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Journal articles on the topic 'Complement regulators'

Author: Grafiati

Published: 14 March 2023

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1

Ferreira, Viviana P., and Michael K. Pangburn. "Cell surface complement regulatory functions of factor H are essential for the survival of normal and paroxysmal nocturnal hemoglobinuric (PNH) red blood cells (53.2)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S103—S104. http://dx.doi.org/10.4049/jimmunol.178.supp.53.2.

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Abstract The complement system uses a complex set of cell-bound and plasma regulators to protect host cells from complement-mediated cytolysis. Although PNH red blood cells (RBCs) are partially (type II) or completely (type III) deficient in GPI-linked complement regulatory molecules CD59 and CD55, they are not rapidly lysed by complement. For instance, the in vivo lifespan of PNH III RBCs is 6–60 days, and is close to that of normal cells for PNH II RBCs. The plasma regulator factor H (fH) plays a key role in complement homeostasis. Here we show that a recombinant protein consisting of its two C-terminal domains (rH19-20) blocks its cell surface complement regulatory functions without affecting fluid phase control of soluble C3b. Also, addition of rH19-20 to normal human serum leads to moderate complement-mediated lysis of normal human RBCs, which possess membrane-bound complement regulators, and to aggressive lysis of PNH II and III cells. In agreement with this, the inhibition of CD59 or CD55 on normal RBCs results in their aggressive lysis only when combined with the loss of fH cell surface control. Taken together, the results highlight the importance of the cell surface protective functions of fH compared to other complement regulatory proteins and indicate that fH is essential for the 6–60 day survival of PNH RBCs, with possible implications in diagnosis and treatment. Research support NIH DK35081.

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2

Zipfel, Peter F., and Christine Skerka. "Complement regulators and inhibitory proteins." Nature Reviews Immunology 9, no. 10 (September 4, 2009): 729–40. http://dx.doi.org/10.1038/nri2620.

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3

Harris, Claire L., Masashi Mizuno, and B. Paul Morgan. "Complement and complement regulators in the male reproductive system." Molecular Immunology 43, no. 1-2 (January 2006): 57–67. http://dx.doi.org/10.1016/j.molimm.2005.06.026.

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4

Meri, T., A. Hartmann, D. Lenk, R. Eck, R. Würzner, J. Hellwage, S. Meri, and P. F. Zipfel. "The Yeast Candida albicans Binds Complement Regulators Factor H and FHL-1." Infection and Immunity 70, no. 9 (September 2002): 5185–92. http://dx.doi.org/10.1128/iai.70.9.5185-5192.2002.

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ABSTRACT The human facultative pathogenic yeast Candida albicans causes mucocutaneous infections and is the major cause of opportunistic fungal infections in immunocompromised patients. C. albicans activates both the alternative and classical pathway of the complement system. The aim of this study was to assay whether C. albicans binds human complement regulators in order to control complement activation at its surface. We observed binding of two central complement regulators, factor H and FHL-1, from normal human serum to C. albicans by adsorption assays, immunostaining, and fluorescence-activated cell sorter (FACS) analyses. Specificity of acquisition was further confirmed in direct binding assays with purified proteins. The surface-attached regulators maintained their complement regulatory activities and mediated factor I-dependent cleavage of C3b. Adsorption assays with recombinant deletion mutant proteins were used to identify binding domains. Two binding sites were localized. One binding domain common to both factor H and FHL-1 is located in the N-terminal short consensus repeat domains (SCRs) 6 and 7, and the other one located in C-terminal SCRs 19 and 20 is unique to factor H. These data indicate that by surface acquisition of host complement regulators, the human pathogenic yeast C. albicans is able to regulate alternative complement activation at its surface and to inactivate toxic complement activation products.

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Kennedy, Alexander T., Christoph Q. Schmidt, Jennifer K. Thompson, Greta E. Weiss, Tana Taechalerpaisarn, Paul R. Gilson, Paul N. Barlow, Brendan S. Crabb, Alan F. Cowman, and Wai-Hong Tham. "Hijacking host complement regulators: Mechanisms of Plasmodium falciparum complement evasion." Immunobiology 221, no. 10 (October 2016): 1155. http://dx.doi.org/10.1016/j.imbio.2016.06.071.

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6

Paul Morgan, B., Carmen W. Berg, and Claire L. Harris. "''Homologous restriction'' in complement lysis: roles of membrane complement regulators." Xenotransplantation 12, no. 4 (July 2005): 258–65. http://dx.doi.org/10.1111/j.1399-3089.2005.00237.x.

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7

Sinha, Anwesha, Anup Kumar Singh, Trupti Satish Kadni, Jayati Mullick, and Arvind Sahu. "Virus-Encoded Complement Regulators: Current Status." Viruses 13, no. 2 (January 29, 2021): 208. http://dx.doi.org/10.3390/v13020208.

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Viruses require a host for replication and survival and hence are subjected to host immunological pressures. The complement system, a crucial first response of the host immune system, is effective in targeting viruses and virus-infected cells, and boosting the antiviral innate and acquired immune responses. Thus, the system imposes a strong selection pressure on viruses. Consequently, viruses have evolved multiple countermeasures against host complement. A major mechanism employed by viruses to subvert the complement system is encoding proteins that target complement. Since viruses have limited genome size, most of these proteins are multifunctional in nature. In this review, we provide up to date information on the structure and complement regulatory functions of various viral proteins.

