degeneration, atypical haemolytic uraemic syndrome, complement regulation, eculizumab, genetics, therapeutics. membrane attack complex (MAC) by nonproteolytic protein–protein interactions; (iv) components that are synthesized primarily in the liver, but also locally by monocytes, macrophages, fibroblasts and many types of epithelial cells; (v) plasma and membrane protein regulators and receptors; and (vi) anaphylatoxins that are liberated by proteolysis to promote the inflammatory response. After engagement of the system by an initiating trigger, the early steps consist of proteolytic cascades grouped into three pathways (classical, alternative and lectin) followed by a terminal membrane attack (cytolytic) pathway common to all. Complement has two major functions: (i) to opsonize and disrupt the membrane integrity of its targets and (ii) to promote the inflammatory response (Fig. 1).
History The complement system was described more than 125 years ago as a relatively unstable and heatlabile lytic substance in blood that ‘complemented’ antibodies (the more stable and nonheat labile fraction of serum) in destroying bacteria. Jules Bordet was awarded the 1919 Nobel Prize in Physiology or Medicine for his discoveries related to the identification of complement and its application in widely employed complement-fixation
ª 2014 The Association for the Publication of the Journal of Internal Medicine
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appreciation of its roles in innate immunity and by new understandings derived from modern genetics. The past decade has witnessed a rapid growth in interest in complement-targeted therapeutics. The future emergence of additional complement inhibitors is much anticipated. Conflict of interest statement MKL has no conflict of interests. JPA has received research funding from Alexion Pharmaceuticals and honoraria or consultancy fees from Compliment Corporation, Celldex Therapeutics, Alnylam Pharmaceuticals, Biothera, Clinical Pharmacy Services, Kypha, iPierian, Allergan and Achillion Pharmaceuticals.
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29 Zipfel PF, Skerka C. Complement regulators and inhibitory proteins. Nat Rev Immunol 2009; 9: 729–40. 30 Lambris JD, Ricklin D, Geisbrecht BV. Complement evasion by human pathogens. Nat Rev Microbiol 2008; 6: 132– 42. 31 Thurman JM, Holers VM. The central role of the alternative complement pathway in human disease. J Immunol 2006; 176: 1305–10. 32 Holers VM. The spectrum of complement alternative pathway-mediated diseases. Immunol Rev 2008; 223: 300– 16. 33 Fang C, Richards A, Liszewski MK, Kavanagh D, Atkinson JP. Advances in understanding of pathogenesis of aHUS and HELLP. Br J Haematol 2008; 143: 336–48. 34 Makou E, Herbert AP, Barlow PN. Functional anatomy of complement factor H. Biochemistry (Mosc) 2013; 52: 3949– 62. 35 Kopp A, Hebecker M, Svobodova E, Jozsi M. Factor h: a complement regulator in health and disease, and a mediator of cellular interactions. Biomolecules 2012; 2: 46–75. 36 Cardone J, Le Friec G, Kemper C. CD46 in innate and adaptive immunity: an update. Clin Exp Immunol 2011; 164: 301–11. 37 Liszewski MK, Kemper C, Price JD, Atkinson JP. Emerging roles and new functions of CD46. Springer Semin Immunopathol 2005; 27: 345–58. 38 Fremeaux-Bacchi V, Goodship T, Regnier CH, Dragon-Durey MA, Janssen B, Atkinson J. Mutations in complement C3 predispose to development of atypical haemolytic uraemic syndrome. Mol Immunol 2007; 44: 3923. 39 Dragon-Durey MA, Blanc C, Garnier A, Hofer J, Sethi SK, Zimmerhackl LB. Anti-factor H autoantibody-associated hemolytic uremic syndrome: review of literature of the autoimmune form of HUS. Semin Thromb Hemost 2010; 36: 633– 40. 40 Loirat C, Fremeaux-Bacchi V. Anti-factor H autoantibody-associated hemolytic uremic syndrome: the earlier diagnosed and treated, the better. Kidney Int 2014; 85: 1019–22. 41 Khandhadia S, Cipriani V, Yates JR, Lotery AJ. Age-related macular degeneration and the complement system. Immunobiology 2012; 217: 127–46. 42 Gehrs KM, Anderson DH, Johnson LV, Hageman GS. Age-related macular degeneration-emerging pathogenetic and therapeutic concepts. Ann Med 2006; 38: 450–71. 