Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).
Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017).
Berraondo, P. et al. Innate immune mediators in cancer: between defense and resistance. Immunol. Rev. 274, 290–306 (2016).
Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).
Hughes, P. E., Caenepeel, S. & Wu, L. C. Targeted therapy and checkpoint immunotherapy combinations for the treatment of cancer. Trends Immunol. 37, 462–476 (2016).
Pio, R., Corrales, L. & Lambris, J. D. The role of complement in tumor growth. Adv. Exp. Med. Biol. 772, 229–262 (2014).
Balkwill, F. R. & Mantovani, A. Cancer-related inflammation: common themes and therapeutic opportunities. Semin. Cancer Biol. 22, 33–40 (2012).
Gotwals, P. et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat. Rev. Cancer 17, 286–301 (2017).
Woo, S. R., Corrales, L. & Gajewski, T. F. Innate immune recognition of cancer. Annu. Rev. Immunol. 33, 445–474 (2015).
Hernandez, C., Huebener, P. & Schwabe, R. F. Damage-associated molecular patterns in cancer: a double-edged sword. Oncogene 35, 5931–5941 (2016).
Markiewski, M. M. & Lambris, J. D. Is complement good or bad for cancer patients? A new perspective on an old dilemma. Trends Immunol. 30, 286–292 (2009).
Taylor, R. P. & Lindorfer, M. A. Cytotoxic mechanisms of immunotherapy: harnessing complement in the action of anti-tumor monoclonal antibodies. Semin. Immunol. 28, 309–316 (2016).
This review discusses the effectiveness of clinical mAbs in inducing CDC.
Ricklin, D., Hajishengallis, G., Yang, K. & Lambris, J. D. Complement: a key system for immune surveillance and homeostasis. Nat. Immunol. 11, 785–797 (2010).
This is a seminal review that offers a broad overview of complement functioning and its role in health and disease states.
Stephan, A. H., Barres, B. A. & Stevens, B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu. Rev. Neurosci. 35, 369–389 (2012).
Mastellos, D. C., Deangelis, R. A. & Lambris, J. D. Complement-triggered pathways orchestrate regenerative responses throughout phylogenesis. Semin. Immunol. 25, 29–38 (2013).
Hajishengallis, G., Abe, T., Maekawa, T., Hajishengallis, E. & Lambris, J. D. Role of complement in host-microbe homeostasis of the periodontium. Semin. Immunol. 25, 65–72 (2013).
Ricklin, D., Reis, E. S. & Lambris, J. D. Complement in disease: a defence system turning offensive. Nat. Rev. Nephrol. 12, 383–401 (2016).
Derer, S., Beurskens, F. J., Rosner, T., Peipp, M. & Valerius, T. Complement in antibody-based tumor therapy. Crit. Rev. Immunol. 34, 199–214 (2014).
Mamidi, S., Hone, S. & Kirschfink, M. The complement system in cancer: ambivalence between tumour destruction and promotion. Immunobiology 222, 45–54 (2017).
Pio, R., Ajona, D. & Lambris, J. D. Complement inhibition in cancer therapy. Semin. Immunol. 25, 54–64 (2013).
Bonavita, E. et al. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160, 700–714 (2015).
This article uncovers a role for PTX3 as a suppressor of tumorigenesis via regulating complement and inflammatory responses.
Markiewski, M. M. et al. Modulation of the antitumor immune response by complement. Nat. Immunol. 9, 1225–1235 (2008).
This is the first article that shows evidence of complement as a promoter of tumorigenesis.
Vadrevu, S. K. et al. Complement c5a receptor facilitates cancer metastasis by altering T-cell responses in the metastatic niche. Cancer Res. 74, 3454–3465 (2014).
Reff, M. E. et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83, 435–445 (1994).
Maloney, D. G. et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 90, 2188–2195 (1997).
Lokhorst, H. M. et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N. Engl. J. Med. 373, 1207–1219 (2015).
de Weers, M. et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J. Immunol. 186, 1840–1848 (2011).
Irie, K., Irie, R. F. & Morton, D. L. Evidence for in vivo reaction of antibody and complement to surface antigens of human cancer cells. Science 186, 454–456 (1974).
Okada, H. & Baba, T. Rosette formation of human erythrocytes on cultured cells of tumour origin and activation of complement by cell membrane. Nature 248, 521–522 (1974).
