Complement Cascade

Total Page:16

File Type:pdf, Size:1020Kb

Complement Cascade The Complement cascade The complement system is a heat labile component of blood that confers bactericidal Carboxypeptidase properties. The functions of complement include the attraction of inflammatory cells, C1qr2s2 C4 MBL/MASPs C3 opsinization to promote phagocytosis, immune complex clearance and direct Chemotaxis and microbial killing through the formation of the membrane attack complex (MAC). Pathway Pathway activation of Three pathways lead to complement activation; the classical pathway initiated by activation Serpin antibodies bound to the surface of foreign bodies and the alternative and lectin activation C3a inflammatory cells, pathways that provide an antibody independent mechanism for complement inducing cytokine activation induced by the presence of bacteria and other micro-organisms. C4a Serpin production, and mast C4b The classical pathway (in light-blue): C1 the first molecule in the classical (C1 inhibitor) cell degranulation, which complement cascade comprises C1q and two molecules of C1r and C1s. C1q binds C3 convertase results in enhanced target bound antibody leading to the activation of C1s. C1s cleaves C4 present in the vascular permeability plasma releasing C4a and C4b. C4b binds C2, which is subsequently cleaved by C2 C2a C4b2a C1s. This results in the release of C2b and C2a. C2a remains associated with C4b and local blood flow. to form the classical pathway C3 convertase (C4b2a). C2a in the convertase complex C5 convertase cleaves C3 releasing C3a and C3b. The latter binds to the C3 convertase complex to form C4b2a3b, the classical pathway C5 convertase. This complex cleaves C5 C2b C3b C4b2a3b Vitronectin, clusterin leading to the release of C5a and C5b. Opsonin C4bp, Factor I, (plasma proteins) and MCP, DAF and CRI CD59 on host cells. The lectin pathway (in white): Mannan-binding lectin (MBL) and MBL-associated serine proteases (MASPs) are involved in the initial step of the lectin pathway of complement activation. The binding of MBL to mannose and N-acetyl glucosamine in micro-organisms leads to the activation of MASPs, which subsequently cleave C4 Hydrolyzed Membrane attack complex and C2. Following these cleavage events, complement pathway activation continues C3 C3i + Factor B Pathway C5 C5b as in the classical pathway. ‘Tickover’ cross-talk + C6 + C7 + C8 + C9 The alternative pathway (in dark-blue): The alternative pathway of complement activation is in a constant state of low-level activation (known as tickover). C3 is Compromised bacterial hydrolysed in the plasma to C3i, which has many of the properties of C3b. C3i then C5a binds the plasma protein, Factor B. Bound Factor B is cleaved by Factor D to produce function due to pore formation Ba and Bb. Ba is released and the remaining complex comprised of C3iBb forms the alternative pathway C3 convertase. Most of the C3b generated by the convertase is Factor I, MCP C3iB hydrolysed. However, if C3b comes into contact with an invading micro-organism it Bacterial lysis binds and amplification of the alternative pathway is promoted by the binding of C3b Stabilized to Factor B. The plasma protein, properdin stabilizes the C3 convertase to prolong activity. C3b produced in this pathway also yields the C5 