Top

Published in:

01-12-2015 | AUTOIMMUNITY/IMMUNOREGULATION/INFLAMMATION

Fundamental role of C1q in autoimmunity and inflammation

Authors: Myoungsun Son, Betty Diamond, Frances Santiago-Schwarz

Published in: Immunologic Research | Issue 1-3/2015

Abstract

C1q, historically viewed as the initiating component of the classical complement pathway, also exhibits a variety of complement-independent activities in both innate and acquired immunity. Recent studies focusing on C1q’s suppressive role in the immune system have provided new insight into how abnormal C1q expression and bioactivity may contribute to autoimmunity. In particular, molecular networks involving C1q interactions with cell surface receptors and other ligands are emerging as mechanisms involved in C1q’s modulation of immunity. Here, we discuss the role of C1q in controlling immune cell function, including recently elucidated mechanisms of action, and suggest how these processes are critical for maintaining tissue homeostasis under steady-state conditions and in preventing autoimmunity.

Walport MJ. Complement: second of two parts. N Engl J Med. 2001;344(15):1140–4. doi:10.1056/NEJM200104123441506.CrossRefPubMed

Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11(9):785–97. doi:10.1038/ni.1923.PubMedCentralCrossRefPubMed

Reid KB, Porter RR. Subunit composition and structure of subcomponent C1q of the first component of human complement. Biochem J. 1976;155(1):19–23.PubMedCentralCrossRefPubMed

Nicholson-Weller A, Klickstein LB. C1q-binding proteins and C1q receptors. Curr Opin Immunol. 1999;11(1):42–6.CrossRefPubMed

Shapiro L, Scherer PE. The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor. Curr biol CB. 1998;8(6):335–8.CrossRefPubMed

Vandivier RW, Ogden CA, Fadok VA, Hoffmann PR, Brown KK, Botto M, Walport MJ, Fisher JH, Henson PM, Greene KE. Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro: calreticulin and CD91 as a common collectin receptor complex. J Immunol. 2002;169(7):3978–86.CrossRefPubMed

Teixeira JE, Heron BT, Huston CD. C1q- and collectin-dependent phagocytosis of apoptotic host cells by the intestinal protozoan Entamoeba histolytica. J Infect Dis. 2008;198(7):1062–70. doi:10.1086/591628.PubMedCentralCrossRefPubMed

Paidassi H, Tacnet-Delorme P, Garlatti V, Darnault C, Ghebrehiwet B, Gaboriaud C, Arlaud GJ, Frachet P. C1q binds phosphatidylserine and likely acts as a multiligand-bridging molecule in apoptotic cell recognition. J Immunol. 2008;180(4):2329–38.PubMedCentralCrossRefPubMed

Nayak A, Pednekar L, Reid KB, Kishore U. Complement and non-complement activating functions of C1q: a prototypical innate immune molecule. Innate Immun. 2012;18(2):350–63. doi:10.1177/1753425910396252.CrossRefPubMed

10.

Gaboriaud C, Frachet P, Thielens NM, Arlaud GJ. The human c1q globular domain: structure and recognition of non-immune self ligands. Front Immunol. 2011;2:92. doi:10.3389/fimmu.2011.00092.PubMedCentralPubMed

11.

Bohlson SS, Fraser DA, Tenner AJ. Complement proteins C1q and MBL are pattern recognition molecules that signal immediate and long-term protective immune functions. Mol Immunol. 2007;44(1–3):33–43. doi:10.1016/j.molimm.2006.06.021.CrossRefPubMed

12.

Korb LC, Ahearn JM. C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited. J Immunol. 1997;158(10):4525–8.PubMed

13.

Brencicova E, Diebold SS. Nucleic acids and endosomal pattern recognition: how to tell friend from foe? Front Cell Infect Microbiol. 2013;3:37. doi:10.3389/fcimb.2013.00037.PubMedCentralCrossRefPubMed

14.

Tacnet-Delorme P, Chevallier S, Arlaud GJ. 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. 2001;167(11):6374–81.CrossRefPubMed

15.

Klein MA, Kaeser PS, Schwarz P, Weyd H, Xenarios I, Zinkernagel RM, Carroll MC, Verbeek JS, Botto M, Walport MJ, Molina H, Kalinke U, Acha-Orbea H, Aguzzi A. Complement facilitates early prion pathogenesis. Nat Med. 2001;7(4):488–92. doi:10.1038/86567.CrossRefPubMed

16.