Zent, C. S. et al. Direct and complement dependent cytotoxicity in CLL cells from patients with high-risk early-intermediate stage chronic lymphocytic leukemia (CLL) treated with alemtuzumab and rituximab. Leuk. Res. 32, 1849–1856 (2008).
Karsten, C. M. & Kohl, J. The immunoglobulin, IgG Fc receptor and complement triangle in autoimmune diseases. Immunobiology 217, 1067–1079 (2012).
Holmberg, M. T., Blom, A. M. & Meri, S. Regulation of complement classical pathway by association of C4b-binding protein to the surfaces of SK-OV-3 and Caov-3 ovarian adenocarcinoma cells. J. Immunol. 167, 935–939 (2001).
Ajona, D. et al. Expression of complement factor H by lung cancer cells: effects on the activation of the alternative pathway of complement. Cancer Res. 64, 6310–6318 (2004).
Zipfel, P. F. & Skerka, C. Complement regulators and inhibitory proteins. Nat. Rev. Immunol. 9, 729–740 (2009).
Carroll, M. C. & Isenman, D. E. Regulation of humoral immunity by complement. Immunity 37, 199–207 (2012).
Schmudde, I., Laumonnier, Y. & Kohl, J. Anaphylatoxins coordinate innate and adaptive immune responses in allergic asthma. Semin. Immunol. 25, 2–11 (2013).
Freeley, S., Kemper, C. & Le Friec, G. The “ins and outs” of complement-driven immune responses. Immunol. Rev. 274, 16–32 (2016).
Liszewski, M. K. et al. Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation. Immunity 39, 1143–1157 (2013).
Li, K. et al. Expression of complement components, receptors and regulators by human dendritic cells. Mol. Immunol. 48, 1121–1127 (2011).
Reis, E. S., Barbuto, J. A., Kohl, J. & Isaac, L. Impaired dendritic cell differentiation and maturation in the absence of C3. Mol. Immunol. 45, 1952–1962 (2008).
Strainic, M. G. et al. Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells. Immunity 28, 425–435 (2008).
Strainic, M. G., Shevach, E. M., An, F., Lin, F. & Medof, M. E. Absence of signaling into CD4+ cells via C3aR and C5aR enables autoinductive TGF-beta1 signaling and induction of Foxp3+ regulatory T cells. Nat. Immunol. 14, 162–171 (2013).
Arbore, G. et al. T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4+ T cells. Science 352, aad1210 (2016).
This article reveals a role for complement-mediated NLRP3 activity in the differentiation of TH1 cells.
Morgan, E. L. et al. Enhancement of in vivo and in vitro immune functions by a conformationally biased, response-selective agonist of human C5a: implications for a novel adjuvant in vaccine design. Vaccine 28, 463–469 (2009).
Hegde, G. V., Meyers-Clark, E., Joshi, S. S. & Sanderson, S. D. A conformationally-biased, response-selective agonist of C5a acts as a molecular adjuvant by modulating antigen processing and presentation activities of human dendritic cells. Int. Immunopharmacol. 8, 819–827 (2008).
Hung, C. Y. et al. An agonist of human complement fragment C5a enhances vaccine immunity against Coccidioides infection. Vaccine 30, 4681–4690 (2012).
Floreani, A. A. et al. Novel C5a agonist-based dendritic cell vaccine in a murine model of melanoma. Cell Cycle 6, 2835–2839 (2007).
Dempsey, P. W., Allison, M. E., Akkaraju, S., Goodnow, C. C. & Fearon, D. T. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 271, 348–350 (1996).
Prise, K. M. & O'Sullivan, J. M. Radiation-induced bystander signalling in cancer therapy. Nat. Rev. Cancer 9, 351–360 (2009).
Gupta, A. et al. Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation. J. Immunol. 189, 558–566 (2012).
Sharma, A. et al. Radiotherapy of human sarcoma promotes an intratumoral immune effector signature. Clin. Cancer Res. 19, 4843–4853 (2013).
Surace, L. et al. Complement is a central mediator of radiotherapy-induced tumor-specific immunity and clinical response. Immunity 42, 767–777 (2015).
Elvington, M. et al. Complement-dependent modulation of antitumor immunity following radiation therapy. Cell Rep. 8, 818–830 (2014).
