Background: Systemic lupus erythematosus (SLE) is an autoimmune disorder caused by loss of tolerance to self-antigens, the production of autoantibodies and deposition of complement-fixing immune complexes (ICs) in injured tissues. SLE is characterized by a wide range of clinical manifestations and targeted organs, with lupus nephritis being one of the most serious complications. The complement system consists of three pathways and is tightly controlled by a set of regulatory proteins to prevent injudicious complement activation on host tissue. The involvement of the complement system in the pathogenesis of SLE is well accepted; yet, its exact role is still not clear. Summary: Complement plays dual roles in the pathogenesis of SLE. On the one hand, the complement system appears to have protective features in that hereditary homozygous deficiencies of classical pathway components, such as C1q and C4, are associated with an increased risk for SLE. On the other hand, IC-mediated activation of complement in affected tissues is clearly evident in both experimental and human SLE along with pathological features that are logical consequences of complement activation. Studies in genetically altered mice have shown that lack of complement inhibitors, such as complement factor H (CFH) or decay-accelerating factor (DAF) accelerates the development of experimental lupus nephritis, while treatment with recombinant protein inhibitors, such as Crry-Ig, CR2-Crry, CR2-DAF and CR2-CFH, ameliorates the disease development. Complement-targeted drugs, including soluble complement receptor 1 (TP10), C1 esterase inhibitor and a monoclonal anti-C5 antibody (eculizumab), have been shown to inhibit complement safely, and are now being investigated in a variety of clinical conditions. Key Messages: SLE is an autoimmune disorder which targets multiple systems. Complement is centrally involved and plays dual roles in the pathogenesis of SLE. Studies from experimental lupus models and clinical trials support the use of complement-targeted therapy in the treatment of SLE.

Keywords:
Animal model, Complement, Lupus nephritis, Systemic lupus erythematosus, Therapy
1.
Walport MJ: Complement. First of two parts. N Engl J Med 2001;344:1058-1066.
2.
Gaboriaud C, Thielens NM, Gregory LA, Rossi V, Fontecilla-Camps JC, Arlaud GJ: Structure and activation of the c1 complex of complement: unraveling the puzzle. Trends Immunol 2004;25:368-373.
3.
Nicholson-Weller A, Halperin JA: Membrane signaling by complement C5b-9, the membrane attack complex. Immunol Res 1993;12:244-257.
4.
Lublin DM, Atkinson JP: Decay-accelerating factor: biochemistry, molecular biology, and function. Annu Rev Immunol 1989;7:35-58.
5.
Ahearn JM, Fearon DT: Structure and function of the complement receptors, CR1 (CD35) and CR2 (CD21). Adv Immunol 1989;46:183-219.
6.
Kim YU, Kinoshita T, Molina H, Hourcade D, Seya T, Wagner LM, Holers VM: Mouse complement regulatory protein Crry/p65 uses the specific mechanisms of both human decay-accelerating factor and membrane cofactor protein. J Exp Med 1995;181:151-159.
7.
Morgan P, Harris C: Regulation in the Activation Pathways; Complement Regulatory Proteins. San Diego, Academic Press, 1999, pp 41-136.
8.
Morgan P, Harris C: Regulation in the Terminal Pathway; Complement Regulatory Proteins. San Diego, Academic Press, 1999.
9.
Valentijn RM, van Overhagen H, Hazevoet HM, Hermans J, Cats A, Daha MR, van ES LA: The value of complement and immune complex determinations in monitoring disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 1985;28:904-913.
10.
Dalmasso AP: Complement in the pathophysiology and diagnosis of human diseases. Crit Rev Clin Lab Sci 1986;24:123-183.
11.
Manzi S, Rairie JE, Carpenter AB, Kelly RH, Jagarlapudi SP, Sereika SM, Medsger TA, Ramsey-Goldman R: Sensitivity and specificity of plasma and urine complement split products as indicators of lupus disease activity. Arthritis Rheum 1996;39:1178-1188.
12.
Jönsen A, Nilsson SC, Ahlqvist E, Svenungsson E, Gunnarsson I, Eriksson KG, Bengtsson A, Zickert A, Eloranta ML, Truedsson L, Rönnblom L, Nordmark G, Sturfelt G, Blom AM: Mutations in genes encoding complement inhibitors CD46 and CFH affect the age at nephritis onset in patients with systemic lupus erythematosus. Arthritis Res Ther 2011;13:R206.
