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The Benefits of Complement Measurements for the Clinical Practice

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The Complement System

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2227))

Abstract

The complement cascade is an evolutionary ancient innate immune defense system, playing a major role in the defense against infections. Its function in maintaining host homeostasis on activated cells has been emphasized by the crucial role of its overactivation in ever growing number of diseases, such as atypical hemolytic uremic syndrome (aHUS), autoimmune diseases as systemic lupus erythematosus (SLE), C3 glomerulopathies (C3GN), age-related macular degeneration (AMD), graft rejection, Alzheimer disease, and cancer, to name just a few. The last decade of research on complement has extended its implication in many pathological processes, offering new insights to potential therapeutic targets and asserting the necessity of reliable, sensitive, specific, accurate, and reproducible biomarkers to decipher complement role in pathology. We need to evaluate accurately which pathway or role should be targeted pharmacologically, and optimize treatment efficacy versus toxicity. This chapter is an introduction to the role of complement in human diseases and the use of complement-related biomarkers in the clinical practice. It is a part of a book intending to give reliable and standardized methods to evaluate complement according to nowadays needs and knowledge.

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References

  1. Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT (2015) Complement system part I—molecular mechanisms of activation and regulation. Front Immunol 6:262

    Article  PubMed  PubMed Central  Google Scholar 

  2. Naughton MA et al (1996) Extrahepatic secreted complement C3 contributes to circulating C3 levels in humans. J Immunol 156:3051–3056

    Article  CAS  PubMed  Google Scholar 

  3. Kemper C, Atkinson JP, Hourcade DE (2010) Properdin: emerging roles of a pattern-recognition molecule. Annu Rev Immunol 28:131–155

    Article  CAS  PubMed  Google Scholar 

  4. Passwell J, Schreiner GF, Nonaka M, Beuscher HU, Colten HR (1988) Local extrahepatic expression of complement genes C3, factor B, C2, and C4 is increased in murine lupus nephritis. J Clin Invest 82:1676–1684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. West EE, Kolev M, Kemper C (2018) Complement and the regulation of T cell responses. Annu Rev Immunol 36:309–338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Matsuda T, Nagasawa S, Koide T, Koyama J (1985) Limited proteolysis of a chemically modified third component of human complement, C3, by cathepsin G of human leukocytes. J Biochem (Tokyo) 98:229–236

    Article  CAS  Google Scholar 

  7. Békássy ZD et al (2018) Aliskiren inhibits renin-mediated complement activation. Kidney Int 94:689–700

    Article  PubMed  CAS  Google Scholar 

  8. Huber-Lang M et al (2006) Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 12:682–687

    Article  CAS  PubMed  Google Scholar 

  9. Medler TR et al (2018) Complement C5a fosters squamous carcinogenesis and limits T cell response to chemotherapy. Cancer Cell 34:561–578.e6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Roumenina LT, Daugan MV, Petitprez F, Sautès-Fridman C, Fridman WH (2019) Context-dependent roles of complement in cancer. Nat Rev Cancer 19:698–715

    Article  CAS  PubMed  Google Scholar 

  11. Yaseen S et al (2017) Lectin pathway effector enzyme mannan-binding lectin-associated serine protease-2 can activate native complement C3 in absence of C4 and/or C2. FASEB J 31:2210–2219

    Article  CAS  PubMed  Google Scholar 

  12. Gadjeva M et al (2002) Macrophage-derived complement component C4 can restore humoral immunity in C4-deficient mice. J Immunol 1950(169):5489–5495

    Article  Google Scholar 

  13. Heeger PS et al (2005) Decay-accelerating factor modulates induction of T cell immunity. J Exp Med 201:1523–1530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lalli PN et al (2008) Locally produced C5a binds to T cell–expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis. Blood 112:1759–1766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pratt JR, Basheer SA, Sacks SH (2002) Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med 8:582–587