Sim RB, Kishore U, Villiers CL, Marche PN, Mitchell DA. C1q binding and complement activation by prions and amyloids. Immunobiology. 2007;212(4–5):355–62. doi:10.1016/j.imbio.2007.04.001.CrossRefPubMed

17.

Biro A, Thielens NM, Cervenak L, Prohaszka Z, Fust G, Arlaud GJ. Modified low density lipoproteins differentially bind and activate the C1 complex of complement. Mol Immunol. 2007;44(6):1169–77. doi:10.1016/j.molimm.2006.06.013.CrossRefPubMed

18.

Garlatti V, Chouquet A, Lunardi T, Vives R, Paidassi H, Lortat-Jacob H, Thielens NM, Arlaud GJ, Gaboriaud C. Cutting edge: C1q binds deoxyribose and heparan sulfate through neighboring sites of its recognition domain. J Immunol. 2010;185(2):808–12. doi:10.4049/jimmunol.1000184.CrossRefPubMed

19.

Bredt W, Wellek B, Brunner H, Loos M. Interactions between mycoplasma pneumoniae and the first components of complement. Infect Immun. 1977;15(1):7–12.PubMedCentralPubMed

20.

Santoro F, Ouaissi MA, Pestel J, Capron A. Interaction between Schistosoma mansoni and the complement system: binding of C1q to schistosomula. J Immunol. 1980;124(6):2886–91.PubMed

21.

Scott D, Botto M. The paradoxical roles of C1q and C3 in autoimmunity. Immunobiology. 2015;. doi:10.1016/j.imbio.2015.05.001.PubMed

22.

Ogden CA, deCathelineau A, Hoffmann PR, Bratton D, Ghebrehiwet B, Fadok VA, Henson PM. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J Exp Med. 2001;194(6):781–95.PubMedCentralCrossRefPubMed

23.

Leffler J, Bengtsson AA, Blom AM. The complement system in systemic lupus erythematosus: an update. Ann Rheum Dis. 2014;73(9):1601–6. doi:10.1136/annrheumdis-2014-205287.CrossRefPubMed

24.

Eggleton P, Tenner AJ, Reid KB. C1q receptors. Clin Exp Immunol. 2000;120(3):406–12.PubMedCentralCrossRefPubMed

25.

Son M, Santiago-Schwarz F, Al-Abed Y, Diamond B. C1q limits dendritic cell differentiation and activation by engaging LAIR-1. Proc Natl Acad Sci USA. 2012;109(46):E3160–7. doi:10.1073/pnas.1212753109.PubMedCentralCrossRefPubMed

26.

Hosszu KK, Valentino A, Vinayagasundaram U, Vinayagasundaram R, Joyce MG, Ji Y, Peerschke EI, Ghebrehiwet B. DC-SIGN, C1q, and gC1qR form a trimolecular receptor complex on the surface of monocyte-derived immature dendritic cells. Blood. 2012;120(6):1228–36. doi:10.1182/blood-2011-07-369728.PubMedCentralCrossRefPubMed

27.

Zutter MM, Edelson BT. The alpha2beta1 integrin: a novel collectin/C1q receptor. Immunobiology. 2007;212(4–5):343–53. doi:10.1016/j.imbio.2006.11.013.CrossRefPubMed

28.

Fraser DA, Pisalyaput K, Tenner AJ. C1q enhances microglial clearance of apoptotic neurons and neuronal blebs, and modulates subsequent inflammatory cytokine production. J Neurochem. 2010;112(3):733–43. doi:10.1111/j.1471-4159.2009.06494.x.PubMedCentralCrossRefPubMed

29.

Fraser DA, Tenner AJ. Innate immune proteins C1q and mannan-binding lectin enhance clearance of atherogenic lipoproteins by human monocytes and macrophages. J Immunol. 2010;185(7):3932–9. doi:10.4049/jimmunol.1002080.PubMedCentralCrossRefPubMed

30.

Duus K, Hansen EW, Tacnet P, Frachet P, Arlaud GJ, Thielens NM, Houen G. Direct interaction between CD91 and C1q. FEBS J. 2010;277(17):3526–37. doi:10.1111/j.1742-4658.2010.07762.x.CrossRefPubMed

31.

Steino A, Jorgensen CS, Laursen I, Houen G. Interaction of C1q with the receptor calreticulin requires a conformational change in C1q. Scand J Immunol. 2004;59(5):485–95. doi:10.1111/j.0300-9475.2004.01425.x.CrossRefPubMed

32.