13.
Alegretti AP, Schneider L, Piccoli AK, Monticielo OA, Lora PS, Brenol JC, Xavier RM: Diminished expression of complement regulatory proteins on peripheral blood cells from systemic lupus erythematosus patients. Clin Dev Immunol 2012;2012:725684.
14.
Arora V, Mondal AM, Grover R, Kumar A, Chattopadhyay P, Das N: Modulation of CR1 transcript in systemic lupus erythematosus (SLE) by IFN-gamma and immune complex. Mol Immunol 2007;44:1722-1728.
15.
Arora V, Grover R, Kumar A, Anand D, Das N: Relationship of leukocyte CR1 transcript and protein with the pathophysiology and prognosis of systemic lupus erythematosus: a follow-up study. Lupus 2011;20:1010-1018.
16.
Biswas B, Kumar U, Das N: Expression and significance of leukocyte membrane cofactor protein transcript in systemic lupus erythematosus. Lupus 2012;21:517-525.
17.
Ross GD, Yount WJ, Walport MJ, Winfield JB, Parker CJ, Fuller CR, Taylor RP, Myones BL, Lachmann PJ: Disease-associated loss of erythrocyte complement receptors (CR1, C3b receptors) in patients with systemic lupus erythematosus and other diseases involving autoantibodies and/or complement activation. J Immunol 1985;135:2005-2014.
18.
Manderson AP, Botto M, Walport MJ: The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol 2004;22:431-456.
19.
Arkwright PD, Riley P, Hughes SM, Alachkar H, Wynn RF: Successful cure of C1q deficiency in human subjects treated with hematopoietic stem cell transplantation. J Allergy Clin Immunol 2014;133:265-267.
20.
Mehta P, Norsworthy PJ, Hall AE, Kelly SJ, Walport MJ, Botto M, Pickering MC: SLE with C1q deficiency treated with fresh frozen plasma: a 10-year experience. Rheumatology (Oxford) 2010;49:823-824.
21.
Yin Y, Wu X, Shan G, Zhang X: Diagnostic value of serum anti-C1q antibodies in patients with lupus nephritis: a meta-analysis. Lupus 2012;21:1088-1097.
22.
Gullstrand B, Mårtensson U, Sturfelt G, Bengtsson AA, Truedsson L: Complement classical pathway components are all important in clearance of apoptotic and secondary necrotic cells. Clin Exp Immunol 2009;156:303-311.
23.
Nielsen CT, Østergaard O, Stener L, Iversen LV, Truedsson L, Gullstrand B, Jacobsen S, Heegaard NH: Increased IgG on cell-derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation. Arthritis Rheum 2012;64:1227-1236.
24.
Degn SE, Jensenius JC, Thiel S: Disease-causing mutations in genes of the complement system. Am J Hum Genet 2011;88:689-705.
25.
Lood C, Eriksson S, Gullstrand B, Jönsen A, Sturfelt G, Truedsson L, Bengtsson AA: Increased C1q, C4 and C3 deposition on platelets in patients with systemic lupus erythematosus - a possible link to venous thrombosis? Lupus 2012;21:1423-1432.
26.
Lood C, Tydén H, Gullstrand B, Sturfelt G, Jönsen A, Truedsson L, Bengtsson AA: Platelet activation and anti-phospholipid antibodies collaborate in the activation of the complement system on platelets in systemic lupus erythematosus. PLoS One 2014;9:e99386.
27.
Parra S, Vives G, Ferré R, González M, Guardiola M, Ribalta J, Castro A: Complement system and small HDL particles are associated with subclinical atherosclerosis in SLE patients. Atherosclerosis 2012;225:224-230.
28.
Hahn BH, Kono D: Animal models of SLE; in Wallace DJ, Hahn BH (eds): Dubois' Lupus Erythematosus and Related Syndromes: Expert Consult. Philadelphia, Elsevier Saunders, 2012, pp 190-236.
29.
Miwa T, Maldonado MA, Zhou L, Sun X, Luo HY, Cai D, Werth VP, Madaio MP, Eisenberg RA, Song WC: Deletion of decay-accelerating factor (CD55) exacerbates autoimmune disease development in MRL/lpr mice. Am J Pathol 2002;161:1077-1086.