    Article  CAS  PubMed  Google Scholar 

  16. Kolev M, Friec GL, Kemper C (2014) Complement — tapping into new sites and effector systems. Nat Rev Immunol 14:811–820

    Article  CAS  PubMed  Google Scholar 

  17. Liszewski MK et al (2013) Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation. Immunity 39:1143–1157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Arbore G et al (2016) T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4+ T cells. Science 352:aad1210

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Ling GS et al (2018) C1q restrains autoimmunity and viral infection by regulating CD8 + T cell metabolism. Science 360:558–563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kremlitzka M et al (2019) Interaction of serum-derived and internalized C3 with DNA in human B cells—a potential involvement in regulation of gene transcription. Front Immunol 10:493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Merle NS, Noe R, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, Roumenina LT (2015) Complement system part II: role in immunity. Front Immunol 6:257

    Article  PubMed  PubMed Central  Google Scholar 

  22. Pettigrew HD, Teuber SS, Gershwin ME (2009) Clinical significance of complement deficiencies. Ann N Y Acad Sci 1173:108–123

    Article  CAS  PubMed  Google Scholar 

  23. Degn SE, Jensenius JC, Thiel S (2011) Disease-causing mutations in genes of the complement system. Am J Hum Genet 88:689–705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rosain J et al (2014) Complement deficiencies and human diseases. Ann Biol Clin (Paris) 72:271–280

    CAS  Google Scholar 

  25. Brocklebank V, Wood KM, Kavanagh D (2018) Thrombotic Microangiopathy and the kidney. Clin J Am Soc Nephrol 13:300–317

    Article  CAS  PubMed  Google Scholar 

  26. Smith RJH et al (2019) C3 glomerulopathy—understanding a rare complement-driven renal disease. Nat Rev Nephrol 15:129–143

    Article  PubMed  PubMed Central  Google Scholar 

  27. Corvillo F et al (2019) Nephritic factors: an overview of classification, diagnostic tools and clinical associations. Front Immunol 10:886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Marinozzi MC et al (2017) Anti-factor B and anti-C3b autoantibodies in C3 Glomerulopathy and Ig-associated Membranoproliferative GN. J Am Soc Nephrol 28:1603–1613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chauvet S et al (2020) Anti-factor B antibodies and acute Postinfectious GN in children. J Am Soc Nephrol 31(4):829–840. https://doi.org/10.1681/ASN.2019080851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vasilev VV et al (2019) Autoantibodies against C3b—functional consequences and disease relevance. Front Immunol 10:64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chauvet S et al (2017) Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy–associated C3 glomerulopathy. Blood 129:1437–1447

    Article  CAS  PubMed  Google Scholar 

  32. Bu F et al (2016) High-throughput genetic testing for thrombotic Microangiopathies and C3 Glomerulopathies. J Am Soc Nephrol 27:1245–1253

    Article  CAS  PubMed  Google Scholar 

  33. Osborne AJ et al (2018) Statistical validation of rare complement variants provides insights into the molecular basis of atypical hemolytic uremic syndrome and C3 Glomerulopathy. J Immunol 200:2464–2478

    Article  CAS  PubMed  Google Scholar 

  34. Truedsson L, Bengtsson AA, Sturfelt G (2007) Complement deficiencies and systemic lupus erythematosus. Autoimmunity 40:560–566

    Article  CAS  PubMed  Google Scholar 

  35. Taylor PR et al (2000) A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J Exp Med 192:359–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Manderson AP, Botto M, Walport MJ (2004) The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol 22:431–456

    Article  CAS  PubMed  Google Scholar 

  37. Trouw LA, Pickering MC, Blom AM (2017) The complement system as a potential therapeutic target in rheumatic disease. Nat Rev Rheumatol 13:538–547

    Article  CAS  PubMed  Google Scholar 

  38. Dragon-Durey M-A, Blanc C, Marinozzi MC, van Schaarenburg RA, Trouw LA (2013) Autoantibodies against complement components and functional consequences. Mol Immunol 56:213–221

