Complement Receptors

The complement system comprises an assembly of liver-manufactured, soluble and cell-bound proteins that participate in innate and adaptive immunity. Activation of the complement cascade by protease cleavage leads to chemotaxis (C5a), inflammation and increased capillary permeability (C3a, C5a), opsonization (C3b), and cytolysis.

 Fc receptors  Immune Cytokines  Immunoglobulins  Interferons

receptor ligands functions
CR1 (CD35) C3b, C3bi, C4b, C4bi opsonization and antigen clearance (phagocytes), antigen persistence (FDC), immune complex clearance (RBC), complement regulation
C1qR C1q immune complex binding to phagocytes(macrophages, neutrophils)
CR2 (CD21) C3d, C3dg, C3bi, EBV B cell activation ( B cells, FDC)
CR3 (MAC-1, CD11b/CD18) C3bi adhesion, extravasation, phagocytosis of macrophages and neutrophils
CR4 (p150.95, CD11c/CD18) C3bi adhesion, extravasation, phagocytosis of macrophages and neutrophils
C5aR C5a adherence, phagocytosis, CR1 and CR3 expression (macrophages, neutrophils)
C3aR, C4aR, C5aRC3a, C4a, C5a

granule release from mast cells, contraction of smooth muscle

 Fc receptors  Immune Cytokines  Immunoglobulins  Interferons


Cytokines are small proteins that regulate and mediate immunity, inflammation, and hematopoiesis. They are secreted de novo in response to immune stimuli, and usually act briefly, locally, at very low concentrations (the exception being endocrine action at distant cells). Cytokines bind to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter cellular activity (gene expression).

 Complement Receptors  Fc receptors  Immune Cytokines  Immunoglobulins  Interferons  Scavenger Receptors  Toll-like Receptors  Cell Adhesion Molecules  Cell signaling  Receptor Tyrosine Kinases (RTKs)  Receptor Signal Transduction  Second Messengers

Immune Cytokines

Cytokine class Producer cell/tissueTarget cellFunctions

Granulocyte/Monocyte Colony Stimulating Factor (CSF)

G-CSF endothelium, macrophages neutrophil progenitor cells growth and differentiation of neutrophils
GM-CSF Th cells progenitor cells growth and differentiation of monocytes and dendritic cells
M-CSF thymic epithelial cells (TEC), PMN, chondrocytes, glomerular mesangial cells, Ishikawa cells macrophage lineage lymphohematopoietic growth and differentiation of monocytes, enhances expression of differentiation- antigens and stimulates chemotactic, phagocytic, and cytotoxic activities of monocytes


IL-1α, IL-1β pro-inflammatory monocytes macrophages B cells dendritic cells Th cells costimulation
B cells maturation and proliferation
NK cells activation
various inflammation, acute phase response, fever
IL-2 hematopoietin Th1 cells activated T cells and B cells, NK cells cell growth, proliferation, activation, synthesis of antibodies
IL-3 (multi-CSF) hematopoietin Th cells, NK cells stem cells growth and differentiation
mast cells growth, and histamine release
IL-4 hematopoietin Th2 cells activated B cells proliferation and differentiation IgG1 and IgE synthesis
macrophages MHC Class II
T cells proliferation
IL-5 hematopoietin Th2 cells activated B cells proliferation and differentiation IgA synthesis
IL-6 hematopoietin pro-inflammatory IL-6 receptor has two subunits - an alpha subunit that produces ligand specificity, and a p130 receptor subunit. Signals through JAK kinases and activation of Ras-mediated signaling monocytes macrophages Th2 cells stromal cells activated B cells differentiation into plasma cells → secretion of antibodies
T cells costimulator of T cells
stem cells differentiation
various acute phase response
neurons, osteoblasts neuronal differentiation, bone loss

IL-7 hematopoietin

marrow stroma thymus stroma stem cells differentiation into progenitor B and T cells
IL-8 chemokine macrophages endothelial cells neutrophils chemotaxis
IL-10 Th2 cells macrophages inhibition of macrophage function, cytokine production
B cells activation
IL-12 macrophages B cells activated Tc cells differentiation into CTL (with IL-2)
NK cells activation
IL-21 CD4+ T cells B cells, T cells, NK cells

costimulator of T cell proliferation, enhances memory response, and modulates homeostasis

regulator of B cell differentiation to plasma cells, regulator of isotype switching

terminal differentiation of NK cells, enhancing cytotoxic function while also decreasing cellular viability

Interferons  Interferons

IFN-α leukocytes various viral replication MHC I expression
IFN-β fibroblasts various viral replication MHC I expression
IFN-γ Th1 cells, Tc cells, NK cells various viral replication
macrophages MHC expression
activated B cells Ig class switch to IgG2a
Th2 cells proliferation
macrophages pathogen elimination

Macrophage Inflammatory Proteins

MIP-1α chemokine macrophages monocytes, T cells chemotaxis
MIP-1β chemokine lymphocytes monocytes, T cells chemotaxis

Transforming Growth Factor

TGF-β T cells, monocytes monocytes, macrophages chemotaxis
activated macrophages IL-1 synthesis
activated B cells IgA synthesis
various proliferation