Becker, J. C., Andersen, M. H., Schrama, D. & Thor Straten, P. Immune-suppressive properties of the tumor microenvironment. Cancer Immunol. Immunother. 62, 1137–1148 (2013).
Morgan, B. P. & Gasque, P. Extrahepatic complement biosynthesis: where, when and why? Clin. Exp. Immunol. 107, 1–7 (1997).
Lubbers, R., van Essen, M. F., van Kooten, C. & Trouw, L. A. Production of complement components by cells of the immune system. Clin. Exp. Immunol. 188, 183–194 (2017).
Cho, M. S. et al. Autocrine effects of tumor-derived complement. Cell Rep. 6, 1085–1095 (2014).
This article shows that tumour cells secrete complement proteins that act in an autocrine fashion to induce tumorigenesis.
Piao, C. et al. Complement 5a enhances hepatic metastases of colon cancer via monocyte chemoattractant protein-1-mediated inflammatory cell infiltration. J. Biol. Chem. 290, 10667–10676 (2015).
Kohl, J. Self, non-self, and danger: a complementary view. Adv. Exp. Med. Biol. 586, 71–94 (2006).
Ajona, D. et al. Investigation of complement activation product c4d as a diagnostic and prognostic biomarker for lung cancer. J. Natl Cancer Inst. 105, 1385–1393 (2013).
Ishida, Y. et al. Activation of complement system in adult T-cell leukemia (ATL) occurs mainly through lectin pathway: a serum proteomic approach using mass spectrometry. Cancer Lett. 271, 167–177 (2008).
Hsieh, C. C. et al. The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells. Blood 121, 1760–1768 (2013).
Shalapour, S. & Karin, M. Immunity, inflammation, and cancer: an eternal fight between good and evil. J. Clin. Invest. 125, 3347–3355 (2015).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Parkin, D. M. The global health burden of infection-associated cancers in the year 2002. Int. J. Cancer 118, 3030–3044 (2006).
Umansky, V., Blattner, C., Gebhardt, C. & Utikal, J. The role of myeloid-derived suppressor cells (MDSC) in cancer progression. Vaccines (Basel) 4, e36 (2016).
Corrales, L. et al. Anaphylatoxin C5a creates a favorable microenvironment for lung cancer progression. J. Immunol. 189, 4674–4683 (2012).
Nitta, H. et al. Cancer cells release anaphylatoxin C5a from C5 by serine protease to enhance invasiveness. Oncol. Rep. 32, 1715–1719 (2014).
Han, X., Zha, H., Yang, F., Guo, B. & Zhu, B. Tumor-derived tissue factor aberrantly activates complement and facilitates lung tumor progression via recruitment of myeloid-derived suppressor cells. Int. J. Mol. Sci. 18, e22 (2017).
An, L. L. et al. Complement C5a induces PD-L1 expression and acts in synergy with LPS through Erk1/2 and JNK signaling pathways. Sci. Rep. 6, 33346 (2016).
Wang, Y. et al. Autocrine complement inhibits IL10-dependent T-cell-mediated antitumor immunity to promote tumor progression. Cancer Discov. 6, 1022–1035 (2016).
This article suggests a novel strategy to enhance the effect of cancer immunotherapy by inhibiting complement receptors.
Ajona, D. et al. A combined PD-1/C5a blockade synergistically protects against lung cancer growth and metastasis. Cancer Discov. 7, 694–703 (2017).
This article shows evidence for a beneficial role of combined therapeutic inhibition of complement and immune checkpoint molecules.
Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).
Tsuji, S. et al. Network-based analysis for identification of candidate genes for colorectal cancer progression. Biochem. Biophys. Res. Commun. 476, 534–540 (2016).
Weaver, D. J. Jr et al. C5a receptor-deficient dendritic cells promote induction of Treg and Th17 cells. Eur. J. Immunol. 40, 710–721 (2010).
Gunn, L. et al. Opposing roles for complement component C5a in tumor progression and the tumor microenvironment. J. Immunol. 189, 2985–2994 (2012).
This article offers insights into the dual role of complement in cancer development.
Nabizadeh, J. A. et al. The complement C3a receptor contributes to melanoma tumorigenesis by inhibiting neutrophil and CD4+ T cell responses. J. Immunol. 196, 4783–4792 (2016).