    Article  CAS  PubMed  Google Scholar 

  39. Leffler J, Bengtsson AA, Blom AM (2014) The complement system in systemic lupus erythematosus: an update. Ann Rheum Dis 73:1601–1606

    Article  CAS  PubMed  Google Scholar 

  40. Brodeur JP, Ruddy S, Schwartz LB, Moxley G (1991) Synovial fluid levels of complement SC5b-9 and fragment bb are elevated in patients with rheumatoid arthritis. Arthritis Rheum 34:1531–1537

    Article  CAS  PubMed  Google Scholar 

  41. Trouw LA, Rispens T, Toes REM (2017) Beyond citrullination: other post-translational protein modifications in rheumatoid arthritis. Nat Rev Rheumatol 13:331–339

    Article  CAS  PubMed  Google Scholar 

  42. Ji H et al (2002) Arthritis critically dependent on innate immune system players. Immunity 16:157–168

    Article  CAS  PubMed  Google Scholar 

  43. Gou S-J, Yuan J, Chen M, Yu F, Zhao M-H (2013) Circulating complement activation in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Kidney Int 83:129–137

    Article  CAS  PubMed  Google Scholar 

  44. Xing G et al (2008) Complement activation is involved in renal damage in human Antineutrophil cytoplasmic autoantibody associated Pauci-immune Vasculitis. J Clin Immunol 29:282

    Article  PubMed  CAS  Google Scholar 

  45. Leffler J et al (2012) Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease. J Immunol 1950(188):3522–3531

    Article  CAS  Google Scholar 

  46. Reis ES, Mastellos DC, Ricklin D, Mantovani A, Lambris JD (2018) Complement in cancer: untangling an intricate relationship. Nat Rev Immunol 18:5–18

    Article  CAS  PubMed  Google Scholar 

  47. Roumenina LT et al (2019) Tumor cells hijack macrophage-produced complement C1q to promote tumor growth. Cancer Immunol Res 7:1091–1105

    Article  CAS  PubMed  Google Scholar 

  48. Bonavita E et al (2015) PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160:700–714

    Article  CAS  PubMed  Google Scholar 

  49. Nabizadeh JA et al (2016) The complement C3a receptor contributes to melanoma tumorigenesis by inhibiting neutrophil and CD4+ T cell responses. J Immunol 1950(196):4783–4792

    Article  CAS  Google Scholar 

  50. Janelle V et al (2014) Transient complement inhibition promotes a tumor-specific immune response through the implication of natural killer cells. Cancer Immunol Res 2:200–206

    Article  CAS  PubMed  Google Scholar 

  51. Bulla R et al (2016) C1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation. Nat Commun 7:10346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hajishengallis G, Reis ES, Mastellos DC, Ricklin D, Lambris JD (2017) Novel mechanisms and functions of complement. Nat Immunol 18:1288–1298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Carpanini SM, Torvell M, Morgan BP (2019) Therapeutic inhibition of the complement system in diseases of the central nervous system. Front Immunol 10:362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Stevens B et al (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–1178

    Article  CAS  PubMed  Google Scholar 

  55. Shi Q et al (2015) Complement C3-deficient mice fail to display age-related hippocampal decline. J Neurosci 35:13029–13042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Heppner FL, Ransohoff RM, Becher B (2015) Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 16:358–372

    Article  CAS  PubMed  Google Scholar 

  57. Brennan FH, Lee JD, Ruitenberg MJ, Woodruff TM (2016) Therapeutic targeting of complement to modify disease course and improve outcomes in neurological conditions. Semin Immunol 28:292–308

    Article  CAS  PubMed  Google Scholar 

  58. Hernandez MX, Namiranian P, Nguyen E, Fonseca MI, Tenner AJ (2017) C5a increases the injury to primary neurons elicited by Fibrillar amyloid Beta. ASN Neuro 9:1759091416687871

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Lambert J-C et al (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41:1094–1099