convertase, C3bBb3b, which Ba Factor D by invading leads to the production of C5a and C5b. Note, C3b generated in the classical micro-organisims pathway feeds into the alternative pathway to amplify the activation of complement. Factor H C3iBb Inhibitors of the complement system (in yellow): The complement system is regulated to protect the host. Complement inhibitors include the plasma serine DAF and CR1 proteinase inhibitor serpin (C1 inhibitor). The plasma proteins, Factor I and C4 C3 convertase C6 binding protein (C4-bp), inhibit the activity of the classical C3 convertase. Classical C5b pathway activation is also inhibited by the surface bound proteins, decay accelerating C9 factor (DAF), CR1 and membrane co-factor protein (MCP). The alternative pathway C8 is regulated by Factor H, DAF and CR1, which inhibit the C3 convertase of the C7 alternative pathway. Factor I promotes the catabolism of C3i and C3b (Factor H and C3 C3b C3bBb3b MCP act as co-factors). C5 Convertase Opsinization (C3bi breakdown product is C3a also an opsonin), Clearance of immune www.abcam.com Factor I complexes and B cell priming. Complement antibodies from Abcam: See more products at: www.abcam.com/immunology Product Clonality Applications Host Cross- Datasheet Product Clonality Applications Host Cross- Datasheet reactivity www.abcam.com/ab… reactivity www.abcam.com/ab… Classical pathway Alternative pathway C1q [7H8] M ELISA, Flow Cyt, IHC-FoFr, Factor B P IHC-Fr Shp Hu 64515 IHC-Fr, IP, WB Rat Ms 11861 Factor D [008-01] M ELISA, WB Mm Hu 36383 C1r P DID, Ie, RID, RIe Shp Hu 8781 Factor P [10-18] M ELISA, FuncS, IHC-Fr Mm Hu 58984 C1s P DID, Ie, RID Shp Hu 8782 Properdin, B factor [008-02] M ELISA, WB Mm Hu 17932 C2 P ELISA, WB Rb Hu, Ms, Rat, Dog and Zfsh 58389 SC5b9 [3R2/0] M ELISA, Flow Cyt, IHC-Fr, WB Mm Hu 59024 C3 / C3b [755] M IP, WB Mm Hu 11871 C3 [11H9] M Flow Cyt, IHC-Fr, IP, WB Rat Ms 11862 Regulatory / Inhibitors C3a / C3a des Arg [013-16] M ELISA, WB Mm Hu 36385 C4 binding protein P IHC-Fr Shp Hu 53894 C3a Receptor [hC3aRZ1] M Flow Cyt, IHC-Fr Mm Hu 59554 CD59 [MEM-43] M Flow Cyt, FuncS, ICC/IF, IHC-Fr, C3c (FITC) P Flow Cyt, IHC-Fr Rb Hu, Ms, Rat, Gt, Cow, Dog, Pig, IHC-P,IP, WB Mm Hu 9182 Pig, Sh, Cat, Gpig, Mink and Kg 4212 Clusterin (Apolipoprotein J) P WB Rb Hu 42673 C3d P ELISA, ICC, IHC-P Rb Hu 15981 Complement Receptor 1 C4 [16D2] M Flow Cyt, IHC-Fr, IP, WB Rat Ms 11863 (CR1) (CD35) [RLB25] M IHC-Fr, IHC-P Mm Hu 49520 C4a [99-H7] M ELISA, WB Mm Hu 63796 Decay Accelerating Factor C4b P ELISA, WB Chk Hu 48582 (DAF) (CD55) [BRIC110] M Flow Cyt, ICC/IF Mm Hu 53353 C4c / C4b (FITC) P IHC-Fr Rb Hu 4216 ECT P WB Rb Hu, Ms and Mk 15053 C4c P ID, WB Chk Hu 61965 Factor H P DID, Flow Cyt, Ie, RID, RIe Shp Hu, Ms, Rat, Hrs, Dog, Cat C4d P Flow Cyt, ICC/IF,IHC-Fr, IHC-P, WB Rb Hu 36075 and Gpig 8842 C5 / C5a P WB Rb Hu 46168 Factor I [061-01] M ELISA, WB Mm Hu 52244 C5 P IHC-Fr, WB Rb Ms 11898 Membrane Co-Factor Protein C5/C5b P WB Rb Hu 46153 (MCP) (CD46) [MEM-258] M Flow Cyt, IP, WB Mm Cow and Hu 789 C5a / C5a des Arg [2952] M ELISA, WB Mm Hu 11878 Properdin [HYB 039-06] M AP, ELISA, WB Mm Hu 25850 C5b-9 [aE11] M ELISA, IHC-Fr, WB Mm Hu, Bb and Pig 15984 Serpin (C1 Inactivator) M IHC-P, WB Mm Hu 54898 C5R1 [P12/1] M Flow Cyt, IHC-Fr, WB Mm Hu and RhMk 33212 Vitronectin [EP873Y] M ICC/IF, IHC-P, WB