30.
Miwa T, Maldonado MA, Zhou L, Yamada K, Gilkeson GS, Eisenberg RA, Song WC: Decay-accelerating factor ameliorates systemic autoimmune disease in MRL/lpr mice via both complement-dependent and -independent mechanisms. Am J Pathol 2007;170:1258-1266.
31.
Xu C, Mao D, Holers VM, Palanca B, Cheng AM, Molina H: A critical role for murine complement regulator Crry in fetomaternal tolerance. Science 2000;287:498-501.
32.
Bao L, Wang Y, Chang A, Minto AW, Zhou J, Kang H, Haas M, Quigg RJ: Unrestricted C3 activation occurs in Crry-deficient kidneys and rapidly leads to chronic renal failure. J Am Soc Nephrol 2007;18:811-822.
33.
Bao L, Haas M, Boackle SA, Kraus DM, Cunningham PN, Park P, Alexander JJ, Anderson RK, Culhane K, Holers VM, Quigg RJ: Transgenic expression of a soluble complement inhibitor protects against renal disease and promotes survival in MRL/lpr mice. J Immunol 2002;168:3601-3607.
34.
Bao L, Haas M, Kraus DM, Hack BK, Rakstang JK, Holers VM, Quigg RJ: Administration of a soluble recombinant complement C3 inhibitor protects against renal disease in MRL/lpr mice. J Am Soc Nephrol 2003;14:670-679.
35.
Bao L, Zhou J, Holers VM, Quigg RJ: Excessive matrix accumulation in the kidneys of MRL/lpr lupus mice is dependent on complement activation. J Am Soc Nephrol 2003;14:2516-2525.
36.
Takahashi K, Kozono Y, Waldschmidt TJ, Berthiaume D, Quigg RJ, Baron A, Holers VM: Mouse complement receptors type 1 (CR1;CD35) and type 2 (CR2;CD21): Expression on normal B cell subpopulations and decreased levels during the development of autoimmunity in MRL/lpr mice. J Immunol 1997;159:1557-1569.
37.
Wilson JG, Ratnoff WD, Schur PH, Fearon DT: Decreased expression of the C3b/C4b receptor (CR1) and the C3d receptor (CR2) on B lymphocytes and of CR1 on neutrophils of patients with systemic lupus erythematosus. Arthritis Rheum 1986;29:739-747.
38.
Boackle SA, Culhane KK, Brown JM, Haas M, Bao L, Quigg RJ, Holers VM: CR1/CR2 deficiency alters IgG3 autoantibody production and IgA glomerular deposition in the MRL/lpr model of SLE. Autoimmunity 2004;37:111-123.
39.
Barnum SR, Dahlbäck B: C4b-binding protein, a regulatory component of the classical pathway of complement, is an acute-phase protein and is elevated in systemic lupus erythematosus. Complement Inflamm 1990;7:71-77.
40.
Wenderfer SE, Soimo K, Wetsel RA, Braun MC: Analysis of C4 and the C4 binding protein in the MRL/lpr mouse. Arthritis Res Ther 2007;9:R114.
41.
Blom AM, Nandakumar KS, Holmdahl R: C4b-binding protein (C4bp) inhibits development of experimental arthritis in mice. Ann Rheum Dis 2009;68:136-142.
42.
Elliott MK, Jarmi T, Ruiz P, Xu Y, Holers VM, Gilkeson GS: Effects of complement factor D deficiency on the renal disease of MRL/lpr mice. Kidney Int 2004;65:129-138.
43.
Watanabe H, Garnier G, Circolo A, Wetsel RA, Ruiz P, Holers VM, Boackle SA, Colten HR, Gilkeson GS: Modulation of renal disease in MRL/lpr mice genetically deficient in the alternative complement pathway factor B. J Immunol 2000;164:786-794.
44.
Mehta G, Ferreira VP, Skerka C, Zipfel PF, Banda NK: New insights into disease-specific absence of complement factor H related protein C in mouse models of spontaneous autoimmune diseases. Mol Immunol 2014;62:235-248.
45.
Bao L, Haas M, Quigg RJ: Complement factor H deficiency accelerates development of lupus nephritis. J Am Soc Nephrol 2011;22:285-295.
46.