    Article  CAS  PubMed  Google Scholar 

  60. Zhou J, Fonseca MI, Pisalyaput K, Tenner AJ (2008) Complement C3 and C4 expression in C1q sufficient and deficient mouse models of Alzheimer’s disease. J Neurochem 106:2080–2092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Maier M et al (2008) Complement C3 deficiency leads to accelerated amyloid β plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci 28:6333–6341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sta M et al (2011) Innate and adaptive immunity in amyotrophic lateral sclerosis: evidence of complement activation. Neurobiol Dis 42:211–220

    Article  CAS  PubMed  Google Scholar 

  63. Mantovani S et al (2014) Elevation of the terminal complement activation products C5a and C5b-9 in ALS patient blood. J Neuroimmunol 276:213–218

    Article  CAS  PubMed  Google Scholar 

  64. Lobsiger CS et al (2013) C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice. Proc Natl Acad Sci U S A 110:E4385–E4392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chiu IM et al (2009) Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice. Proc Natl Acad Sci U S A 106:20960–20965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Woodruff TM et al (2008) The complement factor C5a contributes to pathology in a rat model of amyotrophic lateral sclerosis. J Immunol 181:8727–8734

    Article  CAS  PubMed  Google Scholar 

  67. Lee JD et al (2017) Pharmacological inhibition of complement C5a-C5a1 receptor signalling ameliorates disease pathology in the hSOD1G93A mouse model of amyotrophic lateral sclerosis. Br J Pharmacol 174:689–699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Singhrao SK, Neal JW, Morgan BP, Gasque P (1999) Increased complement biosynthesis by microglia and complement activation on neurons in Huntington’s disease. Exp Neurol 159:362–376

    Article  CAS  PubMed  Google Scholar 

  69. Loeffler DA, Camp DM, Conant SB (2006) Complement activation in the Parkinson’s disease substantia nigra: an immunocytochemical study. J Neuroinflammation 3:29

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Gilhus NE et al (2016) Myasthenia gravis—autoantibody characteristics and their implications for therapy. Nat Rev Neurol 12:259–268

    Article  CAS  PubMed  Google Scholar 

  71. Howard JF (2018) Myasthenia gravis: the role of complement at the neuromuscular junction. Ann N Y Acad Sci 1412:113–128

    Article  CAS  PubMed  Google Scholar 

  72. Nakano S, Engel AG (1993) Myasthenia gravis: quantitative immunocytochemical analysis of inflammatory cells and detection of complement membrane attack complex at the end-plate in 30 patients. Neurology 43:1167–1172

    Article  CAS  PubMed  Google Scholar 

  73. Haines JL et al (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308:419–421

    Article  CAS  PubMed  Google Scholar 

  74. Seddon JM et al (2013) Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat Genet 45:1366–1370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Weismann D et al (2011) Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature 478:76–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Shaw PX et al (2012) Complement factor H genotypes impact risk of age-related macular degeneration by interaction with oxidized phospholipids. Proc Natl Acad Sci U S A 109:13757–13762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. van Lookeren Campagne M, Strauss EC, Yaspan BL (2016) Age-related macular degeneration: complement in action. Immunobiology 221:733–739

    Article  PubMed  CAS  Google Scholar 

  78. Hughes AE et al (2006) A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet 38:1173–1177

    Article  CAS  PubMed  Google Scholar 

  79. Cipriani V et al (2020) Increased circulating levels of factor H-related protein 4 are strongly associated with age-related macular degeneration. Nat Commun 11:778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Brodsky RA (2014) Paroxysmal nocturnal hemoglobinuria. Blood 124:2804–2811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Griffin M et al (2019) Significant hemolysis is not required for thrombosis in paroxysmal nocturnal hemoglobinuria. Haematologica 104:94–96