Rb Hu, Ms and Rat 45139 GC1q R [60.11] M ELISA, Flow Cyt, IP, WB Mm Hu, Ms and Rat 24733 Membrane Attack Complex (MAC) Lectin Pathway C6 P IHC-Fr, WB Rb Ms 11899 Mannan Binding Lectin A [2B4] M IA, WB Rat Ms 36670 C7 P DID, Ie, RID Shp Hu 8791 Mannan Binding Lectin C8 [056B-373] M ELISA, Flow Cyt, IHC-Fr, WB Mm Hu 59140 [HYB 131-01] M ELISA, IHC-Fr, IHC-P, WB Mm Hu 23457 C9 P ELISA, ID, IHC-Fr, IHC-P Shp Hu 53896 MASP1 P WB Rb Hu 65891 MASP1/3 P WB Rb Hu 65887 And many more... MASP2 P WB Rb Hu 65895 Mannan Binding Lectin antibody [HYB 131-01] (ab23457) C5R1 [P12/1] antibody (ab33212) Clonality Applications Host Species cross reactivity Clonality Applications Host Species cross reactivity M ELISA, IHC-Fr, IHC-P, WB Mm Hu M Flow Cyt, IHC-Fr, WB Mm Hu and RhMk Mannan Binding Lectin, MBL, belongs to the C-type family of collectins. It functions as an All cellular responses to C5a are specifically mediated by interactions with the opsonin which activates the complement system on binding to microbial polysaccharides. This membrane bound C5a receptor, a seven transmembrane GTP binding coupled image shows Mannan Binding Lectin staining in formalin fixed and PFA-fixed paraffin receptor that belongs to the rhodopsin supergene family. C5a receptor 1 embedded human liver, using ab23457 expression has been reported in myeloid blood cells, brain, liver, lung, spleen, heart, kidney, and intestinal tract. This image shows FACS analysis of C5R1 expressing cells in human peripheral blood granulocytes, using ab33212..
Recommended publications
  • MASP-1, a Promiscuous Complement Protease: Structure of Its Catalytic Region Reveals the Basis of Its Broad Specificity 1
    MASP-1, a promiscuous complement protease: structure of its catalytic region reveals the basis of its broad specificity 1 József Dobó 2,3* , Veronika Harmat 3† , László Beinrohr *, Edina Sebestyén *, Péter Závodszky *, Péter Gál 2* * Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Karolina út 29, H-1113, Budapest, Hungary † Protein Modeling Group, Hungarian Academy of Sciences, and Laboratory of Structural Chemistry and Biology, Institute of Chemistry, Eötvös Loránd University , Pázmány Péter sétány 1A, H-1117, Budapest, Hungary Running title: Structure of MASP-1 CCP1-CCP2-SP Keywords (not in the title): lectin pathway; innate immunity; modular serine protease; mannan-binding lectin; MBL-associated serine protease; MASP-2; C1r; C1s; thrombin; trypsin; factor D 1 Abstract Mannose-binding lectin (MBL)-associated serine protease-1 (MASP-1) is an abundant component of the lectin pathway of complement. The related enzyme, MASP-2 is capable of activating the complement cascade alone. Though the concentration of MASP-1 far exceeds that of MASP-2 only a supporting role of MASP-1 has been identified regarding lectin pathway activation. Several non-complement substrates, like fibrinogen and factor XIII, have also been reported. MASP-1 belongs to the C1r/C1s/MASP family of modular serine proteases, however its serine protease domain is evolutionary different. We have determined the crystal structure of the catalytic region of active MASP-1 and refined it to 2.55 Å resolution. Unusual features of the structure are: an internal salt bridge (similar to one in factor D) between the S1 Asp189 and Arg224, and a very long 60-loop.