Paidassi H, Tacnet-Delorme P, Verneret M, Gaboriaud C, Houen G, Duus K, Ling WL, Arlaud GJ, Frachet P. Investigations on the C1q-calreticulin-phosphatidylserine interactions yield new insights into apoptotic cell recognition. J Mol Biol. 2011;408(2):277–90. doi:10.1016/j.jmb.2011.02.029.CrossRefPubMed

33.

Ma W, Rai V, Hudson BI, Song F, Schmidt AM, Barile GR. RAGE binds C1q and enhances C1q-mediated phagocytosis. Cell Immunol. 2012;274(1–2):72–82. doi:10.1016/j.cellimm.2012.02.001S0008-8749(12)00022-6.CrossRefPubMed

34.

Ramirez-Ortiz ZG, Pendergraft WF 3rd, Prasad A, Byrne MH, Iram T, Blanchette CJ, Luster AD, Hacohen N, El Khoury J, Means TK. The scavenger receptor SCARF1 mediates the clearance of apoptotic cells and prevents autoimmunity. Nat Immunol. 2013;14(9):917–26. doi:10.1038/ni.2670.PubMedCentralCrossRefPubMed

35.

Galvan MD, Foreman DB, Zeng E, Tan JC, Bohlson SS. Complement component C1q regulates macrophage expression of Mer tyrosine kinase to promote clearance of apoptotic cells. J Immunol. 2012;188(8):3716–23. doi:10.4049/jimmunol.1102920.PubMedCentralCrossRefPubMed

36.

Ghebrehiwet B, Hosszu KK, Valentino A, Peerschke EI. The C1q family of proteins: insights into the emerging non-traditional functions. Frontiers in immunology. 2012;. doi:10.3389/fimmu.2012.00052.

37.

Benoit ME, Clarke EV, Morgado P, Fraser DA, Tenner AJ. Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells. J Immunol. 2012;188(11):5682–93. doi:10.4049/jimmunol.1103760.PubMedCentralCrossRefPubMed

38.

Clarke EV, Weist BM, Walsh CM, Tenner AJ. Complement protein C1q bound to apoptotic cells suppresses human macrophage and dendritic cell-mediated Th17 and Th1 T cell subset proliferation. J Leukoc Biol. 2015;97(1):147–60. doi:10.1189/jlb.3A0614-278R.CrossRefPubMed

39.

Meyaard L, Adema GJ, Chang C, Woollatt E, Sutherland GR, Lanier LL, Phillips JH. LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes. Immunity. 1997;7(2):283–90.CrossRefPubMed

40.

Meyaard L. The inhibitory collagen receptor LAIR-1 (CD305). J Leukoc Biol. 2008;83(4):799–803. doi:10.1189/jlb.0907609.CrossRefPubMed

41.

Son M, Diamond B. C1q-mediated repression of human monocytes is regulated by leukocyte-associated ig-like receptor 1 (LAIR-1). Mol Med. 2015;20(1):559–68. doi:10.2119/molmed.2014.00185.PubMedCentralPubMed

42.

Nordkamp MJ, van Eijk M, Urbanus RT, Bont L, Haagsman HP, Meyaard L. Leukocyte-associated Ig-like receptor-1 is a novel inhibitory receptor for surfactant protein D. J Leukoc Biol. 2014;96(1):105–11. doi:10.1189/jlb.3AB0213-092RR.CrossRef

43.

Kouser L, Madhukaran SP, Shastri A, Saraon A, Ferluga J, Al-Mozaini M, Kishore U. Emerging and novel functions of complement protein C1q. Front Immunol. 2015;6:317. doi:10.3389/fimmu.2015.00317.PubMedCentralCrossRefPubMed

44.

Gill MA, Blanco P, Arce E, Pascual V, Banchereau J, Palucka AK. Blood dendritic cells and DC-poietins in systemic lupus erythematosus. Hum Immunol. 2002;63(12):1172–80.CrossRefPubMed

45.

Walport MJ, Davies KA, Botto M. C1q and systemic lupus erythematosus. Immunobiology. 1998;199(2):265–85. doi:10.1016/S0171-2985(98)80032-6.CrossRefPubMed

46.

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(1):56–9. doi:10.1038/ng0598-56.CrossRefPubMed

47.

Martens HA, Zuurman MW, de Lange AH, Nolte IM, van der Steege G, Navis GJ, Kallenberg CG, Seelen MA, Bijl M. Analysis of C1q polymorphisms suggests association with systemic lupus erythematosus, serum C1q and CH50 levels and disease severity. Ann Rheum Dis. 2009;68(5):715–20. doi:10.1136/ard.2007.085688.CrossRefPubMed

48.