    Google Scholar 

  82. Risitano AM et al (2009) Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab. Blood 113:4094–4100

    Article  CAS  PubMed  Google Scholar 

  83. Hill A et al (2010) Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization. Haematologica 95:567–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lin Z et al (2015) Complement C3dg-mediated erythrophagocytosis: implications for paroxysmal nocturnal hemoglobinuria. Blood 126:891–894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang RH, Phillips G, Medof ME, Mold C (1993) Activation of the alternative complement pathway by exposure of phosphatidylethanolamine and phosphatidylserine on erythrocytes from sickle cell disease patients. J Clin Invest 92:1326–1335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mold C, Tamerius JD, Phillips G (1995) Complement activation during painful crisis in sickle cell anemia. Clin Immunol Immunopathol 76:314–320

    Article  CAS  PubMed  Google Scholar 

  87. Lombardi E et al (2019) Factor H interferes with the adhesion of sickle red cells to vascular endothelium: a novel disease-modulating molecule. Haematologica 104:919–928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Roumenina LT et al (2020) Complement activation in sickle cell disease: dependence on cell density, hemolysis and modulation by hydroxyurea therapy. Am J Hematol 95(5):456–464. https://doi.org/10.1002/ajh.25742

    Article  CAS  PubMed  Google Scholar 

  89. Merle NS et al (2018) Intravascular hemolysis activates complement via cell-free heme and heme-loaded microvesicles. JCI Insight 3(12):e96910

    Article  PubMed Central  Google Scholar 

  90. Vercellotti GM et al (2019) Critical role of C5a in sickle cell disease. Am J Hematol 94:327–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Merle NS et al (2019) P-selectin drives complement attack on endothelium during intravascular hemolysis in TLR-4/heme-dependent manner. Proc Natl Acad Sci 116:6280–6285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Merle NS, Boudhabhay I, Leon J, Fremeaux-Bacchi V, Roumenina LT (2019) Complement activation during intravascular hemolysis: implication for sickle cell disease and hemolytic transfusion reactions. Transfus Clin Biol 26:116–124

    Article  CAS  PubMed  Google Scholar 

  93. Bork K, Witzke G (1989) Long-term prophylaxis with C1-inhibitor (C1 INH) concentrate in patients with recurrent angioedema caused by hereditary and acquired C1-inhibitor deficiency. J Allergy Clin Immunol 83:677–682

    Article  CAS  PubMed  Google Scholar 

  94. Hillmen P et al (2004) Effect of Eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 350:552–559

    Article  CAS  PubMed  Google Scholar 

  95. Hillmen P et al (2006) The complement inhibitor Eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 355:1233–1243

    Article  CAS  PubMed  Google Scholar 

  96. Brodsky RA et al (2008) Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 111:1840–1847

    Article  CAS  PubMed  Google Scholar 

  97. Hillmen P et al (2013) Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 162:62–73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Gruppo RA, Rother RP (2009) Eculizumab for congenital atypical hemolytic–uremic syndrome. N Engl J Med 360:544–546

    Article  CAS  PubMed  Google Scholar 

  99. Legendre CM et al (2013) Terminal complement inhibitor Eculizumab in atypical hemolytic–uremic syndrome. N Engl J Med 368:2169–2181

    Article  CAS  PubMed  Google Scholar 

  100. Greenbaum LA et al (2016) Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int 89:701–711

    Article  CAS  PubMed  Google Scholar 

  101. Percheron L et al (2018) Eculizumab treatment in severe pediatric STEC-HUS: a multicenter retrospective study. Pediatr Nephrol 33:1385–1394

    Article  PubMed  Google Scholar 

  102. Burwick RM, Feinberg BB (2013) Eculizumab for the treatment of preeclampsia/HELLP syndrome. Placenta 34:201–203

    Article  CAS  PubMed  Google Scholar 

  103. de Fontbrune FS et al (2015) Use of Eculizumab in patients with allogeneic stem cell transplant-associated thrombotic Microangiopathy: a study from the SFGM-TC. Transplantation 99:1953–1959

