Complement activation by phospholipids: the interplay of factor H and C1q

Abstract

Complement proteins in blood recognize charged particles. The anionic phospholipid (aPL) cardiolipin binds both complement proteins C1q and factor H. C1q is an activator of the complement classical pathway, while factor H is an inhibitor of the alternative pathway. To examine opposing effects of C1q and factor H on complement activation by aPL, we surveyed C1q and factor H binding, and complement activation by aPL, either coated on microtitre plates or in liposomes. Both C1q and factor H bound to all aPL tested, and competed directly with each other for binding. All the aPL activated the complement classical pathway, but negligibly the alternative pathway, consistent with accepted roles of C1q and factor H. However, in this system, factor H, by competing directly with C1q for binding to aPL, acts as a direct regulator of the complement classical pathway. This regulatory mechanism is distinct from its action on the alternative pathway. Regulation of classical pathway activation by factor H was confirmed by measuring C4 activation by aPL in human sera in which the C1q:factor H molar ratio was adjusted over a wide range. Thus factor H, which is regarded as a down-regulator only of the alternative pathway, has a distinct role in downregulating activation of the classical complement pathway by aPL. A factor H homologue, β2-glycoprotein-1, also strongly inhibits C1q binding to cardiolipin. Recombinant globular domains of C1q A, B and C chains bound aPL similarly to native C1q, confirming that C1q binds aPL via its globular heads.

Keywords

complement / regulation / classical pathway / C1q / factor H / anionic phospholipid

References

[1] Agnello, V., Carr, R.I., Koffler, D., and Kunkel, H. (1969). Gel diffusion reactions of C1 with aggregated globulin, DNA and various anionic substances. Fed Proc 28, 696.
[2] Bradley, A.J., Brooks, D.E., Norris-Jones, R., and Devine, D.V. (1999). C1q binding to liposomes is surface charge dependent and is inhibited by peptides consisting of residues 14-26 of the human C1qA chain in a sequence independent manner. Biochim Biophys Acta 1418, 19–30 .10.1016/S0005-2736(99)00013-9
[3] Carreno, M.P., Labarre, D., Maillet, F., Jozefowicz, M., and Kazatchkine, M.D. (1989). Regulation of the human alternative complement pathway: formation of a ternary complex between factor H, surface-bound C3b and chemical groups on nonactivating surfaces. Eur J Immunol 19, 2145–2150 .10.1002/eji.1830191126
[4] Charlesworth, J.A., Scott, D.M., Pussell, B.A., and Peters, D.K. (1979). Metabolism of human beta 1H: studies in man and experimental animals. Clin Exp Immunol 38, 397–404 .
[5] Chonn, A., Cullis, P.R., and Devine, D.V. (1991). The role of surface charge in the activation of the classical and alternative pathways of complement by liposomes. J Immunol 146, 4234–4241 .
[6] Clas, F., Euteneuer, B., Stemmer, F., and Loos, M. (1989). Interaction of fluid phase C1/C1q and macrophage membrane-associated C1q with gram-negative bacteria. Behring Inst Mitt 84, 236–254 .
[7] Cooper, N.R., Jensen, F.C., Welsh, R.M. Jr, and Oldstone, M.B. (1976). Lysis of RNA tumor viruses by human serum: direct antibody-independent triggering of the classical complement pathway. J Exp Med 144, 970–984 .10.1084/jem.144.4.970
[8] Dillon, S.P., D’Souza, A., Kurien, B.T., and Scofield, R.H. (2009). Systemic lupus erythematosus and C1q: A quantitative ELISA for determining C1q levels in serum. Biotechnol J 4, 1210–1214 .10.1002/biot.200800273
[9] Dodds, A.W., and Porter, R.R. (1979). The activation of complement components by aggregates of antibodies and their fragments. Mol Immunol 16, 1059–1062 .10.1016/0161-5890(79)90039-7
[10] Dodds, A.W., Sim, R.B., Porter, R.R., and Kerr, M.A. (1978). Activation of the first component of human complement (C1) by antibody-antigen aggregates. Biochem J 175, 383–390 .