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8

Hammerschmidt, Claudia, Teresia Hallström, Christine Skerka, Reinhard Wallich, Brian Stevenson, Peter F. Zipfel, and Peter Kraiczy. "Contribution of the Infection-Associated Complement Regulator-Acquiring Surface Protein 4 (ErpC) to Complement Resistance ofBorrelia burgdorferi." Clinical and Developmental Immunology 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/349657.

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Borrelia burgdorferievades complement-mediated killing by interacting with complement regulators through distinct complement regulator-acquiring surface proteins (CRASPs). Here, we extend our analyses to the contribution of CRASP-4 in mediating complement resistance ofB. burgdorferiand its interaction with human complement regulators. CRASP-4 (also known as ErpC) was immobilized onto magnetic beads and used to capture proteins from human serum. Following Western blotting, factor H (CFH), CFH-related protein 1 (CFHR1), CFHR2, and CFHR5 were identified as ligands of CRASP-4. To analyze the impact of native CRASP-4 on mediating survival of serum-sensitive cells in human serum, aB. gariniistrain was generated that ectopically expresses CRASP-4. CRASP-4-producing bacteria bound CFHR1, CFHR2, and CFHR5 but not CFH. In addition, transformed spirochetes deposited significant amounts of lethal complement components on their surface and were susceptible to human serum, thus indicating that CRASP-4 plays a subordinate role in complement resistance ofB. burgdorferi.

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9

Kraiczy, Peter, and Reinhard Würzner. "Complement escape of human pathogenic bacteria by acquisition of complement regulators." Molecular Immunology 43, no. 1-2 (January 2006): 31–44. http://dx.doi.org/10.1016/j.molimm.2005.06.016.

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10

Schmidt, Christoph Q., John D. Lambris, and Daniel Ricklin. "Protection of host cells by complement regulators." Immunological Reviews 274, no. 1 (October 26, 2016): 152–71. http://dx.doi.org/10.1111/imr.12475.

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11

Sayegh, Eli T., Orin Bloch, and Andrew T. Parsa. "Complement anaphylatoxins as immune regulators in cancer." Cancer Medicine 3, no. 4 (April 8, 2014): 747–58. http://dx.doi.org/10.1002/cam4.241.

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12

Ferreira, Viviana P., and Michael K. Pangburn. "Factor H–mediated cell surface protection from complement is critical for the survival of PNH erythrocytes." Blood 110, no. 6 (September 15, 2007): 2190–92. http://dx.doi.org/10.1182/blood-2007-04-083170.

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Abstract Paroxysmal nocturnal hemoglobinuria (PNH) cells are partially (type II) or completely (type III) deficient in GPI-linked complement regulatory proteins CD59 and CD55. PNH III erythrocytes circulate 6 to 60 days in vivo. Why these cells are not lysed as rapidly by complement as unprotected foreign cells, which normally lyse within minutes, remains undetermined. Factor H plays a key role in the homeostasis of complement in fluid phase and on cell surfaces. We have recently shown that a recombinant protein encompassing the C-terminus of factor H (rH19-20) specifically blocks cell-surface complement regulatory functions of factor H without affecting fluid-phase control of complement. Here we show that PNH II and III cells become highly susceptible to complement-mediated lysis by nonacidified normal human serum in vitro, when the cell surface complement-regulatory functions of factor H are blocked. The results indicate that cells deficient in surface-bound regulators are protected for extended periods of time by factor H.

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13

Trouw, L. A., A. M. Blom, and P. Gasque. "Role of complement and complement regulators in the removal of apoptotic cells." Molecular Immunology 45, no. 5 (March 2008): 1199–207. http://dx.doi.org/10.1016/j.molimm.2007.09.008.

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14

Matsuo, Seiichi, Yoshiki Morita, Masashi Mizuno, Kazuhiro Nishikawa, and Yukio Yuzawa. "Complement-mediated renal injury: Mechanisms and role of membrane regulators of complement." Clinical and Experimental Nephrology 2, no. 4 (December 1998): 276–81. http://dx.doi.org/10.1007/bf02480454.

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15

Saadoun, Samira, and Marios C. Papadopoulos. "Role of membrane complement regulators in neuromyelitis optica." Multiple Sclerosis Journal 21, no. 13 (February 19, 2015): 1644–54. http://dx.doi.org/10.1177/1352458515571446.

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Background: It is unclear why AQP4-IgG primarily causes central nervous system lesions by activating complement, but generally spares peripheral AQP4-expressing organs. Objectives: To determine whether peripheral AQP4-expressing cells are protected from complement-mediated damage by expressing complement regulators. Methods: Human tissue and cultured human cells were immunostained for aquaporin-4 (AQP4), CD46, CD55 and CD59. We also determined the vulnerability to AQP4-IgG and complement-mediated damage of astrocytes cultured alone or co-cultured with endothelial cells. Results: In normal brain, astrocyte end-feet express AQP4, but are devoid of CD46, CD55 and CD59. Immunoreactivity for CD46, CD55 and CD59 is not increased in or around neuromyelitis optica lesions. In kidney AQP4 is co-expressed with CD46 and CD55, in stomach AQP4 is co-expressed with CD46 and in skeletal muscle AQP4 is co-expressed with CD46. Astrocytes cultured alone co-express AQP4 and CD59 but, in astrocyte-endothelial co-cultures, AQP4 is found in cell processes devoid of CD59. Astrocytes co-cultured with endothelial cells are more vulnerable to AQP4-IgG and complement-mediated lysis than astrocytes cultured alone. Conclusions: Complement regulators protect peripheral organs, but not the central nervous system, from AQP4-IgG and complement-mediated damage. Our findings may explain why neuromyelitis optica primarily damages the central nervous system, but spares peripheral organs.