Pickering MC, Cook HT, Warren J, Bygrave AE, Moss J, Walport MJ, Botto M: Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat Genet 2002;31:424-428.
47.
Wang Y, Hu Q, Madri JA, Rollins SA, Chodera A, Matis LA: Amelioration of lupus-like autoimmune disease in NZB/WF1 mice after treatment with a blocking monoclonal antibody specific for complement component C5. Proc Natl Acad Sci USA 1996;93:8563-8568.
48.
Miwa T, Zhou L, Maldonado MA, Madaio MP, Eisenberg RA, Song WC: Absence of CD59 exacerbates systemic autoimmunity in MRL/lpr mice. J Immunol 2012;189:5434-5441.
49.
Mizuno M, Blanchin S, Gasque P, Nishikawa K, Matsuo S: High levels of complement C3a receptor in the glomeruli in lupus nephritis. Am J Kidney Dis 2007;49:598-606.
50.
Bao L, Osawe I, Puri T, Lambris JD, Haas M, Quigg RJ: C5a promotes development of experimental lupus nephritis which can be blocked with a specific receptor antagonist. Eur J Immunol 2005;35:2496-2506.
51.
Bao L, Osawe I, Haas M, Quigg RJ: Signaling through up-regulated C3a receptor is key to the development of experimental lupus nephritis. J Immunol 2005;175:1947-1955.
52.
Wenderfer SE, Ke B, Hollmann TJ, Wetsel RA, Lan HY, Braun MC: C5a receptor deficiency attenuates T cell function and renal disease in MRLlpr mice. J Am Soc Nephrol 2005;16:3572-3582.
53.
Wenderfer SE, Wang H, Ke B, Wetsel RA, Braun MC: C3a receptor deficiency accelerates the onset of renal injury in the MRL/lpr mouse. Mol Immunol 2009;46:1397-1404.
54.
Mathieu MC, Sawyer N, Greig GM, Hamel M, Kargman S, Ducharme Y, Lau CK, Friesen RW, O'Neill GP, Gervais FG, Therien AG: The C3a receptor antagonist SB 290157 has agonist activity. Immunol Lett 2005;100:139-145.
55.
Sekine H, Reilly CM, Molano ID, Garnier G, Circolo A, Ruiz P, Holers VM, Boackle SA, Gilkeson GS: Complement component C3 is not required for full expression of immune complex glomerulonephritis in MRL/lpr mice. J Immunol 2001;166:6444-6451.
56.
Sheerin NS, Springall T, Carroll M, Sacks SH: Altered distribution of intraglomerular immune complexes in C3-deficient mice. Immunology 1999;97:393-399.
57.
Taylor PR, Carugati A, Fadok VA, Cook HT, Andrews M, Carroll MC, Savill JS, Henson PM, Botto M, Walport MJ: A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J Exp Med 2000;192:359-366.
58.
Botto M, Dell'Agnola C, Bygrave AE, Thompson EM, Cook HT, Petry F, Loos M, Pandolfi PP, Walport MJ: Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 1998;19:56-59.
59.
Gaipl US, Beyer TD, Heyder P, Kuenkele S, Böttcher A, Voll RE, Kalden JR, Herrmann M: Cooperation between C1q and DNase I in the clearance of necrotic cell-derived chromatin. Arthritis Rheum 2004;50:640-649.
60.
Kenyon KD, Cole C, Crawford F, Kappler JW, Thurman JM, Bratton DL, Boackle SA, Henson PM: IgG autoantibodies against deposited C3 inhibit macrophage-mediated apoptotic cell engulfment in systemic autoimmunity. J Immunol 2011;187:2101-2111.
61.
Papp K, Végh P, Tchorbanov A, Vassilev T, Erdei A, Prechl J: Progression of lupus-like disease drives the appearance of complement-activating IgG antibodies in MRL/lpr mice. Rheumatology (Oxford) 2010;49:2273-2280.
62.
Schifferli JA, Ng YC, Peters DK: The role of complement and its receptor in the elimination of immune complexes. N Engl J Med 1986;315:488-495.
63.
Thurman JM, Kulik L, Orth H, Wong M, Renner B, Sargsyan SA, Mitchell LM, Hourcade DE, Hannan JP, Kovacs JM, Coughlin B, Woodell AS, Pickering MC, Rohrer B, Holers VM: Detection of complement activation using monoclonal antibodies against C3d. J Clin Invest 2013;123:2218-2230.
