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

COMPLEMENT RECEPTORS

Tímea Berki and Ferenc BoldizsárSignal transduction

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

TÁMOP-4.1.2-08/1/A-2009-0011

Basic functions of the complement• Opsonization: enhancing phagocytosis of

antigens • Chemotaxis: attracting macrophages and

neutrophils • Lysis: rupturing membranes of foreign cells • Clumping of antigen-bearing agents • Altering the molecular structure of viruses• Transport of immuncomplexes by RBCs

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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 IgG can function as

an opsonin

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Secreted Pattern Recognition Receptors (PRRs) • Complement receptors, collectins• Pentraxin proteins such as serum amyloid and C-

reactive protein• Lipid transferases• Peptidoglycan recognition proteins (PGRs) and the

LRR, XA21D are all secreted proteins• One very important collectin is mannan-binding

lectin (MBL), a major PRR of the innate immune system that binds to a wide range of bacteria, viruses, fungi and protozoa. MBL predominantly recognizes certain sugar groups on the surface of microorganisms but also binds phospholipids, nucleic acids and non-glycosylated proteins

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Role of complement receptors• Complement receptors are responsible for detecting

pathogens by mechanisms not mediated by antibodies

• Complement activity is not antigen sensitive, but can be triggered by specific antigens

• Therefore complement (a group of proteins in the serum that help achieve phagocytosis and lysis of antigens) is also part of the innate humoral immune system

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Complement receptors

CR # NameCluster of differentiation (CD)

CR1 - CD35

CR2 - CD21

CR3 Macrophage-1 antigen or „integrin alphaMbeta2” CD11b+CD18

CR4 Integrin alphaXbeta2 or „p150,95” CD11c+CD18

- C3a receptor -

- C5a receptor CD88

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Complement receptors

CR1

CR2

CR3

CR4

CR2

CR3

CR4CRIg

SIGNR1

C3aR

C5aR

C1qR

CD46

CD55

CD59

C3aR

C5aR

C1qRP

Antigen recognitionand uptake

Pathogen recognitionand/or clearance

Modulation of TH1/TH2commitment

Antigen recognitionand uptake

Cytokine modulationand APC maturation

CR1 Inhibits cell proliferationExpressed on <15%

UnknownExpressed on <5%

Cytokine modulationExpressed on activation

T-cell traffickingUpregulated by activation

Cytokine modulation

CD46

CD55

CD59

Activation/proliferation, cytokine modulation andlineage commitment

APC T cell

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CR1Erythrocyte complement receptor 1 (CR1, CD35):• Also known as C3b/C4b receptor and immune

adherence receptor• It is found on erythrocytes, leukocytes, glomerular

podocytes, and splenic follicular dendritic cells• The Knops blood group system is a system of

antigens located on this protein. The protein mediates cellular binding to particles and immune complexes that have activated complement

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Role of CR1• CR1 serves as the main system for processing and

clearance of complement opsonized immune complexes

• It has been shown that CR1 can act as a negative regulator of the complement cascade,

• It mediates immune adherence and phagocytosis and inhibits both the classic and alternative pathways

• The number of CR1 molecules decreases with aging of erythrocytes (100-1000/cell) in normal individuals and is also decreased in pathological conditions such as SLE, HIV infection, some HAs and other conditions featuring immune complexes

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CR2Complement component receptor 2 (CR2, CD21):• Also known as, 3d /Epstein Barr virus receptor• CR2 on mature B cells form a complex with two other

membrane proteins, CD19 and CD81(=TAPA-1). The CR2-CD19-CD81 complex is often called the B cell co-receptor complex, because CR2 binds to antigens through attached C3d (or iC3b or C3dg) when the membrane IgM binds to the antigen. This results in the B cell having greatly enhanced response to the antigen.

• Complement receptor 2 has been shown to interact with CD19.• Epstein Barr Virus (EBV) binds to B cells at CR2 during infection

of these cells. Yefenof et al. (1976) found complete overlapping of EBV receptors and C3 receptors on human B cells.

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C5aR

C5a receptor : also known as complement component 5a receptor 1 (C5AR1) or CD88 is a G protein-coupled receptor for C5a

TÁMOP-4.1.2-08/1/A-2009-0011Overview of complement receptor (CR) and Toll-like receptor signaling

TLRCR3 C5aR

C3b

gC1qR

C1q

CD46

iC3b

C5

Bacteria Viruses

Erk1/2 PI3KTLR4-induced IL-12 inhibited

by posttranscriptional mechanism

Nucleus

IL-12p35IL-12/IL-23p40IL-23p19IL-27p28

IRF-1,IRF-8

C5a

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Toll-like receptors-pattern recognition

Peptidoglycan (G+)Lipoprotein

Lipoarabinomannan (Mycobacteria)LPS (Leptospira)

LPS (Porphyromonas)GPI (Trypanosoma cruzi)

Yymosan (Yeast) dsRNA FlagellinUnmethylated

CpG DNA

TLR2TLR1 TLR5TLR3 TLR9TLR6TLR2

Lipoteichoic acids (G+)RVS F protein

LPS (G-)

TLR4CD14 MD-2

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Toll-like receptors (TLRs)• They are single, membrane-spanning, non-catalytic

receptors that recognize structurally conserved molecules derived from microbes

• They receive their name from their similarity to the protein coded by the Toll gene identified in Drosophila in 1985 by Christiane Nüsslein-Volhard. The gene in question, when mutated, makes the Drosophila flies look unusual, or 'weird'. The researchers were so surprised that they spontaneously shouted out in German "Das ist ja toll!" which translates as "That´s wild!"

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MyD88 TRIF

TLR3TLR7

TLR2

PKA TAK1 PKR

p38 JNK

MKKs lkBp50

p65

MyD88

LPS

TLR4

MyD88

MD2LBP

dsRNA

TBK1IKKe

MDA-5RIG-1

IPS1

TLR9JAK2

mTOR

PI3K

CD14

TLR types