    Article  PubMed  CAS  Google Scholar 

  104. Fakhouri F et al (2016) Terminal complement inhibitor Eculizumab in adult patients with atypical hemolytic uremic syndrome: a single-arm, open-label trial. Am J Kidney Dis 68:84–93

    Article  CAS  PubMed  Google Scholar 

  105. Nishimura J et al (2014) Genetic variants in C5 and poor response to Eculizumab. N Engl J Med 370:632–639

    Article  CAS  PubMed  Google Scholar 

  106. Risitano AM et al (2019) Anti-complement treatment for paroxysmal nocturnal hemoglobinuria: time for proximal complement inhibition? A position paper from the SAAWP of the EBMT. Front Immunol 10:1157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Rawal N, Pangburn MK (2000) Functional role of the noncatalytic subunit of complement C5 convertase. J Immunol 164:1379–1385

    Article  CAS  PubMed  Google Scholar 

  108. Ardissino G et al (2015) Discontinuation of Eculizumab treatment in atypical hemolytic uremic syndrome: an update. Am J Kidney Dis 66:172–173

    Article  PubMed  Google Scholar 

  109. Merrill SA et al (2017) Eculizumab cessation in atypical hemolytic uremic syndrome. Blood 130:368–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Fakhouri F et al (2017) Pathogenic variants in complement genes and risk of atypical hemolytic uremic syndrome relapse after Eculizumab discontinuation. Clin J Am Soc Nephrol 12:50–59

    Article  CAS  PubMed  Google Scholar 

  111. Ricklin D, Mastellos DC, Reis ES, Lambris JD (2018) The renaissance of complement therapeutics. Nat Rev Nephrol 14:26–47

    Article  CAS  PubMed  Google Scholar 

  112. Tatapudi VS, Montgomery RA (2019) Therapeutic modulation of the complement system in kidney transplantation: clinical indications and emerging drug leads. Front Immunol 10:2306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Viglietti D et al (2016) C1-inhibitor in acute antibody-mediated rejection non-responsive to conventional therapy in kidney transplant recipients: a pilot study. Am J Transplant 16(5):1596–1603. https://doi.org/10.1111/ajt.13663

    Article  CAS  PubMed  Google Scholar 

  114. Montgomery RA et al (2016) Plasma-derived C1 esterase inhibitor for acute antibody-mediated rejection following kidney transplantation: results of a randomized double-blind placebo-controlled pilot study. Am J Transplant 16:3468–3478

    Article  CAS  PubMed  Google Scholar 

  115. Stegall MD et al (2011) Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant 11:2405–2413

    Article  CAS  PubMed  Google Scholar 

  116. Park DH, Connor KM, Lambris JD (2019) The challenges and promise of complement therapeutics for ocular diseases. Front Immunol 10:1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Pittock SJ et al (2019) Eculizumab in Aquaporin-4–positive Neuromyelitis Optica Spectrum disorder. N Engl J Med 381:614–625

    Article  CAS  PubMed  Google Scholar 

  118. Karasu E, Nilsson B, Köhl J, Lambris JD, Huber-Lang M (2019) Targeting complement pathways in Polytrauma- and sepsis-induced multiple-organ dysfunction. Front Immunol 10:543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Thurman JM, Yapa R (2019) Complement therapeutics in autoimmune disease. Front Immunol 10:672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Pickering MC et al (2015) Eculizumab as rescue therapy in severe resistant lupus nephritis. Rheumatology (Oxford) 54:2286–2288

    Google Scholar 

  121. Park MH, Caselman N, Ulmer S, Weitz IC (2018) Complement-mediated thrombotic microangiopathy associated with lupus nephritis. Blood Adv 2:2090–2094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Howard JF et al (2017) Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol 16:976–986

    Article  CAS  PubMed  Google Scholar 

  123. Lonze BE, Singer AL, Montgomery RA (2010) Eculizumab and renal transplantation in a patient with CAPS. N Engl J Med 362:1744–1745

