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Chapter 15 : The Nature of the Diseases That Arise from Improper Regulation of the Alternative Pathway of Complement

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The Nature of the Diseases That Arise from Improper Regulation of the Alternative Pathway of Complement, Page 1 of 2

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Abstract:

The complement system is the cornerstone of innate immunity. As one of the first lines of host defense, it plays a major role in microbial killing, immune complex handling, apoptotic cell clearance, tissue homeostasis, and modulation of adaptive immunity (1–3). Critical to these functions is the sequential triggering of a series of cascades that result in the generation of metastable protease complexes and culminate in the formation of membrane attack complex (MAC) (4). Improper regulation of these cascades is associated with the development of multiple different diseases. In this chapter, we focus on the clinical consequence of dysregulation of the alternative pathway (AP) of complement. We first provide a review of the AP and then illustrate the consequence of its dysregulation by describing two ultrarare diseases: atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G).

Citation: Smith R. 2016. The Nature of the Diseases That Arise from Improper Regulation of the Alternative Pathway of Complement, p 138-144. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch15
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Image of FIGURE 1
FIGURE 1

The complement system, an important arm of innate immunity, provides host defense and physiologic clearance of immune complexes and plays an adjuvant role in the immune response. Illustrated are the five steps in the complement cascade. Step 1 is the initiation of complement through one of three triggering pathways, the CP, LP, or AP. Step 2 is the formation of C3 convertase, C3bBb. Its amplification through a positive-feedback loop is step 3. The abundance of C3b leads to the generation of C5 convertase, C3bBbC3b, which is step 4. The final step is step 5, or the formation of the MAC. This step is initiated by the cleavage of C5 into C5a and C5b. Control of the amplification phase of complement is required to avoid complement-mediated host damage. This control is impaired in patients with aHUS and DDD. Eculizumab, an anticomplement drug, is a monoclonal antibody to C5. By binding to C5, it prevents C5 convertase-mediated cleavage of C5 to C5a and C5b. Because C5b is not formed, the MAC cannot be generated.

Citation: Smith R. 2016. The Nature of the Diseases That Arise from Improper Regulation of the Alternative Pathway of Complement, p 138-144. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch15
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Image of FIGURE 2
FIGURE 2

(A) Complement activity on host surfaces is prevented by RCA proteins in the “surface zone,” which limits the formation of active complement products, and by membrane-bound RCA proteins, such as CR1, CD55, and CD46. CFH, an important RCA protein for fluid-phase control of the AP, also binds to surfaces to provide local control of complement activity. (B) In aHUS patients, host cell surface control of complement is abnormal. In some patients with aHUS, control is lost due to mutations in CFH, CFI, or CD46 that impair normal RCA protein function. In other patients, control is lost secondarily to the formation of autoantibodies to CFH that prevent CFH from binding to host cell surfaces. C3 and C5 Con, C3 and C5 convertase.

Citation: Smith R. 2016. The Nature of the Diseases That Arise from Improper Regulation of the Alternative Pathway of Complement, p 138-144. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch15
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Image of FIGURE 3
FIGURE 3

Environmental triggers of HUS include nonenteric bacterial infections, viruses, drugs, malignancies, transplantation, pregnancy, and medical conditions like scleroderma, antiphospholipid syndrome, and systemic lupus erythematosus. Following a trigger event, there is some degree of endothelial cell damage, with formation of microthrombi and activation of complement. Dysregulation can ensue if either the complement cascade, the coagulation pathway, or both are overactive. Overactivation of complement causes additional endothelial cell lysis and further clotting. Thrombi in microvessels in turn induce mechanical damage to erythrocytes, which then release heme. Heme directly activates the AP and also represses CD46 and CD55 expression on endothelial cells, which makes cells more susceptible to complement damage. The clinical consequence is aHUS.