Guglietta, S. et al. Coagulation induced by C3aR-dependent NETosis drives protumorigenic neutrophils during small intestinal tumorigenesis. Nat. Commun. 7, 11037 (2016).
Ning, C. et al. Complement activation promotes colitis-associated carcinogenesis through activating intestinal IL-1beta/IL-17A axis. Mucosal Immunol. 8, 1275–1284 (2015).
Phieler, J. et al. The complement anaphylatoxin C5a receptor contributes to obese adipose tissue inflammation and insulin resistance. J. Immunol. 191, 4367–4374 (2013).
Phieler, J., Garcia-Martin, R., Lambris, J. D. & Chavakis, T. The role of the complement system in metabolic organs and metabolic diseases. Semin. Immunol. 25, 47–53 (2013).
Doerner, S. K. et al. High-fat diet-induced complement activation mediates intestinal inflammation and neoplasia, independent of obesity. Mol. Cancer Res. 14, 953–965 (2016).
This is the first study showing evidence of activation of complement by a high-fat diet and promotion of tumorigenesis independent of obesity.
Vlaicu, S. I. et al. Role of C5b-9 complement complex and response gene to complement-32 (RGC-32) in cancer. Immunol. Res. 56, 109–121 (2013).
Towner, L. D., Wheat, R. A., Hughes, T. R. & Morgan, B. P. Complement membrane attack and tumorigenesis: a systems biology approach. J. Biol. Chem. 291, 14927–14938 (2016).
Nunez-Cruz, S. et al. Genetic and pharmacologic inhibition of complement impairs endothelial cell function and ablates ovarian cancer neovascularization. Neoplasia 14, 994–1004 (2012).
Bulla, R. et al. C1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation. Nat. Commun. 7, 10346 (2016).
DeAngelis, R. A. et al. A complement-IL-4 regulatory circuit controls liver regeneration. J. Immunol. 188, 641–648 (2012).
Haynes, T. et al. Complement anaphylatoxin C3a is a potent inducer of embryonic chick retina regeneration. Nat. Commun. 4, 2312 (2013).
Contractor, T. et al. Sexual dimorphism of liver metastasis by murine pancreatic neuroendocrine tumors is affected by expression of complement C5. Oncotarget 7, 30585–30596 (2016).
Riihila, P. et al. Complement component C3 and complement factor B promote growth of cutaneous squamous cell carcinoma. Am. J. Pathol. 187, 1186–1197 (2017).
Boire, A. et al. Complement component 3 adapts the cerebrospinal fluid for leptomeningeal metastasis. Cell 168, 1101–1113 (2017).
This article shows for the first time the involvement of complement in metastasis to the nervous system.
Kaida, T. et al. C5a receptor (CD88) promotes motility and invasiveness of gastric cancer by activating RhoA. Oncotarget 7, 84798–84809 (2016).
Nitta, H. et al. Enhancement of human cancer cell motility and invasiveness by anaphylatoxin C5a via aberrantly expressed C5a receptor (CD88). Clin. Cancer Res. 19, 2004–2013 (2013).
Cho, M. S. et al. Complement component 3 is regulated by TWIST1 and mediates epithelial-mesenchymal transition. J. Immunol. 196, 1412–1418 (2016).
Abdelbaset-Ismail, A. et al. Activation of the complement cascade enhances motility of leukemic cells by downregulating expression of HO-1. Leukemia 31, 446–458 (2017).
Bandini, S. et al. Early onset and enhanced growth of autochthonous mammary carcinomas in C3-deficient Her2/neu transgenic mice. Oncoimmunology 2, e26137 (2013).
Diebolder, C. A. et al. Complement is activated by IgG hexamers assembled at the cell surface. Science 343, 1260–1263 (2014).
Cook, E. M. et al. Antibodies that efficiently form hexamers upon antigen binding can induce complement-dependent cytotoxicity under complement-limiting conditions. J. Immunol. 197, 1762–1775 (2016).
Baig, N. A. et al. Induced resistance to ofatumumab-mediated cell clearance mechanisms, including complement-dependent cytotoxicity, in chronic lymphocytic leukemia. J. Immunol. 192, 1620–1629 (2014).