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16

Fleming, Sherry D., Jonathan Ferm, and Jennifer Amrein. "Female mice express increased complement regulators and decreased intestinal ischemia-reperfusion injury." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 126.21. http://dx.doi.org/10.4049/jimmunol.202.supp.126.21.

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Abstract Intestinal ischemia reperfusion (IR) in male mice results in local and systemic tissue damage due to excessive complement activation and neutrophil infiltration. Complement components differ by sex in animal models of kidney and heart ischemia. In addition, estrogen alters blood vessel diameter during reperfusion and testosterone blockade attenuates nitric oxide production. Clinical studies associated oral contraceptive use with intestinal ischemia. Together, these data suggest that hormonal differences in females may change the mechanisms of intestinal IR injury compared to males. We hypothesized that increased intestinal complement regulator expression in females delays IR-induced C3 deposition compared to males. Male and female C57Bl/6 mice were subjected to Sham treatment or 30 mins intestinal ischemia followed by two hours reperfusion prior to collecting the mid-jejunum and serum. Intestinal sections were analyzed by RT-PCR for complement regulator expression. Additional analyses examined markers of cell death, complement deposition, and LTB4 production. Compared to male mice, female mice sustained delayed intestinal injury and decreased complement C3 deposition. In response to IR, female mice significantly increased autophagy markers and intestinal LTB4 secretion. Sham treatment increased mRNA of complement regulators, CRRY and CD55 in female mice while Factor H increased in response to IR in both sexes. Together these data suggest that local control of complement activation, neutrophil infiltration and autophagy in response to intestinal ischemia/reperfusion varies between sexes and may dictate distinct therapeutic intervention.

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17

Kraiczy, P., J. Schwab, C. Hammerschmidt, D. Richter, C. Skerka, F. R. Matuschka, and P. F. Zipfel. "Borrelia valaisiana overcome complement-mediated killing independendly from the recruitment of complement regulators." Molecular Immunology 48, no. 14 (August 2011): 1696. http://dx.doi.org/10.1016/j.molimm.2011.06.314.

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18

Herbert, A., J. O'Leary, M. Krych-Goldberg, J. P. Atkinson, and P. N. Barlow. "Three-dimensional structure and flexibility of proteins of the RCA family — a progress report." Biochemical Society Transactions 30, no. 6 (November 1, 2002): 990–96. http://dx.doi.org/10.1042/bst0300990.

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Members of the regulator of complement activation (RCA) protein family perform a vital role in health and disease. In this report we describe our efforts to solve the structures of human membrane cofactor protein (CD46), the vaccinia virus complement control protein, which mimics mammalian RCA proteins, and human complement receptor type 1 (CD35). These examples illustrate that, despite good progress over the last decade, the regulators of complement, as extracellular multiple domain glycoproteins, still pose formidable problems to structural biologists. Many important questions remain unanswered, in particular with regard to the flexibility of these proteins and the extent to which they undergo conformational rearrangements on engaging their binding partners

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19

O‘Flynn, J., K. Dixon, M. C. Faber Krol, M. R. Daha, and C. van Kooten. "Neutrophil components as regulators of the complement system." Molecular Immunology 56, no. 3 (December 2013): 245. http://dx.doi.org/10.1016/j.molimm.2013.05.025.

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20

Li, Yan, and Feng Lin. "Mesenchymal stem cells are injured by complement after their contact with serum." Blood 120, no. 17 (October 25, 2012): 3436–43. http://dx.doi.org/10.1182/blood-2012-03-420612.

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Abstract Despite the potent immunosuppressive activity that mesenchymal stem cells (MSCs) display in vitro, recent clinical trial results are disappointing, suggesting that MSC viability and/or function are greatly reduced after infusion. In this report, we demonstrated that human MSCs activated complement of the innate immunity after their contact with serum. Although all 3 known intrinsic cell-surface complement regulators were present on MSCs, activated complement overwhelmed the protection of these regulators and resulted in MSCs cytotoxicity and dysfunction. In addition, autologous MSCs suffered less cellular injury than allogeneic MSCs after contacting serum. All 3 complement activation pathways were involved in generating the membrane attack complex to directly injure MSCs. Supplementing an exogenous complement inhibitor, or up-regulating MSC expression levels of CD55, one of the cell-surface complement regulators, helped to reduce the serum-induced MSC cytotoxicity. Finally, adoptively transferred MSCs in complement deficient mice or complement-depleted mice showed reduced cellular injury in vivo compared with those in wild type mice. These results indicate that complement is integrally involved in recognizing and injuring MSCs after their infusion, suggesting that autologous MSCs may have ad-vantages over allogeneic MSCs, and that inhibiting complement activation could be a novel strategy to improve existing MSC-based therapies.

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21

Behnsen, Judith, Andrea Hartmann, Jeannette Schmaler, Alexander Gehrke, Axel A. Brakhage, and Peter F. Zipfel. "The Opportunistic Human Pathogenic Fungus Aspergillus fumigatus Evades the Host Complement System." Infection and Immunity 76, no. 2 (November 26, 2007): 820–27. http://dx.doi.org/10.1128/iai.01037-07.