64.
Song H, He C, Knaak C, Guthridge JM, Holers VM, Tomlinson S: Complement receptor 2-mediated targeting of complement inhibitors to sites of complement activation. J Clin Invest 2003;111:1875-1885.
65.
Atkinson C, Qiao F, Song H, Gilkeson GS, Tomlinson S: Low-dose targeted complement inhibition protects against renal disease and other manifestations of autoimmune disease in MRL/lpr mice. J Immunol 2008;180:1231-1238.
66.
Sekine H, Kinser TT, Qiao F, Martinez E, Paulling E, Ruiz P, Gilkeson GS, Tomlinson S: The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice. Arthritis Rheum 2011;63:1076-1085.
67.
Sekine H, Ruiz P, Gilkeson GS, Tomlinson S: The dual role of complement in the progression of renal disease in NZB/W F(1) mice and alternative pathway inhibition. Mol Immunol 2011;49:317-323.
68.
Sargsyan SA, Serkova NJ, Renner B, Hasebroock KM, Larsen B, Stoldt C, McFann K, Pickering MC, Thurman JM: Detection of glomerular complement C3 fragments by magnetic resonance imaging in murine lupus nephritis. Kidney Int 2012;81:152-159.
69.
Zimmerman JL, Dellinger RP, Straube RC, Levin JL: Phase I trial of the recombinant soluble complement receptor 1 in acute lung injury and acute respiratory distress syndrome. Crit Care Med 2000;28:3149-3154.
70.
Keshavjee S, Davis RD, Zamora MR, de Perrot M, Patterson GA: A randomized, placebo-controlled trial of complement inhibition in ischemia-reperfusion injury after lung transplantation in human beings. J Thorac Cardiovasc Surg 2005;129:423-428.
71.
Lazar HL, Bokesch PM, van Lenta F, Fitzgerald C, Emmett C, Marsh HC, Ryan U; OBE and the TP10 Cardiac Surgery Study Group: Soluble human complement receptor 1 limits ischemic damage in cardiac surgery patients at high risk requiring cardiopulmonary bypass. Circulation 2004;110:II274-II279.
72.
Zhang Y, Nester CM, Holanda DG, Marsh HC, Hammond RA, Thomas LJ, Meyer NC, Hunsicker LG, Sethi S, Smith RJ: Soluble CR1 therapy improves complement regulation in C3 glomerulopathy. J Am Soc Nephrol 2013;24:1820-1829.
73.
Craig TJ, Levy RJ, Wasserman RL, Bewtra AK, Hurewitz D, Obtułowicz K, Reshef A, Ritchie B, Moldovan D, Shirov T, Grivcheva-Panovska V, Kiessling PC, Keinecke HO, Bernstein JA: Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol 2009;124:801-808.
74.
Riedl MA, Levy RJ, Suez D, Lockey RF, Baker JW, Relan A, Zuraw BL: Efficacy and safety of recombinant C1 inhibitor for the treatment of hereditary angioedema attacks: a North American open-label study. Ann Allergy Asthma Immunol 2013;110:295-299.
75.
Wouters D, Stephan F, Strengers P, de Haas M, Brouwer C, Hagenbeek A, van Oers MH, Zeerleder S: C1-esterase inhibitor concentrate rescues erythrocytes from complement-mediated destruction in autoimmune hemolytic anemia. Blood 2013;121:1242-1244.
76.
Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, Gaya A, Coyle L, de Castro C, Fu CL, Maciejewski JP, Bessler M, Kroon HA, Rother RP, Hillmen P: Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 2008;111:1840-1847.
77.
Hillmen P, Muus P, Röth A, Elebute MO, Risitano AM, Schrezenmeier H, Szer J, Browne P, Maciejewski JP, Schubert J, Urbano-Ispizua A, de Castro C, Socié G, Brodsky RA: Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2013;162:62-73.
78.
Keating GM: Eculizumab: a review of its use in atypical haemolytic uraemic syndrome. Drugs 2013;73:2053-2066.
79.
Barilla-Labarca ML, Toder K, Furie R: Targeting the complement system in systemic lupus erythematosus and other diseases. Clin Immunol 2013;148:313-321.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.