Beurskens, F. J. et al. Exhaustion of cytotoxic effector systems may limit monoclonal antibody-based immunotherapy in cancer patients. J. Immunol. 188, 3532–3541 (2012).
Golay, J. Direct targeting of cancer cells with antibodies: what can we learn from the successes and failure of unconjugated antibodies for lymphoid neoplasias? J. Autoimmun. http://dx.doi.org/10.1016/j.jaut.2017.06.002 (2017).
Wang, S. Y., Racila, E., Taylor, R. P. & Weiner, G. J. NK-cell activation and antibody-dependent cellular cytotoxicity induced by rituximab-coated target cells is inhibited by the C3b component of complement. Blood 111, 1456–1463 (2008).
Wang, S. Y. et al. Depletion of the C3 component of complement enhances the ability of rituximab-coated target cells to activate human NK cells and improves the efficacy of monoclonal antibody therapy in an in vivo model. Blood 114, 5322–5330 (2009).
Janelle, V. et al. Transient complement inhibition promotes a tumor-specific immune response through the implication of natural killer cells. Cancer Immunol. Res. 2, 200–206 (2014).
Werlenius, O. et al. Reactive oxygen species induced by therapeutic CD20 antibodies inhibit natural killer cell-mediated antibody-dependent cellular cytotoxicity against primary CLL cells. Oncotarget 7, 32046–32053 (2016).
Spiller, O. B., Criado-Garcia, O., Rodriguez De Cordoba, S. & Morgan, B. P. Cytokine-mediated up-regulation of CD55 and CD59 protects human hepatoma cells from complement attack. Clin. Exp. Immunol. 121, 234–241 (2000).
Ohta, R. et al. Mouse complement receptor-related gene y/p65-neutralized tumor vaccine induces antitumor activity in vivo. J. Immunol. 173, 205–213 (2004).
Bjorge, L. et al. Ascitic complement system in ovarian cancer. Br. J. Cancer 92, 895–905 (2005).
Okroj, M., Hsu, Y. F., Ajona, D., Pio, R. & Blom, A. M. Non-small cell lung cancer cells produce a functional set of complement factor I and its soluble cofactors. Mol. Immunol. 45, 169–179 (2008).
Kapka-Skrzypczak, L. et al. CD55, CD59, factor H and factor H-like 1 gene expression analysis in tumors of the ovary and corpus uteri origin. Immunol. Lett. 167, 67–71 (2015).
Ajona, D., Hsu, Y. F., Corrales, L., Montuenga, L. M. & Pio, R. Down-regulation of human complement factor H sensitizes non-small cell lung cancer cells to complement attack and reduces in vivo tumor growth. J. Immunol. 178, 5991–5998 (2007).
Manches, O. et al. In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas. Blood 101, 949–954 (2003).
Golay, J. et al. CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59. Blood 98, 3383–3389 (2001).
Hu, W. et al. Human CD59 inhibitor sensitizes rituximab-resistant lymphoma cells to complement-mediated cytolysis. Cancer Res. 71, 2298–2307 (2011).
Zell, S. et al. Down-regulation of CD55 and CD46 expression by anti-sense phosphorothioate oligonucleotides (S-ODNs) sensitizes tumour cells to complement attack. Clin. Exp. Immunol. 150, 576–584 (2007).
Geis, N. et al. Inhibition of membrane complement inhibitor expression (CD46, CD55, CD59) by siRNA sensitizes tumor cells to complement attack in vitro. Curr. Cancer Drug Targets 10, 922–931 (2010).
Mamidi, S., Cinci, M., Hasmann, M., Fehring, V. & Kirschfink, M. Lipoplex mediated silencing of membrane regulators (CD46, CD55 and CD59) enhances complement-dependent anti-tumor activity of trastuzumab and pertuzumab. Mol. Oncol. 7, 580–594 (2013).
Sherbenou, D. W. et al. Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells. J. Clin. Invest. 126, 4640–4653 (2016).
Imai, M., Ohta, R., Varela, J. C., Song, H. & Tomlinson, S. Enhancement of antibody-dependent mechanisms of tumor cell lysis by a targeted activator of complement. Cancer Res. 67, 9535–954 (2007).
Verma, M. K. et al. A novel hemolytic complement-sufficient NSG mouse model supports studies of complement-mediated antitumor activity in vivo. J. Immunol. Methods 446, 47–53 (2017).