Trouw LA, Daha N, Kurreeman FA, Bohringer S, Goulielmos GN, Westra HJ, Zhernakova A, Franke L, Stahl EA, Levarht EW, Stoeken-Rijsbergen G, Verduijn W, Roos A, Li Y, Houwing-Duistermaat JJ, Huizinga TW, Toes RE. Genetic variants in the region of the C1q genes are associated with rheumatoid arthritis. Clin Exp Immunol. 2013;173(1):76–83. doi:10.1111/cei.12097.PubMedCentralCrossRefPubMed

49.

Baumann I, Kolowos W, Voll RE, Manger B, Gaipl U, Neuhuber WL, Kirchner T, Kalden JR, Herrmann M. Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus. Arthritis Rheum. 2002;46(1):191–201. doi:10.1002/1529-0131(200201)46:1<191:AID-ART10027>3.0.CO;2-K.CrossRefPubMed

50.

Gaipl US, Munoz LE, Grossmayer G, Lauber K, Franz S, Sarter K, Voll RE, Winkler T, Kuhn A, Kalden J, Kern P, Herrmann M. Clearance deficiency and systemic lupus erythematosus (SLE). J Autoimmun. 2007;28(2–3):114–21. doi:10.1016/j.jaut.2007.02.005.CrossRefPubMed

51.

Yamada M, Oritani K, Kaisho T, Ishikawa J, Yoshida H, Takahashi I, Kawamoto S, Ishida N, Ujiie H, Masaie H, Botto M, Tomiyama Y, Matsuzawa Y. Complement C1q regulates LPS-induced cytokine production in bone marrow-derived dendritic cells. Eur J Immunol. 2004;34(1):221–30. doi:10.1002/eji.200324026.CrossRefPubMed

52.

Bobak DA, Gaither TA, Frank MM, Tenner AJ. Modulation of FcR function by complement: subcomponent C1q enhances the phagocytosis of IgG-opsonized targets by human monocytes and culture-derived macrophages. J Immunol. 1987;138(4):1150–6.PubMed

53.

Cao W, Bobryshev YV, Lord RS, Oakley RE, Lee SH, Lu J. Dendritic cells in the arterial wall express C1q: potential significance in atherogenesis. Cardiovasc Res. 2003;60(1):175–86.CrossRefPubMed

54.

Hosszu KK, Santiago-Schwarz F, Peerschke EI, Ghebrehiwet B. Evidence that a C1q/C1qR system regulates monocyte-derived dendritic cell differentiation at the interface of innate and acquired immunity. Innate Immun. 2010;16(2):115–27. doi:10.1177/1753425909339815.PubMedCentralCrossRefPubMed

55.

Agnello V, Koffler D, Eisenberg JW, Winchester RJ, Kunkel HG. C1q precipitins in the sera of patients with systemic lupus erythematosus and other hypocomplementemic states: characterization of high and low molecular weight types. J Exp Med. 1971;134(3):228–41.PubMedCentralPubMed

56.

Antes U, Heinz HP, Loos M. Evidence for the presence of autoantibodies to the collagen-like portion of C1q in systemic lupus erythematosus. Arthritis Rheum. 1988;31(4):457–64.CrossRefPubMed

57.

Seelen MA, Trouw LA, Daha MR. Diagnostic and prognostic significance of anti-C1q antibodies in systemic lupus erythematosus. Curr Opin Nephrol Hypertens. 2003;12(6):619–24. doi:10.1097/01.mnh.0000098768.18213.70.CrossRefPubMed

58.

Marto N, Bertolaccini ML, Calabuig E, Hughes GR, Khamashta MA. Anti-C1q antibodies in nephritis: correlation between titres and renal disease activity and positive predictive value in systemic lupus erythematosus. Ann Rheum Dis. 2005;64(3):444–8. doi:10.1136/ard.2004.024943.PubMedCentralCrossRefPubMed

59.

Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B, Sher A, Litke AM, Lambris JD, Smith SJ, John SW, Barres BA. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131(6):1164–78. doi:10.1016/j.cell.2007.10.036.CrossRefPubMed

60.

Stephan AH, Barres BA, Stevens B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci. 2012;35:369–89. doi:10.1146/annurev-neuro-061010-113810.CrossRefPubMed

61.

