Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen

Medical Biotechnology Master’s Programmes

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

COMPLEMENT RECEPTORS

Tímea Berki and Ferenc Boldizsár Signal transduction

at the University of Pécs and at the University of Debrecen

Identification number: 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

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

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

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

Complement receptors

CR # Name Cluster 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

Complement receptors

CR1 CR2 CR3 CR4

CR2 CR3 CR4 CRIg

SIGNR1 C3aR C5aR C1qR

CD46 CD55 CD59

C3aR

C5aR

C1qRP Antigen recognition

and uptake

Pathogen recognition and/or clearance

Modulation of T_H1/T_H2 commitment Antigen recognition and uptake

Cytokine modulation and APC maturation

CR1 Inhibits cell proliferation Expressed on <15%

Unknown

Expressed on <5%

Cytokine modulation Expressed on activation T-cell trafficking

Upregulated by activation

Cytokine modulation

CD46 CD55 CD59

Activation/proliferation, cytokine modulation and lineage commitment

APC T cell

CR1

Erythrocyte 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

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

CR2

Complement 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.

C5aR

C5a receptor : also known as complement

component 5a receptor 1 (C5AR1) or CD88 is a G

protein-coupled receptor for C5a

Overview of complement receptor

(CR) and Toll-like receptor signaling

TLR

CR3 C5aR

C3b

gC1qR C1q

CD46 iC3b

C5

Bacteria Viruses

Erk1/2 PI3K

TLR4-induced IL-12 inhibited by posttranscriptional mechanism

Nucleus

IL-12p35 IL-12/IL-23p40 IL-23p19 IL-27p28 IRF-1,

IRF-8

C5a

Toll-like receptors-pattern recognition

Peptidoglycan (G+) Lipoprotein

Lipoarabinomannan (Mycobacteria) LPS (Leptospira)

LPS (Porphyromonas) GPI (Trypanosoma cruzi)

Yymosan (Yeast) dsRNA Flagellin

Unmethylated CpG DNA

TLR2

TLR1 TLR2 TLR6 TLR3 TLR5 TLR9

Lipoteichoic acids (G+) RVS F protein

LPS (G-)

TLR4 CD14 MD-2

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!"

MyD88 TRIF TLR3 TLR7

TLR2

PKA TAK1 PKR

p38 JNK

MKKs lkB

p50 p65 MyD88

LPS

TLR4

MyD88 MD2 LBP

dsRNA

TBK1 IKKe

MDA-5 RIG-1

IPS1 TLR9

JAK2

mTOR PI3K CD14

TLR types