[11] Easterbrook-Smith, S.B., Wilson, M.R., and Wines, B.D. (1992). RHP is antigenically related to factor H and binds to the globular heads of C1q. Mol Immunol 29, 1203–1207 .10.1016/0161-5890(92)90056-4
[12] Edey, M., Strain, L., Ward, R., Ahmed, S., Thomas, T., and Goodship, T.H. (2009). Is complement factor H a susceptibility factor for IgA nephropathy? Mol Immunol 46, 1405–1408 .10.1016/j.molimm.2008.12.002
[13] Fairbanks, G., Steck, T.L., and Wallach, D.F. (1971). Electrophoretic analysis of the major polypeptides of the human erythrocyte membrane. Biochemistry 10, 2606–2617 .10.1021/bi00789a030
[14] Ferluga, J., Yu, B.B., Guerin, J., Jackson, J., and Sim, R.B. (1998). Similarities between complement Factor H and beta-2 glycoprotein 1: phospholipid binding and auto-antibodies. Mol Immunol 35, 375.10.1016/S0161-5890(98)90711-8
[15] Fraker, P.J., and Speck, J.C. Jr. (1978). Protein and cell membrane iodinations with a sparingly soluble chloroamide, 1,3,4,6-tetrachloro-3a,6a-diphrenylglycoluril. Biochem Biophys Res Commun 80, 849–857 .10.1016/0006-291X(78)91322-0
[16] Gadd, K.J., and Reid, K.B.M. (1981). Importance of the integrity of the inter-heavy-chain disulphide bond of rabbit IgG in the activation of the alternative pathway of human complement by the F(ab’)2 region of rabbit IgG antibody in immune aggregates. Immunology 42, 75–82 .
[17] Harris, E.N., Gharavi, A.E., Patel, S.P., and Hughes, G.R. (1987). Evaluation of the anti-cardiolipin antibody test: report of an international workshop held 4 April 1986. Clin Exp Immunol 68, 215–222 .
[18] Holme, E.R., Qi, M., Ahmed, A.E., Veitch, J., Auda, G., and Whaley, K. (1992). Purification and characterization of RHP (factor H) and study of its interactions with the first component of complement. Mol Immunol 29, 957–964 .10.1016/0161-5890(92)90134-J
[19] Hurwitz, C., Rosano, C.L., Hechemy, K.E., Weber, P., and Parhami, N. (1995). Structural, immunological and functional comparisons of factor H, rheumatoid arthritis protein (RHP), and its apparent normal counterpart (N-RHP). Mol Immunol 32, 1259–1269 .10.1016/0161-5890(95)00068-2
[20] Ingram, G., Hakobyan, S., Hirst, C.L., Harris, C.L., Pickersgill, T.P., Cossburn, M.D., Loveless, S., Robertson, N.P., and Morgan, B.P. (2010). Complement regulator factor H as a serum biomarker of multiple sclerosis disease state. Brain 133, 1602–1611 .10.1093/brain/awq085
[21] Jiang, H., Burdick, D., Glabe, C.G., Cotman, C.W., and Tenner, A.J. (1994). beta-Amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain. J Immunol 152, 5050–5059 .
[22] Jiang, H., Cooper, B., Robey, F.A., and Gewurz, H. (1992). DNA binds and activates complement via residues 14-26 of the human C1q A chain. J Biol Chem 267, 25597–25601 .
[23] Johnstone, A., and Thorpe, R. (1987) Purification of immunoglobulins, constituent chains and fragments. Immunochemistry in Practice. Blackwell Scientific Publications, Oxford, UK . pp 48–85 .
[24] Kang, Y.H., Tan, L.A., Carroll, M.V., Gentle, M.E., and Sim, R.B. (2009). Target pattern recognition by complement proteins of the classical and alternative pathways. Adv Exp Med Biol 653, 117–128 .10.1007/978-1-4419-0901-5_8
[25] Kertesz, Z., Yu, B.B., Steinkasserer, A., Haupt, H., Benham, A., and Sim, R.B. (1995). Characterization of binding of human 2-glycoprotein I to cardiolipin. Biochem J 310, 315–321 .
[26] Kishore, U., and Reid, K.B.M. (2000). C1q: structure, function, and receptors. Immunopharmacology 49, 159–170 .10.1016/S0162-3109(00)80301-X
[27] Kishore, U., Strong, P., Perdikoulis, M.V., and Reid, K.B.M. (2001). A recombinant homotrimer, composed of the alpha helical neck region of human surfactant protein D and C1q B chain globular domain, is an inhibitor of the classical complement pathway. J Immunol 166, 559–565 .
[28] Kojouharova, M.S., Panchev, I.D., Tchorbadjieva, M.I., Reid, K.B.M., and Hoppe, H.J. (1998). Differential binding of IgG and of a HIV gp41 peptide by the B chain and A chain globular head sequences of C1q, respectively. J Immunol 161, 4325–4331 .