Citation: Smith R. 2016. The Nature of the Diseases That Arise from Improper Regulation of the Alternative Pathway of Complement, p 138-144. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch15
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Image of FIGURE 4
FIGURE 4

DDD and C3GN are driven by dysregulation of the C3 and C5 convertases, represented by the circular arrows. Biomarker profiling in these patients provides mechanistic insight into the degree of complement dysregulation. Serum C3 levels are significantly reduced in C3G patients compared to those in controls, with the reduction in C3 tending to be greater in patients with DDD. Although properdin is not shown in this illustration, it combines with and stabilizes C3 convertase, increasing its half-life about 10-fold. The addition of another C3b molecule to properdin-stabilized C3 convertase results in the formation of C5 convertase. C5 convertase cleaves C5 to form C5a and C5b, and in both C3GN and DDD patients, C5 levels are reduced compared to levels in normal controls. Because of the availability of eculizumab, the most important finding from a clinical perspective is the elevation in soluble C5b-9, a finding more often detected in patients with C3GN than in patients with DDD. The red arrows represent the relative degrees of convertase dysregulation in DDD and C3GN. iC3b, inactive C3b; sC5b-9, soluble C5b-9.

Citation: Smith R. 2016. The Nature of the Diseases That Arise from Improper Regulation of the Alternative Pathway of Complement, p 138-144. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch15
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References