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ABSTRACT The opportunistic human pathogenic fungus Aspergillus fumigatus causes severe systemic infections and is a major cause of fungal infections in immunocompromised patients. A. fumigatus conidia activate the alternative pathway of the complement system. In order to assess the mechanisms by which A. fumigatus evades the activated complement system, we analyzed the binding of host complement regulators to A. fumigatus. The binding of factor H and factor H-like protein 1 (FHL-1) from human sera to A. fumigatus conidia was shown by adsorption assays and immunostaining. In addition, factor H-related protein 1 (FHR-1) bound to conidia. Adsorption assays with recombinant factor H mutants were used to localize the binding domains. One binding region was identified within N-terminal short consensus repeats (SCRs) 1 to 7 and a second one within C-terminal SCR 20. Plasminogen was identified as the fourth host regulatory molecule that binds to A. fumigatus conidia. In contrast to conidia, other developmental stages of A. fumigatus, like swollen conidia or hyphae, did not bind to factor H, FHR-1, FHL-1, and plasminogen, thus indicating the developmentally regulated expression of A. fumigatus surface ligands. Both factor H and plasminogen maintained regulating activity when they were bound to the conidial surface. Bound factor H acted as a cofactor to the factor I-mediated cleavage of C3b. Plasminogen showed proteolytic activity when activated to plasmin by urokinase-type plasminogen activator. These data show that A. fumigatus conidia bind to complement regulators, and these bound host regulators may contribute to evasion of a host complement attack.

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22

Haapasalo, Karita, Taru Meri, and T. Sakari Jokiranta. "Loa loa Microfilariae Evade Complement Attack In Vivo by Acquiring Regulatory Proteins from Host Plasma." Infection and Immunity 77, no. 9 (June 15, 2009): 3886–93. http://dx.doi.org/10.1128/iai.01583-08.

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ABSTRACT Loa loa is a filarial nematode that infects humans. The adults live in subcutaneous tissues and produce microfilariae that live for several weeks in the blood circulation in order to be transmitted to another person via blood meals of a dipterian vector. As microfilariae live in continuous contact with plasma, it is obvious that they evade the complement system. We studied markers of complement activation and signs of complement regulation on Loa loa microfilariae in vivo. The microfilariae were isolated from anticoagulated blood samples of a Loa loa-infected Caucasian patient. C1q and some mannose-binding lectin but only a limited amount of C3b or C4b fragments and practically no C5 or C5b-9 were present on the microfilariae. The covalently microfilaria-bound C3 and C4 depositions were mainly inactive iC3b, C3c, and iC4b fragments indicating that microfilariae had regulated complement activation in vivo. Also, in vitro deposition of C3b onto the microfilariae upon serum exposure was limited. The patient-isolated microfilariae were found to carry the host complement regulators factor H and C4b-binding protein on the outermost layer, so called sheath. The microfilaria-bound factor H was functionally active. Binding of the complement regulators to the microfilariae was confirmed in vitro using 125I-labeled factor H and C4b-binding protein. In conclusion, our study shows that Loa loa microfilariae block complement activation and acquire the host complement regulators factor H and C4b-binding protein in blood circulation. This is the first time that binding of complement regulators onto nonviral pathogens has been demonstrated to occur in humans in vivo.

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23

Molina, Hector, Takashi Miwa, Lin Zhou, Brendan Hilliard, Dimitrios Mastellos, Michael A. Maldonado, John D. Lambris, and Wen-Chao Song. "Complement-mediated clearance of erythrocytes: mechanism and delineation of the regulatory roles of Crry and DAF." Blood 100, no. 13 (December 15, 2002): 4544–49. http://dx.doi.org/10.1182/blood-2002-06-1875.

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The role of complement in the pathogenesis of autoimmune hemolytic anemia (AIHA) has been controversial and may depend on a number of factors, including the affinity and isotype of the pathogenic antibodies involved. We have recently shown that mouse erythrocytes deficient in the membrane C3 regulatory protein, complement receptor 1–related gene/protein y (Crry), but not decay-accelerating factor (DAF), were spontaneously eliminated in vivo by complement. Here, by generating a mouse deficient in both DAF and Crry, we further delineated the roles of Crry and DAF in regulating alternative and classical pathway C3 activation. By using immunoglobulin-, Fcγ receptor (FcγR)–, C3-, C4-, and C5-deficient mice, we also determined the mechanism by which membrane C3 regulator-deficient erythrocytes are cleared from the circulation. Finally, we evaluated the relative importance of the Fc receptor versus the complement pathway in disposing antibody-opsonized DAF/Crry–deficient erythrocytes. We conclude that (1) Crry plays a more dominant role than DAF in regulating the alternative pathway of complement, whereas DAF and Crry are equally effective in preventing antibody-induced runaway complement activation on mouse erythrocytes; (2) DAF/Crry–deficient erythrocytes are eliminated by the alternative pathway of complement via complement receptor–mediated erythrophagocytosis in the spleen; and (3) when opsonized with an immunoglobulin G2a (IgG2a) autoantibody, Crry/DAF–deficient erythrocytes are eliminated more rapidly by complement than by the Fc receptor pathway. These results shed new light on the relative activities of Crry and DAF and underscore the critical roles of membrane C3 regulators in preventing spontaneous and antibody-induced erythrocyte damage in vivo.

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Harris, C. L., D. A. Fraser, and B. P. Morgan. "Tailoring anti-complement therapeutics." Biochemical Society Transactions 30, no. 6 (November 1, 2002): 1019–26. http://dx.doi.org/10.1042/bst0301019.