43 Hageman GS, Anderson DH, Johnson LV et al. A common haplotype in the complement regulatory gene factor H (HF1/ CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 2005; 102: 7227–32. 44 Edwards AO, Ritter R III, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science 2005; 308: 421–4. 45 Haines JL, Hauser MA, Schmidt S et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005; 308: 419–21. 46 Haapasalo K, Vuopio J, Syrjanen J et al. Acquisition of complement factor H is important for pathogenesis of Streptococcus pyogenes infections: evidence from bacterial in vitro survival and human genetic association. J Immunol 2012; 188: 426–35. 47 Haapasalo K, Jarva H, Siljander T, Tewodros W, Vuopio-Varkila J, Jokiranta TS. Complement factor H allotype 402H is
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associated with increased C3b opsonization and phagocytosis of Streptococcus pyogenes. Mol Microbiol 2008; 70: 583–94. Avery RL. The plague and macular degeneration. Ophthalmology 2010; 117: 2442. Hageman GS, Hancox LS, Taiber AJ et al. Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann Med 2006; 38: 592–604. Yates JR, Sepp T, Matharu BK et al. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 2007; 357: 553–61. Raychaudhuri S, Iartchouk O, Chin K et al. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat Genet 2011; 43: 1232–6. Yu Y, Triebwasser MP, Wong KS, et al. Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration. Hum Mol Gen 2014; 23: 5283–93. Zhan X, Larson DE, Wang C et al. Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. Nat Genet 2013; 45: 1375–9. Helgason H, Sulem P, Duvvari MR et al. A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration. Nat Genet 2013; 45: 1371–4. Salmon JE, Heuser C, Triebwasser M et al. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med 2011; 8: e1001013. Fang CJ, Fremeaux-Bacchi V, Liszewski MK et al. Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood 2008; 111: 624– 32. Fakhouri F, Jablonski M, Lepercq J et al. Factor H, membrane cofactor protein and Factor I mutations in patients with HELLP syndrome. Blood 2008; 112: 4542–5. Wagner E, Frank MM. Therapeutic potential of complement modulation. Nat Rev Drug Discov 2010; 9: 43–56. Ricklin D, Lambris JD. Complement-targeted therapeutics. Nat Biotechnol 2007; 25: 1265–75. Legendre CM, Licht C, Muus P et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013; 368: 2169–81. Keating GM. Eculizumab: a review of its use in atypical haemolytic uraemic syndrome. Drugs 2013; 73: 2053–66. Kavanagh D, Goodship TH, Richards A. Atypical hemolytic uremic syndrome. Semin Nephrol 2013; 33: 508–30. Java A, Atkinson J, Salmon J. Defective complement inhibitory function predisposes to renal disease. Annu Rev Med 2013; 64: 307–24. Kavanagh D, Richards A, Fremeaux-Bacchi V et al. Screening for complement system abnormalities in patients with atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 2007; 2: 591–6. Wehling C, Kirschfink M. Tailored eculizumab regimen for patients with atypical hemolytic uremic syndrome: requirement for comprehensive complement analysis. J Thromb Haemost 2014; 12: 1437–9. Cugno M, Gualtierotti R, Possenti I et al. Complement functional tests for monitoring eculizumab treatment in patients
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with atypical hemolytic uremic syndrome. J Thromb Haemost 2014; 12: 1440–8. 67 Noris M, Galbusera M, Gastoldi S et al. Dynamics of complement activation in atypical HUS and how to monitor eculizumab therapy. Blood 2014; 124: 1715–26. 68 Cataland SR, Wu HM. How I treat: the clinical differentiation and initial treatment of adult patients with atypical hemolytic uremic syndrome. Blood 2014; 123: 2478–84.
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69 Cataland SR, Wu HM. Diagnosis and management of complement mediated thrombotic microangiopathies. Blood Rev 2014; 28: 67–74. Correspondence: John P. Atkinson, MD, Division of Rheumatology, Washington University School of Medicine, 660 S Euclid, Box 8045, St. Louis, MO 63110, USA. (fax: 314-362-9257; e-mail: [email protected]).