    Article  CAS  PubMed  Google Scholar 

  124. Shapira I, Andrade D, Allen SL, Salmon JE (2012) Brief report: induction of sustained remission in recurrent catastrophic antiphospholipid syndrome via inhibition of terminal complement with eculizumab. Arthritis Rheum 64:2719–2723

    Article  CAS  PubMed  Google Scholar 

  125. Jayne DRW et al (2017) Randomized trial of C5a receptor inhibitor Avacopan in ANCA-associated Vasculitis. J Am Soc Nephrol 28:2756–2767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Pio R, Ajona D, Ortiz-Espinosa S, Mantovani A, Lambris JD (2019) Complementing the cancer-immunity cycle. Front Immunol 10:774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Crew PE et al (2020) Antibiotic prophylaxis in vaccinated eculizumab recipients who developed meningococcal disease. J Infect 80:350–371

    Article  PubMed  CAS  Google Scholar 

  128. Mohebnasab M et al (2019) Current and future approaches for monitoring responses to anti-complement therapeutics. Front Immunol 10:2539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. He Y et al (2020) Normal range of complement components during pregnancy: a prospective study. Am J Reprod Immunol 83:e13202

    Article  PubMed  Google Scholar 

  130. Ekdahl KN et al (2018) Interpretation of serological complement biomarkers in disease. Front Immunol 9:2237

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Nilsson PH et al (2017) Eculizumab-C5 complexes express a C5a neoepitope in vivo: consequences for interpretation of patient complement analyses. Mol Immunol 89:111–114

    Article  CAS  PubMed  Google Scholar 

  132. Platts-Mills TA, Ishizaka K (1974) Activation of the alternate pathway of human complements by rabbit cells. J Immunol 1950(113):348–358

    Article  Google Scholar 

  133. Yamamoto S et al (1995) Automated homogeneous liposome-based assay system for total complement activity. Clin Chem 41:586–590

    Article  CAS  PubMed  Google Scholar 

  134. Seelen MA et al (2005) Functional analysis of the classical, alternative, and MBL pathways of the complement system: standardization and validation of a simple ELISA. J Immunol Methods 296:187–198

    Article  CAS  PubMed  Google Scholar 

  135. Gavriilaki E et al (2015) Modified ham test for atypical hemolytic uremic syndrome. Blood 125:3637–3646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Noris M et al (2014) Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. Blood 124:1715–1726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Palomo M et al (2019) Complement activation and thrombotic Microangiopathies. Clin J Am Soc Nephrol 14:1719–1732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Daha MR, Fearon DT, Austen KF (1976) C3 nephritic factor (C3NeF): stabilization of fluid phase and cell-bound alternative pathway convertase. J Immunol 1950(116):1–7

    Article  Google Scholar 

  139. Servais A et al (2012) Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int 82:454–464

    Article  CAS  PubMed  Google Scholar 

  140. Marinozzi M-C et al (2017) C5 nephritic factors drive the biological phenotype of C3 glomerulopathies. Kidney Int 92:1232–1241

    Article  CAS  PubMed  Google Scholar 

  141. Halbwachs L, Leveillé M, Lesavre P, Wattel S, Leibowitch J (1980) Nephritic factor of the classical pathway of complement: immunoglobulin G autoantibody directed against the classical pathway C3 convertase enzyme. J Clin Invest 65:1249–1256

    Google Scholar 

  142. Gigli I, Sorvillo J, Mecarelli-Halbwachs L, Leibowitch J (1981) Mechanism of action of the C4 nephritic factor. Deregulation of the classical pathway of C3 convertase. J Exp Med 154:1–12

    Article  CAS  PubMed  Google Scholar 

  143. Zhang Y et al (2017) C4 nephritic factors in C3 Glomerulopathy: a case series. Am J Kidney Dis 70:834–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Zipfel PF et al (2007) Deletion of complement factor H–related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome. PLoS Genet 3:e41