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Complement is a core component of the immune system, which performs vital roles in immune surveillance. However, the active products that enable complement to perform its physiological roles can inappropriately target self tissues and cause pathology. Complement-mediated inflammation and tissue destruction is an important drive to pathology in diseases as diverse as rheumatoid arthritis and dementia. Two decades ago there were no agents that could be used therapeutically to inhibit the activation of complement, but increased understanding of the natural control of complement in vivo has markedly changed this situation. The realization that drugs mimicking the action of the complement regulatory proteins present on self cells, and in plasma, could effectively control pathological activation of complement has opened the door to the use of anti-complement therapy in disease. Here we will review the development of anticomplement therapeutics from the first generation agents, which are unmodified recombinant forms of natural regulators, to recent strategies for making better drugs. We will describe strategies for targeting the anticomplement activity to the site of disease, and for extending the plasma half-life of the agent. Finally, we will illustrate a novel approach to the delivery of anticomplement agents, making prodrugs that are activated only at disease sites thus minimizing the deleterious effects of systemic complement inhibition.

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Meri, T., A. M. Blom, A. Hartmann, D. Lenk, S. Meri, and P. F. Zipfel. "The Hyphal and Yeast Forms of Candida albicans Bind the Complement Regulator C4b-Binding Protein." Infection and Immunity 72, no. 11 (November 2004): 6633–41. http://dx.doi.org/10.1128/iai.72.11.6633-6641.2004.

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ABSTRACT Candida albicans, an important pathogenic yeast, activates all three pathways of the complement system. To understand how this yeast evades the effects of the activated system, we have analyzed the binding of the classical pathway inhibitor C4b-binding protein (C4BP) by C. albicans. Purified native as well as recombinant C4BP bound dose dependently to the yeast and hyphal forms, as shown by multiple methods, such as confocal microscopy, flow cytometry, a novel enzyme-linked immunosorbent assay, absorption from human serum, and direct binding assays with purified proteins. A prominent binding site was identified at the tip of the germ tube, a structure that is considered important for tissue penetration and pathogenesis. The binding site in C4BP was localized to the two N-terminal complement control protein domains by using recombinant deletion constructs and site-specific monoclonal antibodies. As the alternative pathway inhibitors factor H and FHL-1 also bind to C. albicans, the binding of all three plasma proteins was compared. Simultaneous binding of the classical regulator C4BP and the alternative pathway regulator factor H was demonstrated by confocal microscopy. In addition, FHL-1 competed for binding with C4BP, suggesting that these two related complement regulators bind to the same structures on the yeast surface. The surface-attached C4BP maintains its complement regulatory activities and inactivates C4b. The surface-attached human C4BP serves multiple functions relevant for immune evasion and likely pathogenicity. It inhibits complement activation at the yeast surface and, in addition, mediates adhesion of C. albicans to host endothelial cells.

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26

Panwar, Hemendra Singh, Hina Ojha, Payel Ghosh, Sagar H. Barage, Sunil Raut, and Arvind Sahu. "Molecular engineering of an efficient four-domain DAF-MCP chimera reveals the presence of functional modularity in RCA proteins." Proceedings of the National Academy of Sciences 116, no. 20 (April 29, 2019): 9953–58. http://dx.doi.org/10.1073/pnas.1818573116.

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The complement system is highly efficient in targeting pathogens, but lack of its apposite regulation results in host-cell damage, which is linked to diseases. Thus, complement activation is tightly regulated by a series of proteins, which primarily belong to the regulators of complement activation (RCA) family. Structurally, these proteins are composed of repeating complement control protein (CCP) domains where two to four successive domains contribute to the regulatory functions termed decay-accelerating activity (DAA) and cofactor activity (CFA). However, the precise constitution of the functional units and whether these units can be joined to form a larger composition with dual function have not been demonstrated. Herein, we have parsed the functional units for DAA and CFA by constructing chimeras of the decay-accelerating factor (DAF) that exhibits DAA and membrane cofactor protein (MCP) that exhibits CFA. We show that in a four-CCP framework, a functional unit for each of the regulatory activities is formed by only two successive CCPs wherein each participates in the function, albeit CCP2 has a bipartite function. Additionally, optimal activity requires C-terminal domains that enhance the avidity of the molecule for C3b/C4b. Furthermore, by composing a four-CCP DAF-MCP chimera with robust CFA (for C3b and C4b) and DAA (for classical and alternative pathway C3 convertases), named decay cofactor protein, we show that CCP functional units can be linked to design a dual-activity regulator. These data indicate that the regulatory determinants for these two biological processes are distinct and modular in nature.

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27

Liszewski, M. K., and J. P. Atkinson. "Complement regulators in human disease: lessons from modern genetics." Journal of Internal Medicine 277, no. 3 (January 16, 2015): 294–305. http://dx.doi.org/10.1111/joim.12338.

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28

Hourcade, Dennis, Theodore W. Post, V. Michael Holers, Douglas M. Lublin, and John P. Atkinson. "Polymorphisms of the Regulators of Complement Activation Gene Cluster." Complement and Inflammation 7, no. 4-6 (1990): 302–14. http://dx.doi.org/10.1159/000463165.

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29

Ojha, Hina, Hemendra Singh Panwar, Ronald D. Gorham, Dimitrios Morikis, and Arvind Sahu. "Viral regulators of complement activation: Structure, function and evolution." Molecular Immunology 61, no. 2 (October 2014): 89–99. http://dx.doi.org/10.1016/j.molimm.2014.06.004.