/content/book/10.1128/9781555818722.ch15
1. Volanakis JE. 2002. The role of complement in innate and adaptive immunity. Curr Top Microbiol Immunol 266:4156.[PubMed].[CrossRef]
2. Walport MJ. 2001. Complement. First of two parts. N Engl J Med 344:10581066.[CrossRef].[PubMed]
3. Walport MJ. 2001. Complement. Second of two parts. N Engl J Med 344:11401144.[CrossRef].[PubMed]
4. Smith RJH, Harris CL, Pickering MC. 2011. Dense deposit disease. Mol Immunol 48:16041610.[CrossRef].[PubMed]
5. Zipfel PF, Skerka C. 2009. Complement regulators and inhibitory proteins. Nat Rev Immunol 9:729740.[CrossRef].[PubMed]
6. Pangburn MK, Ferreira VP, Cortes C. 2008. Discrimination between host and pathogens by the complement system. Vaccine 26(Suppl 8):I15I21.[PubMed].[CrossRef]
7. Pangburn MK, Schreiber RD, Muller-Eberhard HJ. 1981. Formation of the initial C3 convertase of the alternative complement pathway. Acquisition of C3b-like activities by spontaneous hydrolysis of the putative thioester in native C3. J Exp Med 154:856867.[PubMed].[CrossRef]
8. Mullereberhard HJ, Dalmasso AP, Calcott MA. 1966. The reaction mechanism of beta-1C-globulin (C′3) in immune hemolysis. J Exp Med 123:3354.[PubMed].[CrossRef]
9. Law SK, Dodds AW. 1997. The internal thioester and the covalent binding properties of the complement proteins C3 and C4. Protein Sci 6:263274.[CrossRef].[PubMed]
10. Kim YU, Carroll MC, Isenman DE, Nonaka M, Pramoonjago P, Takeda J, Inoue K, Kinoshita T. 1992. Covalent binding of C3b to C4b within the classical complement pathway C5 convertase. Determination of amino acid residues involved in ester linkage formation. J Biol Chem 267:41714176.[PubMed]
11. Whiteman LY, Purkall DB, Ruddy S. 1995. Covalent linkage of C3 to properdin during complement activation. Eur J Immunol 25:14811484.[CrossRef].[PubMed]
12. van Dam AP, Hack CE. 1987. Formation of C3-IgG complexes in serum by aggregated IgG and by non-immunoglobulin activators of complement. Immunology 61:105110.[PubMed]
13. Fritsche LG, Lauer N, Hartmann A, Stippa S, Keilhauer CN, Oppermann M, Pandey MK, Köhl J, Zipfel PF, Weber BH, Skerka C. 2010. An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD). Hum Mol Genet 19:46944704.[CrossRef].[PubMed]
14. Ferreira VP, Pangburn MK. 2007. Factor H mediated cell surface protection from complement is critical for the survival of PNH erythrocytes. Blood 110:21902192.[CrossRef].[PubMed]
15. Manuelian T, Hellwage J, Meri S, Caprioli J, Noris M, Heinen S, Jozsi M, Neumann HP, Remuzzi G, Zipfel PT. 2003. Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J Clin Invest 111:11811190.[CrossRef].[PubMed]
16. Sanchez-Corral P, Gonzalez-Rubio C, Rodriguez de Cordoba S, Lopez-Trascasa M. 2004. Functional analysis in serum from atypical hemolytic uremic syndrome patients reveals impaired protection of host cells associated with mutations in factor H. Mol Immunol 41:8184.[CrossRef].[PubMed]
17. He JQ, Wiesmann C, van Lookeren Campagne M. 2008. A role of macrophage complement receptor CRIg in immune clearance and inflammation. Mol Immunol 45:40414047.[CrossRef].[PubMed]
18. Isaak A, Prechl J, Gergely J, Erdei A. 2006. The role of CR2 in autoimmunity. Autoimmunity 39:357366.[CrossRef].[PubMed]
19. Khera R, Das N. 2009. Complement receptor 1: disease associations and therapeutic implications. Mol Immunol 46:761772.[CrossRef].[PubMed]
20. Kimberley FC, Sivasankar B, Morgan BP. 2007. Alternative roles for CD59. Mol Immunol 44:7381.[CrossRef].[PubMed]
21. Roozendaal R, Carroll MC. 2007. Complement receptors CD21 and CD35 in humoral immunity. Immunol Rev 219:157166.[CrossRef].[PubMed]
22. Seya T, Atkinson JP. 1989. Functional properties of membrane cofactor protein of complement. Biochem J 264:581538.[PubMed].[CrossRef]
23. Spendlove I, Ramage JM, Bradley R, Harris C, Durrant LG. 2006. Complement decay accelerating factor (DAF)/CD55 in cancer. Cancer Immunol Immunother 55:987995.[CrossRef].[PubMed]
24. Wiesmann C, Katschke KJ, Yin J, Helmy KY, Steffek M, Fairbrother WJ, McCallum SA, Embuscado L, DeForge L, Hass PE, van Lookeren Campagne M. 2006. Structure of C3b in complex with CRIg gives insights into regulation of complement activation. Nature 444:217220.[CrossRef].[PubMed]
25. Noris M, Remuzzi G. 2009. Atypical hemolytic-uremic syndrome. N Engl J Med 361:16761687.[CrossRef].[PubMed]
26. Nester CM, Smith RJ. 2013. Treatment options for C3 glomerulopathy. Curr Opin Nephrol Hypertens 22:231237.[CrossRef].[PubMed]
27. Nester CM, Smith RJ. 2013. Diagnosis and treatment of C3 glomerulopathy. Clin Nephrol 80:395403.[CrossRef].[PubMed]
28. Pickering MC, D'Agati VD, Nester CM, Smith RJ, Haas M, Appel GB, Alpers CE, Bajema IM, Bedrosian C, Braun M, Doyle M, Fakhouri F, Fervenza FC, Fogo AB, Frémeaux-Bacchi V, Gale DP, Goicoechea de Jorge E, Griffin G, Harris CL, Holers VM, Johnson S, Lavin PJ, Medjeral-Thomas N, Morgan BP, Nast CC, Noel L-H, Peters DK, Rodríguez de Córdoba S, Servais A, Sethi S, Song W-C, Tamburini P, Thurman JM, Zavros M, Cook TH. 2013. C3 glomerulopathy: consensus report. Kidney Int 84:10791089.[CrossRef].[PubMed]