    [Show full text]
  • C3b Catalog Number: A114 Sizes Available
    Name: C3b Catalog Number: A114 Sizes Available: 250 µg/vial Concentration: 1.0 mg/mL (see Certificate of Analysis for actual concentration) Form: Liquid Purity: >90% by SDS-PAGE Buffer: 10 mM sodium phosphate, 145 mM NaCl, pH 7.3 Extinction Coeff. A280 nm = 1.03 at 1.0 mg/mL Molecular Weight: 176,000 Da (2 chains) Preservative: None, 0.22 µm filtered Storage: -70oC or below. Avoid freeze/thaw. Source: Normal human serum (shown by certified tests to be negative for HBsAg and for antibodies to HCV, HIV-1 and HIV-II). Precautions: Use normal precautions for handling human blood products. Origin: Manufactured in the USA. General Description C3b is derived from native C3 upon cleavage and release of C3a. It is prepared by cleavage with the alternative pathway C3 convertase. This is important because only a single bond in C3 is cleaved by the native convertase, while cleavage by other proteases, such as trypsin, results in multiple cleavages at many other sites in the protein. Native human C3b is a glycosylated (~2.8%) polypeptide containing two disulfide-linked chains. C3b is central to the function of all three pathways of complement (Law, S.K.A. and Reid, K.B.M. (1995)). Initiation of each pathway generates proteolytic enzyme complexes (C3 convertases) which are bound to the target surface. These enzymes cleave a peptide bond in C3 releasing the anaphylatoxin C3a and activating C3b. For a brief time (~60 µs) this nascent C3b is capable of reacting with and covalently coupling to hydroxyl groups on the target surface.
    [Show full text]
  • The Membrane Complement Regulatory Protein CD59 and Its Association with Rheumatoid Arthritis and Systemic Lupus Erythematosus
    Current Medicine Research and Practice 9 (2019) 182e188 Contents lists available at ScienceDirect Current Medicine Research and Practice journal homepage: www.elsevier.com/locate/cmrp Review Article The membrane complement regulatory protein CD59 and its association with rheumatoid arthritis and systemic lupus erythematosus * Nibhriti Das a, Devyani Anand a, Bintili Biswas b, Deepa Kumari c, Monika Gandhi c, a Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India b Department of Zoology, Ramjas College, University of Delhi, India c University School of Biotechnology, Guru Gobind Singh Indraprastha University, India article info abstract Article history: The complement cascade consisting of about 50 soluble and cell surface proteins is activated in auto- Received 8 May 2019 immune inflammatory disorders. This contributes to the pathological manifestations in these diseases. In Accepted 30 July 2019 normal health, the soluble and membrane complement regulatory proteins protect the host against Available online 5 August 2019 complement-mediated self-tissue injury by controlling the extent of complement activation within the desired limits for the host's benefit. CD59 is a membrane complement regulatory protein that inhibits the Keywords: formation of the terminal complement complex or membrane attack complex (C5b6789n) which is CD59 generated on complement activation by any of the three pathways, namely, the classical, alternative, and RA SLE the mannose-binding lectin pathway. Animal experiments and human studies have suggested impor- Pathophysiology tance of membrane complement proteins including CD59 in the pathophysiology of rheumatoid arthritis Disease marker (RA) and systemic lupus erythematosus (SLE). Here is a brief review on CD59 and its distribution, structure, functions, and association with RA and SLE starting with a brief introduction on the com- plement system, its activation, the biological functions, and relations of membrane complement regu- latory proteins, especially CD59, with RA and SLE.