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30

Mizuno, Tomohiro, Fumihiko Nagano, Masashi Mizuno, Ayumi Iwata, Kazuo Takahashi, Naotake Tsuboi, Shoichi Maruyama, Tadashi Nagamatsu, and Masaki Imai. "Extracellular histones decrease the expression of membrane complement regulators." Molecular Immunology 102 (October 2018): 189. http://dx.doi.org/10.1016/j.molimm.2018.06.158.

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31

Wu, Jin, Daniel Ricklin, Georgia Sfyroera, Apostolia Tzekou, John P. Atkinson, John D. Lambris, and Piet Gros. "Characterization of the interactions between C3b and complement regulators." Molecular Immunology 47, no. 13 (August 2010): 2259. http://dx.doi.org/10.1016/j.molimm.2010.05.184.

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32

Das, Nibhriti, Vaishali Arora, and Bintili Biswas. "Regulators of complement activation (RCA): Significance in autoimmune disorders." Molecular Immunology 44, no. 1-3 (January 2007): 163. http://dx.doi.org/10.1016/j.molimm.2006.07.041.

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33

Spitzer, Dirk, and John P. Atkinson. "Targeted complement regulators protect PNH erythrocytes from acid hemolysis." Molecular Immunology 44, no. 1-3 (January 2007): 243–44. http://dx.doi.org/10.1016/j.molimm.2006.07.228.

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34

Jurianz, K., H. Garcia-Schüler, Zvi Fishelson, and M. Kirschfink. "Modulation of membrane-associated complement regulators on tumor cells." Molecular Immunology 35, no. 6-7 (April 1998): 363. http://dx.doi.org/10.1016/s0161-5890(98)90661-7.

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Lindahl, Gunnar, Ulf Sjöbring, and Eskil Johnsson. "Human complement regulators: a major target for pathogenic microorganisms." Current Opinion in Immunology 12, no. 1 (February 2000): 44–51. http://dx.doi.org/10.1016/s0952-7915(99)00049-7.

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Gelderman, Kyra A., Suzanne Lam, and Arko Gorter. "Inhibiting complement regulators in cancer immunotherapy with bispecific mAbs." Expert Opinion on Biological Therapy 5, no. 12 (November 30, 2005): 1593–601. http://dx.doi.org/10.1517/14712598.5.12.1593.

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Thielen, Astrid J. F., Sacha Zeerleder, and Diana Wouters. "Consequences of dysregulated complement regulators on red blood cells." Blood Reviews 32, no. 4 (July 2018): 280–88. http://dx.doi.org/10.1016/j.blre.2018.01.003.

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Kusner, Linda L., Jose A. Halperin, and Henry J. Kaminski. "Cell surface complement regulators moderate experimental myasthenia gravis pathology." Muscle & Nerve 47, no. 1 (October 5, 2012): 33–40. http://dx.doi.org/10.1002/mus.23448.

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Wu, Miaomiao, Jennifer Rowe, and Sherry D. Fleming. "Complement regulators and mechanisms vary by sex in intestinal ischemia reperfusion injury." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 69.11. http://dx.doi.org/10.4049/jimmunol.204.supp.69.11.

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Abstract Complement activation plays a pivotal role in intestinal ischemia reperfusion (I/R)-induced injury, leads to significant morbidity and mortality. The injury includes significant inflammation including complement activation. Although established primarily using a male models, intestinal I/R-related diseases occur in both sexes. However, multiple animal models of ischemia and complement activation demonstrate sexual. Thus, we hypothesized that complement regulation may differ by sex during intestinal I/R altering the timing, quantity or required molecules. Both sexes of C57Bl/6 mice were subjected to Sham treatment or 30 min intestinal ischemia followed by 15 min, 30 min, 60 min, and 120 min reperfusion. We demonstrate that compared to male mice, females sustain attenuated intestinal I/R-induced tissue damage. In response to I/R, males produce PGE2 regulated by COX-2, while females produce LTB4 by A5-LOX. Complement initiation pathways differed with males tending to use classical pathway while females tend to use MBL pathway. Together these data suggest that local control of complement activation and regulation, eicosanoid production and neutrophil infiltration in response to intestinal I/R varies between sexes suggesting that distinct therapeutic intervention may be needed in clinical ischemic diseases.

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Yuan, Meng, Li Liu, Chenlin Wang, Yan Zhang, and Jiandong Zhang. "The Complement System: A Potential Therapeutic Target in Liver Cancer." Life 12, no. 10 (September 30, 2022): 1532. http://dx.doi.org/10.3390/life12101532.

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Liver cancer is the sixth most common cancer and the fourth most fatal cancer in the world. Immunotherapy has already achieved modest results in the treatment of liver cancer. Meanwhile, the novel and optimal combinatorial strategies need further research. The complement system, which consists of mediators, receptors, cofactors and regulators, acts as the connection between innate and adaptive immunity. Recent studies demonstrate that complement system can influence tumor progression by regulating the tumor microenvironment, tumor cells, and cancer stem cells in liver cancer. Our review concentrates on the potential role of the complement system in cancer treatment, which is a promising strategy for killing tumor cells by the activation of complement components. Conclusions: Our review demonstrates that complement components and regulators might function as biomarkers and therapeutic targets for liver cancer diagnosis and treatment.