[29] Korb, L.C., and Ahearn, J.M. (1997). C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited. J Immunol 158, 4525–4528 .
[30] Kovacsovics, T., Tschopp, J., Kress, A., and Isliker, H. (1985). Antibody-independent activation of C1 by cardiolipin. J Immunol 135, 2695–2700 .
[31] Laemmli, U.K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680–685 .10.1038/227680a0
[32] Marjan, J., Xie, Z., and Devine, D.V. (1994). Liposome-induced activation of the classical complement pathway does not require immunoglobulin. Biochim Biophys Acta 1192, 35–44 .10.1016/0005-2736(94)90140-6
[33] Martin, S.J., Reutelingsperger, C.P., McGahon, A.J., Rader, J.A., van Schie, R.C., LaFace, D.M., and Green, D.R. (1995). Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med 182, 1545–1556 .10.1084/jem.182.5.1545
[34] New, R.C.C. (1990). Preparation of liposomes. In New, R. C. C. (Ed.) Liposomes — a practical approach. IRL Press , Oxford, UK. pp 33–104 .
[35] Ogden, C.A., deCathelineau, A., Hoffmann, P.R., Bratton, D., Ghebrehiwet, B., Fadok, V.A., and Henson, P.M. (2001). C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J Exp Med 194, 781–795 .10.1084/jem.194.6.781
[36] Okada, M., Udaka, K., and Utsumi, S. (1985). Co-operative interaction of subcomponents of the first component of complement with IgG: a functional defect of dimeric Facb from rabbit IgG. Mol Immunol 22, 1399–1406 .10.1016/0161-5890(85)90063-X
[37] Pa?dassi, H., Tacnet-Delorme, P., Garlatti, V., Darnault, C., Ghebrehiwet, B., Gaboriaud, C., Arlaud, G.J., and Frachet, P. (2008). C1q binds phosphatidylserine and likely acts as a multiligand-bridging molecule in apoptotic cell recognition. J Immunol 180, 2329–2338 .
[38] Peitsch, M.C., Tschopp, J., Kress, A., and Isliker, H. (1988). Antibody-independent activation of the complement system by mitochondria is mediated by cardiolipin. Biochem J 249, 495–500 .
[39] Presanis, J.S., Hajela, K., Ambrus, G., Gál, P., and Sim, R.B. (2004). Differential substrate and inhibitor profiles for human MASP-1 and MASP-2. Mol Immunol 40, 921–929 .10.1016/j.molimm.2003.10.013
[40] Reid, K.B.M., and Porter, R.R. (1976). Subunit composition and structure of subcomponent C1q of the first component of human complement. Biochem J 155, 19–23 .
[41] Ripoche, J., Day, A.J., Harris, T.J., and Sim, R.B. (1988a). The complete amino acid sequence of human complement factor H. Biochem J 249, 593–602 .
[42] Ripoche, J., Erdei, A., Gilbert, D., Al Salihi, A., Sim, R.B., and Fontaine, M. (1988b). Two populations of complement factor H differ in their ability to bind to cell surfaces. Biochem J 253, 475–480 .
[43] Roumenina, L., Bureeva, S., Kantardjiev, A., Karlinsky, D., Andia-Pravdivy, J.E., Sim, R., Kaplun, A., Popov, M., Kishore, U., and Atanasov, B. (2007). Complement C1q-target proteins recognition is inhibited by electric moment effectors. J Mol Recognit 20, 405–415 .10.1002/jmr.853
[44] Rybak-Smith, M.J., Pondman, K.M., Flahaut, E., Salvador-Morales, C., and Sim, R.B. (2010). Recognition of carbon nanotubes by the human innate immune system. In Multi-functional carbon nanotubes for biomedical applications (Klingeler, R., and Sim, R.B. editors) pp 183–210 . Springer Verlag Berlin/Heidelberg.
[45] Schneider, M.C., Exley, R.M., Chan, H., Feavers, I., Kang, Y.H., Sim, R.B., and Tang, C.M. (2006). Functional significance of factor H binding to Neisseria meningitidis. J Immunol 176, 7566–7575 .