    [Show full text]
  • Blocking Properdin Prevents Complement-Mediated Hemolytic Uremic Syndrome and Systemic Thrombophilia
    BASIC RESEARCH www.jasn.org Blocking Properdin Prevents Complement-Mediated Hemolytic Uremic Syndrome and Systemic Thrombophilia Yoshiyasu Ueda,1 Takashi Miwa,1 Damodar Gullipalli,1 Sayaka Sato,1 Daisuke Ito,1 Hangsoo Kim,1 Matthew Palmer,2 and Wen-Chao Song1 Departments of 1Systems Pharmacology and Translational Therapeutics and 2Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania ABSTRACT Background Properdin (P) is a positive regulator of the alternative pathway of complement activation. Although P inhibition is expected and has been shown to ameliorate the alternative pathway of comple- ment-mediated tissue injury in several disease models, it unexpectedly exacerbated renal injury in a murine model of C3 glomerulopathy. The role of P in atypical hemolytic uremic syndrome (aHUS) is uncertain. Methods We blocked P function by genetic deletion or mAb-mediated inhibition in mice carrying a factor H (FH) point mutation, W1206R (FHR/R), that causes aHUS and systemic thrombophilia with high mortality. Results Pdeficiency completely rescued FHR/R mice from premature death and prevented thrombocyto- penia, hemolytic anemia, and renal disease. It also eliminated macrovessel thrombi that were prevalent in FHR/R mice. All mice that received a function-blocking anti-P mAb for 8 weeks survived the experimental period and appeared grossly healthy. Platelet counts and hemoglobin levels were significantly improved in FHR/R mice after 4 weeks of anti-P mAb treatment. One half of the FHR/R mice treated with an isotype control mAb but none of the anti-P mAb-treated mice developed stroke-related neurologic disease. Anti-P mAb-treated FHR/R mice showed largely normal renal histology, and residual liver thrombi were detected in only three of 15 treated mice.
    [Show full text]
  • Activation Regulates Alternative Pathway Complement Necrotic
    Properdin Binds to Late Apoptotic and Necrotic Cells Independently of C3b and Regulates Alternative Pathway Complement Activation This information is current as of September 27, 2021. Wei Xu, Stefan P. Berger, Leendert A. Trouw, Hetty C. de Boer, Nicole Schlagwein, Chantal Mutsaers, Mohamed R. Daha and Cees van Kooten J Immunol 2008; 180:7613-7621; ; doi: 10.4049/jimmunol.180.11.7613 Downloaded from http://www.jimmunol.org/content/180/11/7613 References This article cites 56 articles, 27 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/180/11/7613.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 27, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Properdin Binds to Late Apoptotic and Necrotic Cells Independently of C3b and Regulates Alternative Pathway Complement Activation1,2 Wei Xu,* Stefan P. Berger,* Leendert A.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • The 'C3ar Antagonist' SB290157 Is a Partial C5ar2 Agonist
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.01.232090; this version posted August 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. The ‘C3aR antagonist’ SB290157 is a partial C5aR2 agonist Xaria X. Li1, Vinod Kumar1, John D. Lee1, Trent M. Woodruff1* 1School of Biomedical Sciences, The University of Queensland, St Lucia, 4072 Australia. * Correspondence: Prof. Trent M. Woodruff School of Biomedical Sciences, The University of Queensland, St Lucia, 4072 Australia. Ph: +61 7 3365 2924; Fax: +61 7 3365 1766; E-mail: [email protected] Keywords: Complement C3a, C3aR, SB290157, C5aR1, C5aR2 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.01.232090; this version posted August 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abbreviations used in this article: BRET, bioluminescence resonance energy transfer; BSA, bovine serum albumin; C3aR, C3a receptor C5aR1, C5a receptor 1; CHO-C3aR, Chinese hamster ovary cells stably expressing C3aR; CHO-C5aR1, Chinese hamster ovary cells stably expressing C5aR1; DMEM, Dulbecco's Modified Eagle's Medium; ERK1/2, extracellular signal-regulated kinase 1/2; FBS, foetal bovine serum; HEK293, human embryonic kidney 293 cells; HMDM, human monocyte-derived macrophage; i.p., intraperitoneal; i.v., intravenous; rhC5a, recombinant human C5a; RT, room temperature; S.E.M.