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Budding, Kevin, Lill Eva Johansen, Inge Van de Walle, Kim Dijkxhoorn, Elisabeth de Zeeuw, Lauri M. Bloemenkamp, Jeroen W. Bos, et al. "Anti-C2 Antibody ARGX-117 Inhibits Complement in a Disease Model for Multifocal Motor Neuropathy." Neurology - Neuroimmunology Neuroinflammation 9, no. 1 (November 10, 2021): e1107. http://dx.doi.org/10.1212/nxi.0000000000001107.

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Background and ObjectivesTo determine the role of complement in the disease pathology of multifocal motor neuropathy (MMN), we investigated complement activation, and inhibition, on binding of MMN patient-derived immunoglobulin M (IgM) antibodies in an induced pluripotent stem cell (iPSC)-derived motor neuron (MN) model for MMN.MethodsiPSC-derived MNs were characterized for the expression of complement receptors and membrane-bound regulators, for the binding of circulating IgM anti-GM1 from patients with MMN, and for subsequent fixation of C4 and C3 on incubation with fresh serum. The potency of ARGX-117, a novel inhibitory monoclonal antibody targeting C2, to inhibit fixation of complement was assessed.ResultsiPSC-derived MNs moderately express the complement regulatory proteins CD46 and CD55 and strongly expressed CD59. Furthermore, MNs express C3aR, C5aR, and complement receptor 1. IgM anti-GM1 antibodies in serum from patients with MMN bind to MNs and induce C3 and C4 fixation on incubation with fresh serum. ARGX-117 inhibits complement activation downstream of C4 induced by patient-derived anti-GM1 antibodies bound to MNs.DiscussionBinding of IgM antibodies from patients with MMN to iPSC-derived MNs induces complement activation. By expressing complement regulatory proteins, particularly CD59, MNs are protected against complement-mediated lysis. Yet, because of expressing C3aR, the function of these cells may be affected by complement activation upstream of membrane attack complex formation. ARGX-117 inhibits complement activation upstream of C3 in this disease model for MMN and therefore represents an intervention strategy to prevent harmful effects of complement in MMN.

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Rowe, Jennifer M., Miaomiao Wu, and Sherry D. Fleming. "Complement initiation and regulation differ by sex in intestinal ischemia reperfusion injury." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 79.15. http://dx.doi.org/10.4049/jimmunol.204.supp.79.15.

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Abstract Males and females frequently sustain distinct symptoms during ischemic events and subsequent inflammatory events. The inflammatory events include significant complement activation, neutrophil infiltration and significant cytokine secretions. The past literature suggests that complement activation may include a sex-linked protein. Therefore, we hypothesized that complement activation may vary by sex during intestinal ischemia/reperfusion (IR) injury. We subjected male and female mice to 30 min intestinal ischemia followed by 15, 30, 60 or 120 min reperfusion. Additional mice of each sex was subjected to sham surgery. Intestinal sections were stained and complement initiation pathways and time points of deposition determined. Complement regulatory molecules were also examined. Initial results suggest that males expressed more C1q compared to females, while females expressed more MBL than males. In addition, complement regulators varied by sex. Our data demonstrate that complement initiation and regulation differ between sexes during intestinal IR. These response differences in intestinal IR provide insight into the sexual dimorphism of ischemic intestine diseases and may aid in the development of sex-specific therapies that reduce intestinal injury.

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Meri, T., S. J. Cutler, A. M. Blom, S. Meri, and T. S. Jokiranta. "Relapsing Fever Spirochetes Borrelia recurrentis and B. duttonii Acquire Complement Regulators C4b-Binding Protein and Factor H." Infection and Immunity 74, no. 7 (July 2006): 4157–63. http://dx.doi.org/10.1128/iai.00007-06.

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ABSTRACT Relapsing fever is a rapidly progressive and severe septic disease caused by certain Borrelia spirochetes. The disease is divided into two forms, i.e., epidemic relapsing fever, caused by Borrelia recurrentis and transmitted by lice, and the endemic form, caused by several Borrelia species, such as B. duttonii, and transmitted by soft-bodied ticks. The spirochetes enter the bloodstream by the vector bite and live persistently in plasma even after the development of specific antibodies. This leads to fever relapses and high mortality and clearly indicates that the Borrelia organisms utilize effective immune evasion strategies. In this study, we show that the epidemic relapsing fever pathogen B. recurrentis and an endemic relapsing fever pathogen, B. duttonii, are serum resistant, i.e., resistant to complement in vitro. They acquire the host alternative complement pathway regulator factor H on their surfaces in a similar way to that of the less serum-resistant Lyme disease pathogen, B. burgdorferi sensu stricto. More importantly, the relapsing fever spirochetes specifically bind host C4b-binding protein, a major regulator of the antibody-mediated classical complement pathway. Both complement regulators retained their functional activities when bound to the surfaces of the spirochetes. In conclusion, this is the first report of complement evasion by Borrelia recurrentis and B. duttonii and the first report showing capture of C4b-binding protein by spirochetes.

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Rau, Annette, Susan Wyllie, Judy Whittimore, and Jane E. Raulston. "Identification of Chlamydia trachomatis Genomic Sequences Recognized by Chlamydial Divalent Cation-Dependent Regulator A (DcrA)." Journal of Bacteriology 187, no. 2 (January 15, 2005): 443–48. http://dx.doi.org/10.1128/jb.187.2.443-448.2005.