Diaz-Zaragoza, M., Hernandez-Avila, R., Viedma-Rodriguez, R., Arenas-Aranda, D. & Ostoa-Saloma, P. Natural and adaptive IgM antibodies in the recognition of tumor-associated antigens of breast cancer (Review). Oncol. Rep. 34, 1106–1114 (2015).
Ricklin, D. & Lambris, J. D. Complement therapeutics. Semin. Immunol. 28, 205–207 (2016).
Morgan, B. P. & Harris, C. L. Complement, a target for therapy in inflammatory and degenerative diseases. Nat. Rev. Drug Discov. 14, 857–877 (2015).
Buckanovich, R. J. et al. Tumor vascular proteins as biomarkers in ovarian cancer. J. Clin. Oncol. 25, 852–861 (2007).
Manning, M. L., Williams, S. A., Jelinek, C. A., Kostova, M. B. & Denmeade, S. R. Proteolysis of complement factors iC3b and C5 by the serine protease prostate-specific antigen in prostatic fluid and seminal plasma. J. Immunol. 190, 2567–2574 (2013).
Ricklin, D. & Lambris, J. D. Complement in immune and inflammatory disorders: pathophysiological mechanisms. J. Immunol. 190, 3831–3838 (2013).
Gros, P., Milder, F. J. & Janssen, B. J. Complement driven by conformational changes. Nat. Rev. Immunol. 8, 48–58 (2008).
Nilsson, B. & Nilsson Ekdahl, K. The tick-over theory revisited: is C3 a contact-activated protein? Immunobiology 217, 1106–1110 (2012).
Mastellos, D. C., Reis, E. S., Ricklin, D., Smith, R. J. & Lambris, J. D. Complement C3-targeted therapy: replacing long-held assertions with evidence-based discovery. Trends Immunol, 38, 383–394 (2017).
Amara, U. et al. Molecular intercommunication between the complement and coagulation systems. J. Immunol. 185, 5628–5636 (2010).
Elvington, M., Liszewski, M. K. & Atkinson, J. P. Evolution of the complement system: from defense of the single cell to guardian of the intravascular space. Immunol. Rev. 274, 9–15 (2016).
Le Friec, G. et al. The CD46-Jagged1 interaction is critical for human TH1 immunity. Nat. Immunol. 13, 1213–1221 (2012).
Schmidt, C. Q., Lambris, J. D. & Ricklin, D. Protection of host cells by complement regulators. Immunol. Rev. 274, 152–171 (2016).
This review summarizes the function of complement inhibitors and their involvement in pathologic conditions.
Longhurst, H. et al. Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor. N. Engl. J. Med. 376, 1131–1140 (2017).
Degn, S. E. et al. MAp19, the alternative splice product of the MASP2 gene. J. Immunol. Methods 373, 89–101 (2011).
Degn, S. E. et al. MAp44, a human protein associated with pattern recognition molecules of the complement system and regulating the lectin pathway of complement activation. J. Immunol. 183, 7371–7378 (2009).
Rooryck, C. et al. Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome. Nat. Genet. 43, 197–203 (2011).
Blom, A. M. et al. A novel non-synonymous polymorphism (p. Arg240His) in C4b-binding protein is associated with atypical hemolytic uremic syndrome and leads to impaired alternative pathway cofactor activity. J. Immunol. 180, 6385–6391 (2008).
Mohlin, F. C. et al. Analysis of genes coding for CD46, CD55, and C4b-binding protein in patients with idiopathic, recurrent, spontaneous pregnancy loss. Eur. J. Immunol. 43, 1617–1629 (2013).
Ross, G. D. et al. 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. 135, 2005–2014 (1985).
Rondelli, T. et al. Polymorphism of the complement receptor 1 gene correlates with the hematologic response to eculizumab in patients with paroxysmal nocturnal hemoglobinuria. Haematologica 99, 262–266 (2014).
Cockburn, I. A. et al. A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria. Proc. Natl Acad. Sci. USA 101, 272–277 (2004).
Ohi, H. et al. Two cases of mesangiocapillary glomerulonephritis with CR1 deficiency. Nephron 43, 307 (1986).
Klein, R. J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).
Edwards, A. O. et al. Complement factor H polymorphism and age-related macular degeneration. Science 308, 421–424 (2005).