    [Show full text]
  • Properdin Factor D: Effects on Thrombin-Induced Platelet Aggregation
    Properdin factor D: effects on thrombin-induced platelet aggregation. A E Davis 3rd, D M Kenney J Clin Invest. 1979;64(3):721-728. https://doi.org/10.1172/JCI109515. Research Article Factor D, when preincubated with platelet suspensions, at concentrations as low as 1.2 micrograms/ml, inhibited thrombin-induced platelet aggregation. No inhibition of collagen or arachidonic acid-induced platelet aggregation was found. Inhibition occurred, but to a lesser extent, when thrombin and factor D were added to platelets at the same time. No inhibition occurred when factor D was added after thrombin. Thrombin was able to overcome inhibition by factor D by increasing its concentration. Diisopropyl-phosphorofluoridate-inactivated factor D also inhibited thrombin-induced platelet aggregation so that enzymatic activity of factor D was not required for inhibition. Factor D absorbed with hirudin coupled to Sepharose 6B showed no decrease in inhibitory capacity. 125I-Factor D bound to platelets in a manner suggesting an equilibrium reaction similar to thrombin. At low factor D input, binding was linear, whereas at higher input, binding began to approach saturation. Binding of 125I-labeled thrombin to platelets was inhibited by factor D. Analysis of these data show that factor D does not alter the total number of thrombin molecules which bind to the platelet surface at saturation. However, the dissociation constant for thrombin is altered from 2.78 to 6.90 nM in the presence of factor D (20 micrograms/ml). Factor D is thus a competitive inhibitor of thrombin binding, although the affinity of factor D for the platelet thrombin receptor is much less […] Find the latest version: https://jci.me/109515/pdf Properdin Factor D EFFECTS ON THROMBIN-INDUCED PLATELET AGGREGATION ALVIN E.
    [Show full text]
  • An Anticomplement Agent That Homes to the Damaged Brain and Promotes Recovery After Traumatic Brain Injury in Mice
    An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice Marieta M. Rusevaa,1,2, Valeria Ramagliab,1, B. Paul Morgana, and Claire L. Harrisa,3 aInstitute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom; and bDepartment of Genome Analysis, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands Edited by Douglas T. Fearon, Cornell University, Cambridge, United Kingdom, and approved September 29, 2015 (received for review July 15, 2015) Activation of complement is a key determinant of neuropathology to rapidly and specifically inhibit MAC at sites of complement and disability after traumatic brain injury (TBI), and inhibition is activation, and test its therapeutic potential in experimental TBI. neuroprotective. However, systemic complement is essential to The construct, termed CD59-2a-CRIg, comprises CD59a linked fight infections, a critical complication of TBI. We describe a to CRIg via the murine IgG2a hinge. CD59a prevents assembly targeted complement inhibitor, comprising complement receptor of MAC in cell membranes (16), whereas CRIg binds C3b/iC3b of the Ig superfamily (CRIg) fused with complement regulator CD59a, deposited at sites of complement activation (17). The IgG2a designed to inhibit membrane attack complex (MAC) assembly at hinge promotes dimerization to increase ligand avidity. CD59- sites of C3b/iC3b deposition. CRIg and CD59a were linked via the 2a-CRIg protected in the TBI model, demonstrating that site- IgG2a hinge, yielding CD59-2a-CRIg dimer with increased iC3b/C3b targeted anti-MAC therapeutics may be effective in prevention binding avidity and MAC inhibitory activity. CD59-2a-CRIg inhibited of secondary neuropathology and improve neurologic recovery MAC formation and prevented complement-mediated lysis in vitro.
    [Show full text]
  • Properdin Contributes to Allergic Airway Inflammation Through Local C3a Generation Yuan Wang, Takashi Miwa, Blerina Ducka-Kokalari, Imre G
    Properdin Contributes to Allergic Airway Inflammation through Local C3a Generation Yuan Wang, Takashi Miwa, Blerina Ducka-Kokalari, Imre G. Redai, Sayaka Sato, Damodar Gullipalli, James G. This information is current as Zangrilli, Angela Haczku and Wen-Chao Song of September 26, 2021. J Immunol 2015; 195:1171-1181; Prepublished online 26 June 2015; doi: 10.4049/jimmunol.1401819 http://www.jimmunol.org/content/195/3/1171 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2015/06/26/jimmunol.140181 Material 9.DCSupplemental http://www.jimmunol.org/ References This article cites 66 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/195/3/1171.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Properdin Contributes to Allergic Airway Inflammation through Local C3a Generation Yuan Wang,* Takashi Miwa,* Blerina Ducka-Kokalari,† Imre G.