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ABSTRACT The Chlamydia trachomatis divalent cation-dependent regulator (DcrA), encoded by open reading frame CT296, is a distant relative of the ferric uptake regulator (Fur) family of iron-responsive regulators. Chlamydial DcrA specifically binds to a consensus Escherichia coli Fur box and is able to complement an E. coli Fur mutant. In this report, the E. coli Fur titration assay (FURTA) was used to locate chlamydial genomic sequences that are recognized by E. coli Fur. The predictive regulatory regions of 28 C. trachomatis open reading frames contained sequences functionally recognized by E. coli Fur; targets include components of the type III secretion pathway, elements involved in envelope and cell wall biogenesis, predicted transport proteins, oxidative defense enzymes, and components of metabolic pathways. Selected FURTA-positive sequences were subsequently examined for recognition by C. trachomatis DcrA using an electrophoretic mobility shift assay. The resultant data show that C. trachomatis DcrA binds to native chlamydial genomic sequences and, overall, substantiate a functional relationship between chlamydial DcrA and the Fur family of regulators.

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Wu, Jin, You-Qiang Wu, Daniel Ricklin, Bert J. C. Janssen, John D. Lambris, and Piet Gros. "Structure of complement fragment C3b–factor H and implications for host protection by complement regulators." Nature Immunology 10, no. 7 (June 7, 2009): 728–33. http://dx.doi.org/10.1038/ni.1755.

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Yasojima, Koji, Edith G. McGeer, and Patrick L. McGeer. "Complement regulators C1 inhibitor and CD59 do not significantly inhibit complement activation in Alzheimer disease." Brain Research 833, no. 2 (July 1999): 297–301. http://dx.doi.org/10.1016/s0006-8993(99)01514-0.

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47

Gautam, Avneesh Kumar, Yogesh Panse, Payel Ghosh, Malik Johid Reza, Jayati Mullick, and Arvind Sahu. "Mutational analysis of Kaposica reveals that bridging of MG2 and CUB domains of target protein is crucial for the cofactor activity of RCA proteins." Proceedings of the National Academy of Sciences 112, no. 41 (September 29, 2015): 12794–99. http://dx.doi.org/10.1073/pnas.1506449112.

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The complement system has evolved to annul pathogens, but its improper regulation is linked with diseases. Efficient regulation of the system is primarily provided by a family of proteins termed regulators of complement activation (RCA). The knowledge of precise structural determinants of RCA proteins critical for imparting the regulatory activities and the molecular events underlying the regulatory processes, nonetheless, is still limited. Here, we have dissected the structural requirements of RCA proteins that are crucial for one of their two regulatory activities, the cofactor activity (CFA), by using the Kaposi’s sarcoma-associated herpesvirus RCA homolog Kaposica as a model protein. We have scanned the entire Kaposica molecule by sequential mutagenesis using swapping and site-directed mutagenesis, which identified residues critical for its interaction with C3b and factor I. Mapping of these residues onto the modeled structure of C3b–Kaposica–factor I complex supported the mutagenesis data. Furthermore, the model suggested that the C3b-interacting residues bridge the CUB (complement C1r-C1s, Uegf, Bmp1) and MG2 (macroglobulin-2) domains of C3b. Thus, it seems that stabilization of the CUB domain with respect to the core of the C3b molecule is central for its CFA. Identification of CFA-critical regions in Kaposica guided experiments in which the equivalent regions of membrane cofactor protein were swapped into decay-accelerating factor. This strategy allowed CFA to be introduced into decay-accelerating factor, suggesting that viral and human regulators use a common mechanism for CFA.

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S Thompson, L., and E. J Harry. "Alternative sigma factors: the master regulators." Microbiology Australia 27, no. 3 (2006): 118. http://dx.doi.org/10.1071/ma06118.

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When a bacterial cell encounters a change in environmental conditions, it responds by producing a different complement of cellular proteins. Which proteins are produced and maintained is regulated in a number of ways, including regulation of gene transcription, stabilising or degrading mRNA transcripts, post translational modifications and targeted degradation of proteins.

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Atkinson, John P., and Timothy H. J. Goodship. "Complement factor H and the hemolytic uremic syndrome." Journal of Experimental Medicine 204, no. 6 (June 4, 2007): 1245–48. http://dx.doi.org/10.1084/jem.20070664.

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Immune recognition is coupled to powerful proinflammatory effector pathways that must be tightly regulated. The ancient alternative pathway of complement activation is one such proinflammatory pathway. Genetic susceptibility factors have been identified in both regulators and activating components of the alternative pathway that are associated with thrombotic microangiopathies, glomerulonephritides, and chronic conditions featuring debris deposition. These observations indicate that excessive alternative pathway activation promotes thrombosis in the microvasculature and tissue damage during debris accumulation. Intriguingly, distinct genetic changes in factor H (FH), a key regulator of the alternative pathway, are associated with hemolytic uremic syndrome (HUS), membranoproliferative glomerulonephritis (dense deposit disease), or age-related macular degeneration (AMD). A mouse model of HUS designed to mirror human mutations in FH has now been developed, providing new understanding of the molecular pathogenesis of complement-related endothelial disorders.

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Tudoran, Ruxandra, and Michael Kirschfink. "Modern complement analysis: indications, methods and outlook^1),2)." LaboratoriumsMedizin 36, no. 3 (May 1, 2012): ———. http://dx.doi.org/10.1515/labmed-2012-0009.

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Abstract Complement is one of the key systems of innate immunity and homeostasis. Its excessive activation and also a deficiency of complement components or regulators can lead to life-threatening conditions. This review aims to provide the basic knowledge that clinicians need in order to understand complement-related diseases. Moreover, it shows possible indications and interpretations of a complement analysis and explains the rationale behind complement-targeted therapies.

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