[46] Sim, E., Palmer, M.S., Puklavec, M., and Sim, R.B. (1983). Monoclonal antibodies against the complement control protein factor H (beta 1 H). Biosci Rep 3, 1119–1131 .10.1007/BF01120205
[47] Sim, R.B., Day, A.J., Moffatt, B.E., and Fontaine, M. (1993). Complement factor I and cofactors in control of complement system convertase enzymes. Methods Enzymol 223, 13–35 .10.1016/0076-6879(93)23035-L
[48] Sim, R.B., Kishore, U., Villiers, C.L., Marche, P.N., and Mitchell, D.A. (2007). C1q binding and complement activation by prions and amyloids. Immunobiology 212, 355–362 .10.1016/j.imbio.2007.04.001
[49] Sim, R.B., and Malhotra, R. (1994). Interactions of carbohydrates and lectins with complement. Biochem Soc Trans 22, 106–111 .
[50] Sim, R.B., Moffatt, B.E., Shaw, J.M., and Ferluga, J. (2008). Complement control proteins and receptors: from FH to CR4. In Molecular Aspects of Innate and Adaptive Immunity (Reid, K.B.M., and Sim, R.B., editors) pp 84–104 . Royal Society of Chemistry, Cambridge 2008.10.1039/9781847558848-00084
[51] Sj?berg, A.P., Trouw, L.A., and Blom, A.M. (2009). Complement activation and inhibition: a delicate balance. Trends Immunol 30, 83–90 .10.1016/j.it.2008.11.003
[52] Sorice, M., Circella, A., Misasi, R., Pittoni, V., Garofalo, T., Cirelli, A., Pavan, A., Pontieri, G.M., and Valesini, G. (2000). Cardiolipin on the surface of apoptotic cells as a possible trigger for antiphospholipids antibodies. Clin Exp Immunol 122, 277–284 .10.1046/j.1365-2249.2000.01353.x
[53] Stewart, J.C.M. (1980). Colorimetric determination of phospholipids with ammonium ferrothiocyanate. Anal Biochem 104, 10–14 .10.1016/0003-2697(80)90269-9
[54] Szebeni, J. (1998). The interaction of liposomes with the complement system. Crit Rev Ther Drug Carrier Syst 15, 57–88 .
[55] Tacnet-Delorme, P., Chevallier, S., and Arlaud, G.J. (2001). Beta-amyloid fibrils activate the C1 complex of complement under physiological conditions: evidence for a binding site for A beta on the C1q globular regions. J Immunol 167, 6374–6381 .
[56] Tambourgi, D.V., De Sousa Da Silva, M., Billington, S.J., Gon?alves De Andrade, R.M., Magnoli, F.C., Songer, J.G., and Van Den Berg, C.W. (2002). Mechanism of induction of complement susceptibility of erythrocytes by spider and bacterial sphingomyelinases. Immunology 107, 93–101 .10.1046/j.1365-2567.2002.01483.x
[57] Tambourgi, D.V., Pedrosa, M.F., de Andrade, R.M., Billington, S.J., Griffiths, M., and van den Berg, C.W. (2007). Sphingomyelinases D induce direct association of C1q to the erythrocyte membrane causing complement mediated autologous haemolysis. Mol Immunol 44, 576–582 .10.1016/j.molimm.2006.02.002
[58] Tan, L.A., Kishore, U., Ferluga, J., Yu, B., and Sim, R.B. (2002). A role for factor H in regulating classical pathway activation. Int Immunopharmacol 2, 1264.
[59] Tan, L.A., and Sim, R.B. (2001). Complement activation by phospholipids (PL). Mol Immunol 38, 125.
[60] Wallis, R., Mitchell, D.A., Schmid, R., Schwaeble, W.J., and Keeble, A.H. (2010). Paths reunited: Initiation of the classical and lectin pathways of complement activation. Immunobiology 215, 1–11 .10.1016/j.imbio.2009.08.006
[61] Whaley, K., and North, J. (1997). Haemolytic assays for whole complement activity and individual components. In Complement - a practical approach (Dodds, A. W., and Sim, R. B. editors). IRL Press, Oxford, UK. pp 19–48 .
[62] Williams, S.C., and Sim, R.B. (1993). Dye-ligand affinity purification of human complement factor B and beta 2 glycoprotein I. J Immunol Methods 157, 25–30 .10.1016/0022-1759(93)90066-G
[63] Yu, B.B., Moffatt, B.E., Willis, A.C., and Sim, R.B. (1997). A generalised method for purifying complement factor H and β2-glycoprotein 1, based on their binding to cardiolipin. Exp Clin Immunogenet 14, 39.
[64] Yu, B.B., Moffatt, B.E., Willis, A.C., and Sim, R.B. (1995). Binding of human and animal serum proteins to cardiolipin - a generalised method for purifying beta-2 glycoprotein 1 and complement factor H. Immunology 86, 161.