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Dragon-Durey M-A et al (2009) The high frequency of complement factor H related CFHR1 gene deletion is restricted to specific subgroups of patients with atypical haemolytic uraemic syndrome. J Med Genet 46:447–450

    Article  CAS  PubMed  Google Scholar 

  146. Chen Q et al (2011) Combined C3b and factor B autoantibodies and MPGN type II. N Engl J Med 365:2340–2342 

    Google Scholar 

  147. Grumach AS, Kirschfink M (2014) Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol 61:110–117

    Article  CAS  PubMed  Google Scholar 

  148. El Sissy C et al (2019) Clinical and genetic Spectrum of a large cohort with Total and sub-total complement deficiencies. Front Immunol 10:1936

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Fremeaux-Bacchi V et al (2013) Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol 8:554–562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Noris M et al (2010) Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 5:1844–1859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Toomey CB, Johnson LV, Bowes Rickman C (2018) Complement factor H in AMD: bridging genetic associations and pathobiology. Prog Retin Eye Res 62:38–57

    Article  CAS  PubMed  Google Scholar 

  152. Servais A et al (2007) Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome. J Med Genet 44:193–199

    Article  CAS  PubMed  Google Scholar 

  153. Zipfel PF et al (2015) The role of complement in C3 glomerulopathy. Mol Immunol 67:21–30

    Article  CAS  PubMed  Google Scholar 

  154. Quintrec ML et al (2013) Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome. Am J Transplant 13:663–675

    Article  PubMed  CAS  Google Scholar 

  155. de Cordoba SR, Tortajada A, Harris CL, Morgan BP (2012) Complement dysregulation and disease: from genes and proteins to diagnostics and drugs. Immunobiology 217:1034–1046

    Article  PubMed  CAS  Google Scholar 

  156. Heinen S et al (2006) De novo gene conversion in the RCA gene cluster (1q32) causes mutations in complement factor H associated with atypical hemolytic uremic syndrome. Hum Mutat 27:292–293

    Article  PubMed  Google Scholar 

  157. Francis NJ et al (2012) A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome. Blood 119:591–601

    Article  CAS  PubMed  Google Scholar 

  158. de Jorge EG et al (2018) Factor H Competitor Generated by Gene Conversion Events Associates with Atypical Hemolytic Uremic Syndrome. J Am Soc Nephrol 29:240–249

    Article  Google Scholar 

  159. Xiao X et al (2016) Familial C3 glomerulonephritis caused by a novel CFHR5-CFHR2 fusion gene. Mol Immunol 77:89–96

    Article  CAS  PubMed  Google Scholar 

  160. Gale DP et al (2010) Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet 376:794–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Tortajada A et al (2012) Complement factor H variants I890 and L1007 while commonly associated with atypical hemolytic uremic syndrome are polymorphisms with no functional significance. Kidney Int 81:56–63

    Article  CAS  PubMed  Google Scholar 

  162. Marinozzi MC et al (2014) Complement factor B mutations in atypical hemolytic uremic syndrome-disease-relevant or benign? J Am Soc Nephrol 25:2053–2065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Roumenina LT et al (2012) A prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain of function. Blood 119:4182–4191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. INSERM, UMRS 1138, Inflammation, Complement and Cancer Team, Centre de Recherche des Cordelier, Sorbonne Universités, Université de Paris, Paris, France

    Anne Grunenwald & Lubka T. Roumenina

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  1. Anne Grunenwald
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  2. Lubka T. Roumenina
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Correspondence to Lubka T. Roumenina .

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  1. Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France

    Lubka T. Roumenina

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Grunenwald, A., Roumenina, L.T. (2021). The Benefits of Complement Measurements for the Clinical Practice. In: Roumenina, L.T. (eds) The Complement System. Methods in Molecular Biology, vol 2227. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1016-9_1

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  • DOI: https://doi.org/10.1007/978-1-0716-1016-9_1

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