Tumor Necrosis Factor

TNF-α pro-inflammatory macrophages, mast cells, NK cells macrophages CAM and cytokine expression
tumor cells cell death
TNF-β lymphotoxin-α (LT) pro-inflammatory Th1 and Tc cells phagocytes B cells phagocytosis, with no production; activation effector cells to infection sites, leukocyte adhesion to endothelial cells, peripheral lymphoid organogenesis, stimulation of B cells
tumor cells cell death through inhibition of tumor angiogenesis

Fc receptors

Fc receptors – the constant region (Fc) of IgG on bacterial surfaces can bind to the Fc receptor on phagocytes. Such binding requires prior antigen-antibody interaction. The binding of IgG-coated bacteria to Fc receptors on phagocytes stimulates both metabolic activity in the phagocytes (respiratory burst) and phagocytic engulfment of the target. Fc receptors include the clusters of differentiation, CD16 (Fcγ RIII), CD32 (Fcγ RII-A, Fcγ RII-B2, Fcγ RII-B1), and CD64 (Fcγ RI), Fcε RI, and Fcα RI. All FcR are stimulatory except the inhibitory Fcγ RII-B1 and B2, which contain immunoreceptor tyrosine based inhibition motifs (ITIMs) in their cytoplasmic tail.  Immune Cytokines  Immunoglobulins  Interferons


relative binding

expressed on


Fcγ RI (CD64)

IgG1 ~200

macrophages, neutrophils, eosinophils, dendritic cells



Activation of respiratory burst

Induction of killing

Fcγ RII-A (CD32)


macrophages, neutrophils, eosinophils, platelets, Langerhans cells


Granule release from eosinophils

Fcγ RII-B2 (CD32)


macrophages, neutrophils, eosinophils


Inhibition of stimulation

Fcγ RII-B1 (CD32)


B cells, mast cells

No uptake

Inhibition of stimulation

Fcγ RIII (CD16)


NK cells, eosinophils, macrophages, neutrophils, mast cells, FDCs

Induction of killing by NK cells

Fcε RI


mast cells, eosinophils, basophils, FDCs

Secretion of granules

Eosinophilic attack of parasites such as Schistosoma mansoni

Fcα RI

IgA1, IgA2~20

macrophages, neutrophils, eosinophils


Induction of killing


Depending upon the character of the heavy chain, immunoglobulins are divided into five classes – IgG, IgD, IgE, IgA, IgM – that are expressed in different tissues.

Their frequency of occurrence is G > A > M > D > E.

The classes are further subdivided into isotypes, which have different properties in terms of complement fixation and binding to Fc receptors for immunoglobulins.

 Fc receptors  Immune Cytokines  Interferons

Ig class

tissue location/function

IgG primary immunity against invading pathogens
IgA mucus – gut, respiratory tract
IgM early B cell-mediated response to invading pathogens
IgD antigen receptor on B cells
IgE mast cells – releases histamines in response to allergens

Ig class - heavy chains



IgG - γ - Gamma


Fixes complement

Opsonin promotion of phagocytosis.

Macrophages, monocytes, neutrophils, and some lymphocytes have Fc receptors for the Fc region of IgG. (not IgG2 or IgG4)

Only Ig class that crosses placenta.

IgA - α - Alpha

monomer or dimer (J chain)

Secretions - secretory piece or T piece attached (11S immunoglobulin). No complement fixation. IgA can bind to neutrophils and some lymphocytes.

IgM - μ - Mu

J chain in pentamer (19s); can be a monomer

Fixes complement IgM binds to some cells via Fc receptors

IgD - δ - Delta


No complement fixation On B cell surfaces, IgD functions as an antigen receptor, and has extra amino acids at C-terminal end for anchoring to the membrane. IgD also associates with the Ig-α and Ig-β chains.

IgE - ε - Epsilon

monomer with extra domain in the constant region

No complement fixation Binds very tightly to Fc receptors on basophils and mast cells, so involved in allergic reactions

The immunoglobulin superfamily is evolutionarily ancient, is widely expressed, and is constitutive or long-term up-regulated. Immunoglobulin antibodies are released by activated B cells of the immune system, on which they also act as surface marker proteins. Adherence of immunoglobilins to foreign substances or to cellular invaders may be sufficient to disarm the invader, or the antibodies attached to foreign substances function as attack signals to macrophages and cytotoxic T cells.

Adhesion molecules of the immunoglobulin supergene family, activate specific kinases through phosphorylation, resulting in activation of transcription factors, increased cytokine production, increased cell membrane protein expression, production of reactive oxygen species, and cell proliferation.


Interferons are immune cytokines that are classified, as type I, II, or III, according to the receptors through which they signal. Interferon (INF) family receptors have conserved cysteine residues and include the receptors for IFN-α, IFN-β, and IFN-γ.