Chu Y, Jin X, Parada I, Pesic A, Stevens B, Barres B, Prince DA. Enhanced synaptic connectivity and epilepsy in C1q knockout mice. Proc Natl Acad Sci USA. 2010;107(17):7975–80. doi:10.1073/pnas.0913449107.PubMedCentralCrossRefPubMed

62.

Ma Y, Ramachandran A, Ford N, Parada I, Prince DA. Remodeling of dendrites and spines in the C1q knockout model of genetic epilepsy. Epilepsia. 2013;54(7):1232–9. doi:10.1111/epi.12195.PubMedCentralCrossRefPubMed

63.

Stephan AH, Madison DV, Mateos JM, Fraser DA, Lovelett EA, Coutellier L, Kim L, Tsai HH, Huang EJ, Rowitch DH, Berns DS, Tenner AJ, Shamloo M, Barres BA. A dramatic increase of C1q protein in the CNS during normal aging. J Neurosc Off J Soc Neurosci. 2013;33(33):13460–74. doi:10.1523/JNEUROSCI.1333-13.2013.CrossRef

64.

Fan R, Tenner AJ. Complement C1q expression induced by Abeta in rat hippocampal organotypic slice cultures. Exp Neurol. 2004;185(2):241–53.CrossRefPubMed

65.

Wyss-Coray T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med. 2006;12(9):1005–15. doi:10.1038/nm1484.PubMed

66.

Rogers J, Cooper NR, Webster S, Schultz J, McGeer PL, Styren SD, Civin WH, Brachova L, Bradt B, Ward P, et al. Complement activation by beta-amyloid in Alzheimer disease. Proc Natl Acad Sci USA. 1992;89(21):10016–20.PubMedCentralCrossRefPubMed

67.

Sarvari M, Vago I, Weber CS, Nagy J, Gal P, Mak M, Kosa JP, Zavodszky P, Pazmany T. Inhibition of C1q-beta-amyloid binding protects hippocampal cells against complement mediated toxicity. J Neuroimmunol. 2003;137(1–2):12–8.CrossRefPubMed

68.

Schmidt AM, Hori O, Cao R, Yan SD, Brett J, Wautier JL, Ogawa S, Kuwabara K, Matsumoto M, Stern D. RAGE: a novel cellular receptor for advanced glycation end products. Diabetes. 1996;45(Suppl 3):S77–80.CrossRefPubMed

69.

Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature. 1996;382(6593):685–91. doi:10.1038/382685a0.CrossRefPubMed

70.

Pisalyaput K, Tenner AJ. Complement component C1q inhibits beta-amyloid- and serum amyloid P-induced neurotoxicity via caspase- and calpain-independent mechanisms. J Neurochem. 2008;104(3):696–707. doi:10.1111/j.1471-4159.2007.05012.x.PubMed

71.

Benoit ME, Tenner AJ. Complement protein C1q-mediated neuroprotection is correlated with regulation of neuronal gene and microRNA expression. J neurosci Off J Soc Neurosci. 2011;31(9):3459–69. doi:10.1523/JNEUROSCI.3932-10.2011.CrossRef

72.

Benoit ME, Hernandez MX, Dinh ML, Benavente F, Vasquez O, Tenner AJ. C1q-induced LRP1B and GPR6 proteins expressed early in Alzheimer disease mouse models, are essential for the C1q-mediated protection against amyloid-beta neurotoxicity. J Biol Chem. 2013;288(1):654–65. doi:10.1074/jbc.M112.400168.PubMedCentralCrossRefPubMed

73.

Sun S, Jiao Y, Wei W, Postlethwaite AE, Gu W, Sun D. Comparison of LAIR-1 genetic pathways in murine versus human internal organs. Gene. 2014;552(1):140–5. doi:10.1016/j.gene.2014.09.027.CrossRefPubMed

Title: Fundamental role of C1q in autoimmunity and inflammation
Authors: Myoungsun Son
Betty Diamond
Frances Santiago-Schwarz
Publication date: 01-12-2015
Publisher: Springer US
Published in: Immunologic Research / Issue 1-3/2015
Print ISSN: 0257-277X
Electronic ISSN: 1559-0755
DOI: https://doi.org/10.1007/s12026-015-8705-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Fundamental role of C1q in autoimmunity and inflammation

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1-3/2015

Chronic intermittent hypoxia exposure-induced atherosclerosis: a brief review

Lupus brain fog: a biologic perspective on cognitive impairment, depression, and fatigue in systemic lupus erythematosus

The role of B-1 cells in inflammation

Integrative neuroscience approach to neuropsychiatric lupus

Immunology and cartilage regeneration

Neural circuitry and immunity