Haines, J. L. et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419–421 (2005).
Abrera-Abeleda, M. A. et al. Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease). J. Med. Genet. 43, 582–589 (2006).
Bernabeu-Herrero, M. E. et al. Complement factor H, FHR-3 and FHR-1 variants associate in an extended haplotype conferring increased risk of atypical hemolytic uremic syndrome. Mol. Immunol. 67, 276–286 (2015).
Vernon, K. A. et al. Partial complement factor H deficiency associates with C3 glomerulopathy and thrombotic microangiopathy. J. Am. Soc. Nephrol. 27, 1334–1342 (2016).
Clark, S. J. et al. Identification of factor H-like protein 1 as the predominant complement regulator in Bruch's membrane: implications for age-related macular degeneration. J. Immunol. 193, 4962–4970 (2014).
Hakobyan, S., Tortajada, A., Harris, C. L., de Cordoba, S. R. & Morgan, B. P. Variant-specific quantification of factor H in plasma identifies null alleles associated with atypical hemolytic uremic syndrome. Kidney Int. 78, 782–788 (2010).
Bresin, E. et al. Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. J. Am. Soc. Nephrol. 24, 475–486 (2013).
van de Ven, J. P. et al. A functional variant in the CFI gene confers a high risk of age-related macular degeneration. Nat. Genet. 45, 813–817 (2013).
Reis, E. S., Falcao, D. A. & Isaac, L. Clinical aspects and molecular basis of primary deficiencies of complement component C3 and its regulatory proteins factor I and factor H. Scand. J. Immunol. 63, 155–168 (2006).
Nomura, M. et al. Genomic analysis of idiopathic infertile patients with sperm-specific depletion of CD46. Exp. Clin. Immunogenet. 18, 42–50 (2001).
Medof, M. E. et al. Relationship between decay accelerating factor deficiency, diminished acetylcholinesterase activity, and defective terminal complement pathway restriction in paroxysmal nocturnal hemoglobinuria erythrocytes. J. Clin. Invest. 80, 165–174 (1987).
Wilcox, L. A., Ezzell, J. L., Bernshaw, N. J. & Parker, C. J. Molecular basis of the enhanced susceptibility of the erythrocytes of paroxysmal nocturnal hemoglobinuria to hemolysis in acidified serum. Blood 78, 820–829 (1991).
Nevo, Y. et al. CD59 deficiency is associated with chronic hemolysis and childhood relapsing immune-mediated polyneuropathy. Blood 121, 129–135 (2013).
Milis, L., Morris, C. A., Sheehan, M. C., Charlesworth, J. A. & Pussell, B. A. Vitronectin-mediated inhibition of complement: evidence for different binding sites for C5b-7 and C9. Clin. Exp. Immunol. 92, 114–119 (1993).
McDonald, J. F. & Nelsestuen, G. L. Potent inhibition of terminal complement assembly by clusterin: characterization of its impact on C9 polymerization. Biochemistry 36, 7464–7473 (1997).
Sigler, C., Annis, K., Cooper, K., Haber, H. & Van deCarr, S. Examination of baseline levels of carboxypeptidase N and complement components as potential predictors of angioedema associated with the use of an angiotensin-converting enzyme inhibitor. Arch. Dermatol. 133, 972–975 (1997).
Mathews, K. P., Pan, P. M., Amendola, M. A. & Lewis, F. H. Plasma protease inhibitor and anaphylatoxin inactivator levels in chronic urticaria/angioedema and in patients experiencing anaphylactoid reactions to radiographic contrast media. Int. Arch. Allergy Appl. Immunol. 79, 220–223 (1986).
Downs-Canner, S. et al. Complement inhibition: a novel form of immunotherapy for colon cancer. Ann. Surg. Oncol. 23, 655–662 (2016).
Liang, T. et al. Identification of complement C3f-desArg and its derivative for acute leukemia diagnosis and minimal residual disease assessment. Proteomics 10, 90–98 (2010).
Miguet, L. et al. Discovery and identification of potential biomarkers in a prospective study of chronic lymphoid malignancies using SELDI-TOF-MS. J. Proteome Res. 5, 2258–2269 (2006).
Villanueva, J. et al. Differential exoprotease activities confer tumor-specific serum peptidome patterns. J. Clin. Invest. 116, 271–284 (2006).