    [Show full text]
  • Are Complement Deficiencies Really Rare?
    G Model MIMM-4432; No. of Pages 8 ARTICLE IN PRESS Molecular Immunology xxx (2014) xxx–xxx Contents lists available at ScienceDirect Molecular Immunology j ournal homepage: www.elsevier.com/locate/molimm Review Are complement deficiencies really rare? Overview on prevalence, ଝ clinical importance and modern diagnostic approach a,∗ b Anete Sevciovic Grumach , Michael Kirschfink a Faculty of Medicine ABC, Santo Andre, SP, Brazil b Institute of Immunology, University of Heidelberg, Heidelberg, Germany a r a t b i c s t l e i n f o r a c t Article history: Complement deficiencies comprise between 1 and 10% of all primary immunodeficiencies (PIDs) accord- Received 29 May 2014 ing to national and supranational registries. They are still considered rare and even of less clinical Received in revised form 18 June 2014 importance. This not only reflects (as in all PIDs) a great lack of awareness among clinicians and gen- Accepted 23 June 2014 eral practitioners but is also due to the fact that only few centers worldwide provide a comprehensive Available online xxx laboratory complement analysis. To enable early identification, our aim is to present warning signs for complement deficiencies and recommendations for diagnostic approach. The genetic deficiency of any Keywords: early component of the classical pathway (C1q, C1r/s, C2, C4) is often associated with autoimmune dis- Complement deficiencies eases whereas individuals, deficient of properdin or of the terminal pathway components (C5 to C9), are Warning signs Prevalence highly susceptible to meningococcal disease. Deficiency of C1 Inhibitor (hereditary angioedema, HAE) Meningitis results in episodic angioedema, which in a considerable number of patients with identical symptoms Infections also occurs in factor XII mutations.
    [Show full text]
  • Complement Herbert L
    Host Defense 2011 Complement Herbert L. Mathews, Ph.D. COMPLEMENT Date: 4/11/11 Reading Assignment: Janeway’s Immunobiology, 7th Edition, pp. 54-55, 61-82, 406- 409, 514-515. Figures: (Unless otherwise noted) Janeway’s Immunobiology, 7th Edition, Murphy et al., Garland Publishing. KEY CONCEPTS AND LEARNING OBJECTIVES You will be able to describe the mechanism and consequences of the activation of the complement system. To attain the goals for these lectures you will be able to: a. List the components of the complement system. b. Describe the three activation pathways for complement. c. Explain the consequences of complement activation. d. Describe the consequence of complement deficiency. Page 1 Host Defense 2011 Complement Herbert L. Mathews, Ph.D. CONTENT SUMMARY Introduction Nomenclature Activation of Complement The classical pathway The mannan-binding lectin pathway The alternative pathway Biological Consequence of Complement Activation Cell lysis and viral neutralization Opsonization Clearance of Immune Complexes Inflammation Regulation of Complement Activation Human Complement Component Deficiencies Page 2 Host Defense 2011 Complement Herbert L. Mathews, Ph.D. Introduction The complement system is a group of more than 30 plasma and membrane proteins that play a critical role in host defense. When activated, complement components interact in a highly regulated fashion to generate products that: Recruit inflammatory cells (promoting inflammation). Opsonize microbial pathogens and immune complexes (facilitating antigen clearance). Kill microbial pathogens (via a lytic mechanism known as the membrane attack complex). Generate an inflammatory response. Complement activation takes place on antigenic surfaces. However, the activation of complement generates several soluble fragments that have important biologic activity.
    [Show full text]