1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Tímea Berki and Ferenc Boldizsár Signaltransduction Complementreceptors

3. Basic functions of thecomplement • Opsonization: enhancingphagocytosis of antigens • Chemotaxis: attractingmacrophages and neutrophils • Lysis: rupturingmembranes of foreigncells • Clumping of antigen-bearingagents • Alteringthemolecularstructure of viruses • Transport of immuncomplexesbyRBCs

4. Opsonins • Acute phase proteins like mannose-binding lectin (MBL), C-reactive protein (CRP) • C3b, C4b complement factors • Surfactant proteins in the alveoli SP-A and SP-D • The antibody molecule IgGcan function as an opsonin

5. SecretedPatternRecognitionReceptors(PRRs) • Complementreceptors, collectins • Pentraxinproteinssuchasserumamyloid and C-reactive protein • Lipidtransferases • Peptidoglycanrecognitionproteins (PGRs) and the LRR, XA21D areallsecretedproteins • Oneveryimportantcollectin is mannan-bindinglectin (MBL), a major PRR of theinnateimmunesystemthatbindsto a widerange of bacteria, viruses, fungi and protozoa. MBL predominantlyrecognizescertainsugargroupsonthesurface of microorganismsbutalsobindsphospholipids, nucleicacids and non-glycosylatedproteins

6. Role of complementreceptors • Complementreceptorsareresponsiblefordetectingpathogensbymechanismsnotmediatedbyantibodies • Complementactivity is notantigensensitive, butcan be triggeredbyspecificantigens • Thereforecomplement (a group of proteinsintheserumthathelpachievephagocytosis and lysis of antigens) is also part of theinnatehumoralimmunesystem

7. Complementreceptors

8. Complementreceptors APC T cell CR1 Inhibits cell proliferation Expressed on <15% CR1 CR2 Antigenrecognition and uptake CR2 CR3 CR3 Unknown Expressed on <5% CR4 CR4 CRIg Pathogen recognition and/or clearance SIGNR1 Cytokinemodulation Expressed onactivation C3aR C3aR Modulation of TH1/TH2 commitment T-cell trafficking Upregulated by activation C5aR C5aR Antigen recognition and uptake C1qR C1qRP Cytokine modulation CD46 CD46 Activation/proliferation, cytokine modulation and lineage commitment Cytokine modulation and APC maturation CD55 CD55 CD59 CD59

9. CR1 • Erythrocytecomplement receptor 1(CR1, CD35): • Alsoknownas C3b/C4b receptor and immuneadherence receptor • It is foundonerythrocytes, leukocytes, glomerularpodocytes, and splenicfolliculardendriticcells • The Knopsbloodgroupsystem is a system of antigenslocatedonthis protein. The protein mediatescellularbindingtoparticles and immunecomplexesthathaveactivatedcomplement

10. Role of CR1 • CR1 servesasthe main systemforprocessing and clearance of complementopsonizedimmunecomplexes • It has beenshownthat CR1 canactas a negative regulator of thecomplementcascade, • Itmediatesimmuneadherence and phagocytosisandinhibitsboththeclassicandalternativepathways • The number of CR1 moleculesdecreaseswithaging of erythrocytes (100-1000/cell) innormalindividuals and is alsodecreasedinpathologicalconditionssuchas SLE, HIV infection, someHAs and otherconditionsfeaturingimmunecomplexes

11. CR2 • Complementcomponent receptor 2 (CR2, CD21): • Alsoknownas, 3d /EpsteinBarrvirus receptor • CR2 onmature B cellsform a complexwithtwoothermembraneproteins, CD19 and CD81(=TAPA-1). The CR2-CD19-CD81 complex is oftencalledthe B cellco-receptorcomplex, because CR2 bindstoantigensthroughattached C3d (or iC3b or C3dg) whenthemembraneIgMbindstotheantigen. Thisresultsinthe B cellhavinggreatlyenhancedresponsetotheantigen. • Complement receptor 2 has beenshowntointeractwith CD19. • EpsteinBarrVirus (EBV) bindsto B cellsat CR2 duringinfection of thesecells. Yefenof et al. (1976) foundcompleteoverlapping of EBV receptors and C3 receptorson human B cells.

12. C5aR • C5a receptor : alsoknownascomplementcomponent 5a receptor 1 (C5AR1) orCD88 is a G protein-coupled receptor for C5a

13. Overview of complement receptor (CR) and Toll-like receptor signaling Bacteria Viruses C3b C5 iC3b C1q C5a CR3 TLR C5aR gC1qR CD46 TLR4-induced IL-12 inhibited by posttranscriptional mechanism PI3K Erk1/2 IRF-1, IRF-8 IL-12p35 IL-12/IL-23p40 IL-23p19 IL-27p28 Nucleus

14. Toll-likereceptors-patternrecognition Peptidoglycan (G+) Lipoprotein Lipoarabinomannan(Mycobacteria) LPS (Leptospira) LPS (Porphyromonas) GPI (Trypanosomacruzi) Yymosan(Yeast) Lipoteichoic acids (G+) RVS F protein LPS (G-) Unmethylated CpG DNA dsRNA Flagellin TLR1 TLR2 TLR2 TLR6 TLR3 CD14 TLR4 TLR5 TLR9 MD-2

15. Toll-likereceptors(TLRs) • Theyaresingle, membrane-spanning, non-catalyticreceptorsthatrecognizestructurallyconservedmoleculesderivedfrommicrobes • Theyreceivetheirnamefromtheirsimilaritytothe protein codedbythe Toll geneidentifiedinDrosophilain 1985 byChristianeNüsslein-Volhard. The geneinquestion, whenmutated, makesthe Drosophila flieslookunusual, or 'weird'. The researchersweresosurprisedthattheyspontaneouslyshouted out inGerman "Dasist ja toll!" whichtranslatesas "That´s wild!"

16. TLR types LPS dsRNA LBP TLR2 TLR4 MD2 TLR9 TLR7 TLR3 CD14 MDA-5 RIG-1 TBK1 IKKe IPS1 MyD88 MyD88 JAK2 PI3K p38 JNK mTOR MyD88 TRIF PKA TAK1 PKR MKKs lkB p50 p65