Gast, M. C. et al. Serum protein profiling for diagnosis of breast cancer using SELDI-TOF MS. Oncol. Rep. 22, 205–213 (2009).
Michlmayr, A. et al. Modulation of plasma complement by the initial dose of epirubicin/docetaxel therapy in breast cancer and its predictive value. Br. J. Cancer 103, 1201–1208 (2010).
Chung, L. et al. Novel serum protein biomarker panel revealed by mass spectrometry and its prognostic value in breast cancer. Breast Cancer Res. 16, R63 (2014).
Imamura, T. et al. Influence of the C5a-C5a receptor system on breast cancer progression and patient prognosis. Breast Cancer 23, 876–885 (2016).
Habermann, J. K. et al. Increased serum levels of complement C3a anaphylatoxin indicate the presence of colorectal tumors. Gastroenterology 131, 1020–1029 (2006).
Storm, L. et al. Evaluation of complement proteins as screening markers for colorectal cancer. Cancer Immunol. Immunother. 64, 41–50 (2015).
Xi, W. et al. Enrichment of C5a-C5aR axis predicts poor postoperative prognosis of patients with clear cell renal cell carcinoma. Oncotarget 7, 80925–80934 (2016).
Xi, W. et al. High level of anaphylatoxin C5a predicts poor clinical outcome in patients with clear cell renal cell carcinoma. Sci. Rep. 6, 29177 (2016).
Maher, S. G. et al. Serum proteomic profiling reveals that pretreatment complement protein levels are predictive of esophageal cancer patient response to neoadjuvant chemoradiation. Ann. Surg. 254, 809–816 (2011).
Agatea, L. et al. Peptide patterns as discriminating biomarkers in plasma of patients with familial adenomatous polyposis. Clin. Colorectal Cancer 15, e75–e92 (2016).
Song, Q., Zhang, Z., Liu, Y., Han, S. & Zhang, X. The tag SNP rs10746463 in decay-accelerating factor is associated with the susceptibility to gastric cancer. Mol. Immunol. 63, 473–478 (2015).
Bouwens, T. A. et al. Complement activation in Glioblastoma multiforme pathophysiology: evidence from serum levels and presence of complement activation products in tumor tissue. J. Neuroimmunol. 278, 271–276 (2015).
Bassig, B. A. et al. Polymorphisms in complement system genes and risk of non-Hodgkin lymphoma. Environ. Mol. Mutag. 53, 145–151 (2012).
Lin, K. et al. Complement component 3 is a prognostic factor of nonsmall cell lung cancer. Mol. Med. Rep. 10, 811–817 (2014).
Zhang, Y. et al. A common CD55 rs2564978 variant is associated with the susceptibility of non-small cell lung cancer. Oncotarget 8, 6216–6221 (2017).
Swierzko, A. S. et al. Mannose-binding lectin (MBL) and MBL-associated serine protease-2 (MASP-2) in women with malignant and benign ovarian tumours. Cancer Immunol. Immunother. 63, 1129–1140 (2014).
Mikami, M. et al. Fully-sialylated alpha-chain of complement 4-binding protein: diagnostic utility for ovarian clear cell carcinoma. Gynecol. Oncol. 139, 520–528 (2015).
Hanas, J. S. et al. Biomarker identification in human pancreatic cancer sera. Pancreas 36, 61–69 (2008).
Chen, J. et al. Profiling the potential tumor markers of pancreatic ductal adenocarcinoma using 2D-DIGE and MALDI-TOF-MS: up-regulation of complement C3 and alpha-2-HS-glycoprotein. Pancreatology 13, 290–297 (2013).
Lee, M. J. et al. Identification of human complement factor B as a novel biomarker candidate for pancreatic ductal adenocarcinoma. J. Proteome Res. 13, 4878–4888 (2014).
Karczmarski, J. et al. Pre-analytical-related variability influencing serum peptide profiles demonstrated in a mass spectrometry-based search for colorectal and prostate cancer biomarkers. Acta Biochim. Pol. 60, 417–425 (2013).
Villanueva, J. et al. Serum peptidome patterns that distinguish metastatic thyroid carcinoma from cancer-free controls are unbiased by gender and age. Mol. Cell. Proteomics 5, 1840–1852 (2006).