29. Loirat C, Fremeaux-Bacchi V. 2011. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis 6:60.[CrossRef].[PubMed]
30. Zimmerhackl LB, Besbas N, Jungraithmay T, van de Kar N, Karch H, Karpman D, Landau D, Loirat C, Proesmans W, Prufer F, Rizzoni G, Taylor MC European Study Group for Haemolytic Uraemic Syndromes and Related Disorders. 2006. Epidemiology, clinical presentation, and pathophysiology of atypical and recurrent hemolytic uremic syndrome. Semin Thromb Hemost 32:113120.[CrossRef].[PubMed]
31. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, Daina E, Fenili C, Castelletti F, Sorosina A, Piras R, Donadelli R, Maranta R, van der Meer I, Conway EM, Zipfel PF, Goodship TH, Remuzzi G. 2010. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 5:18441859.[CrossRef].[PubMed]
32. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, Macher MA, Niaudet P, Guest G, Boudailliez B, Bouissou F, Deschenes G, Gie S, Tsimaratos M, Fischbach M, Morin D, Nivet H, Alberti C, Loirat C French Society of Pediatric Nephrology. 2007. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 18:23922400.[CrossRef].[PubMed]
33. Bu F, Borsa N, Gianluigi A, Smith RJH. 2012. Familial atypical hemolytic uremic syndrome: a review of its genetic and clinical aspects. Clin Dev Immunol 2012:370426.[CrossRef].[PubMed]
34. Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, Bingham C, Cohen DJ, Delmas Y, Douglas K, Eitner F, Feldkamp T, Fouque D, Furman RR, Gaber O, Herthelius M, Hourmant M, Karpman D, Lebranchu Y, Mariat C, Menne J, Moulin B, Nürnberger J, Ogawa M, Remuzzi G, Richard T, Sberro-Soussan R, Severino B, Sheerin NS, Trivelli A, Zimmerhackl LB, Goodship T, Loirat C. 2013. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 368:21692181.[CrossRef].[PubMed]
35. Zimmerhackl LB, Hofer J, Cortina G, Mark W, Würzner R, Jungraithmayr TC, Khursigara G, Kliche KO, Radauer W. 2010. Prophylactic eculizumab after renal transplantation in atypical hemolytic-uremic syndrome. N Engl J Med 362:17461748.[CrossRef].[PubMed]
36. Roumenina LT, Loirat C, Dragon-Durey MA, Halbwachs-Mecarelli L, Sautes-Fridman C, Fremeaux-Bacchi V. 2011. Alternative complement pathway assessment in patients with atypical HUS. J Immunol Methods 365:826.[CrossRef].[PubMed]
37. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F, Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G International Registry of Recurrent and Familial HUS/TTP. 2006. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108:12671279.[CrossRef].[PubMed]
38. Bu F, Maga T, Meyer NC, Wang K, Thomas CP, Nester CM, Smith RJH. 2014. Comprehensive genetic analysis of complement-coagulation genes in atypical hemolytic uremic syndrome. J Am Soc Nephrol 25:5564.[CrossRef].[PubMed]
39. Gale DP, de Jorge EG, Cook HT, Martinez-Barricarte R, Hadjisavvas A, McLean AG, Pusey CD, Pierides A, Kyriacou K, Athanasiou Y, Voskarides K, Deltas C, Palmer A, Frémeaux-Bacchi V, de Cordoba SR, Maxwell PH, Pickering MC. 2010. Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet 376:794801.[CrossRef].[PubMed]
40. Athanasiou Y, Voskarides K, Gale DP, Damianou L, Patsias C, Zavros M, Maxwell PH, Cook HT, Demosthenous P, Hadjisavvas A, Kyriacou K, Zouvani I, Pierides A, Deltas C. 2011. Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees. Clin J Am Soc Nephrol6:14361446.[CrossRef].[PubMed]
41. McCaughan JA, O'Rourke DM, Courtney AE. 2012. Recurrent dense deposit disease after renal transplantation: an emerging role for complementary therapies. Am J Transplant12:10461051.[CrossRef].[PubMed]
42. Daina E, Noris M, Remuzzi G. 2012. Eculizumab in a patient with dense-deposit disease. N Engl J Med.366:11611163.[CrossRef].[PubMed]
43. Vivarelli M, Pasini A, Emma F. 2012. Eculizumab for the treatment of dense-deposit disease. N Engl J Med 366:11631165.[CrossRef].[PubMed]
44. Bomback AS, Smith RJ, Barile GR, Zhang Y, Heher EC, Herlitz L, Stokes MB, Markowitz GS, D'Agati VD, Canetta PA, Radhakrishnan J, Appel GB. 2012. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin J Am Soc Nephrol 7:748756.[CrossRef].[PubMed]
45. Palarasah Y, Skjodt K, Brandt J, Teisner B, Koch C, Vitved L, Skjoedt MO. 2010. Generation of a C3c specific monoclonal antibody and assessment of C3c as a putative inflammatory marker derived from complement factor C3. J Immunol Methods 362:14250.[CrossRef].[PubMed]

Tables

Generic image for table
TABLE 1

Interpretation of complement protein levels in aHUS

Citation: Smith R. 2016. The Nature of the Diseases That Arise from Improper Regulation of the Alternative Pathway of Complement, p 138-144. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch15
Generic image for table
TABLE 2

Biomarker assays for C3G

Citation: Smith R. 2016. The Nature of the Diseases That Arise from Improper Regulation of the Alternative Pathway of Complement, p 138-144. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch15

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