 Fc receptors  Immune Cytokines  Immunoglobulins



Secreting cell / action

IFN type I

IFN-α (1, 2, 4, 5, 6, 7, 8, 10, a3, 14, 16, 17, 21), IFN-β (1, 3), IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω (with pseudogenes), IFN-ζ (limitin)

IFN-α receptor (IFNAR)

IFNAR1 and IFNAR2 chains

plasmacytoid dendritic cells (pDCs) are the most potent producers of type I IFNs, but virtually all cells are capable of production of type I IFNs – lymphocytes (NK cells, B cells, T cells), macrophages, fibroblasts, endothelial cells, osteoblasts

IFN-β is expressed primarily in nonimmune cells, and and IFN-α primarily in leukocytes

IFN type II

single isotype IFN-γ

IFN-γ receptor (IFNGR)


activated T cells, Th1 cells, and natural killer cells.

potentiates the effects of the type I IFNs, stimulates macrophages to kill engulfed bacteria, regulates Th2 response, regulation of immune response (IFN-γ production can lead to autoimmune disorders)

IFN type III

types IFN-λ1(IL29), IFN-λ2 (IL28A), IFN-λ3 (IL28B)

(originally called macrophage-activating factor)

IL10R2 (CRF2-4) plus IFNLR1 (CRF2-12)

IFN-λs induced by both type I and type III IFNs (belong to IFN-stimulated genes (ISGs))

induced after stimulation by viruses and display antiviral activity

IFN-λs are produced by plasmacytoid dendritic cells to a greater extent than by myeloid dendritic cells

specific interferons


IFN-β1a (Avonex, Rebif) employed in treatment of multiple sclerosis (MS, DS)
IFN-β1b (Betaseron) employed in treatment of multiple sclerosis (MS, DS)

Scavenger Receptors

Scavenger receptors bind a variety of polyanions on bacterial surfaces, stimulating phagocytosis of the polyanion-coated bacteria. Macrophage scavenger receptors appear to mediate important, conserved functions, so may be pattern-recognition receptors that arose early in the evolution of host-defense mechanisms.

Scavenger receptors also bind and internalize modified lipoproteins (LDL), and are expressed on macrophages where they can contribute to foam cell formation in atherosclerosis. Cholesterol-laden macrophage foam cells are the primary component of the fatty streak, which is the earliest atherosclerotic lesion. Thus, lipid uptake by scavenger receptor pathways is considered a requisite and initiating event in the pathogenesis of atherosclerosis. The removal of proinflammatory modified LDLs from the artery wall via scavenger receptors can prove proatherogenic when the metabolic pathways distal to scavenger receptor uptake are overwhelmed, leading to the accumulation of cholesterol-laden macrophages and establishment of a chronic inflammatory setting.

In addition to modified lipoprotein uptake, scavenger receptor proteins regulate apoptotic cell clearance, initiate signal transduction, and serve as pattern recognition receptors for pathogens. These activities may contribute both to proinflammatory and anti-inflammatory forces regulating atherogenesis.[s]

 Complement Receptors  Fc receptors  Immune Cytokines  Immunoglobulins  Interferons

scavenger receptors


Class A - macrophage expressed trimers with cytosol domain, transmembrane domain, spacer domain, α-helical coiled-coil domain, collagen-like domain, +/- cysteine-rich domain. Class A scavenger receptors, macrophages, and atherosclerosis.

human SR-AI/II cysteine-rich domain

expressed by foam cells in athero lesions, binds acetylated and oxLDL
murine SR-AI/II expressed by foam cells in athero lesions, binds acetylated and oxLDL
MARCO collagen-like and cysteine-rich domains
SRCL scavenger receptor C-type lectin endothelial receptor similar in organization to type A scavenger receptors, but contains a C-type carbohydrate-recognition domain (CRD), SRCL might be involved in selective clearance of specific desialylated glycoproteins from circulation and/or interaction of cells bearing Lewis[x]-type structures with the vascular endothelium, shares with the dendritic cell receptor DC-SIGN the ability to bind the Lewis[x] epitope.[s]
Class B - oxidized LDL receptors, concentrated in specific plasma membrane microdomains (caveolae), two transmembrane domains
human CD36 binds oxLDL, expressed by foam cells in athero lesions
murine CD36 binds oxLDL, CD36 knockout mice have less atherosclerosis
murine SR-B1 mediates reverse cholesterol transport (HDL metabolism) (paraoxonase-1, PON-1)
human CLA-1 human homologue of rodent SR-B1
Class C - transmembrane protein with extracellular N-terminus

Drosophila class C scavenger receptor with a mucin-like structure [s], and with expression restricted to macrophages/hemocytes during embryonic development [s1]

Class D - unique N-terminal mucin-like domain
human CD68 stains all macrophages in athero lesions, binds oxLDL
murine Cd68 (macrosialin) stains all macrophages in athero lesions, binds oxLDL
Class E - LOX-1 is located in various cell types within atherosclerotic plaque (humans, other animals), and it accumulates during the progression of the plaque. The receptor is highly expressed in hypertension, hyperhomocysteinaemia and diabetes mellitus.
human LOX-1 lectin-like oxidized LDL receptor-1 Binds oxLDL, expressed by endothelial cells, macrophages, smooth muscle cells. Complex interaction exists between LOX-1 and inflammation, lipid accumulation and oxidative stress. The receptor is upregulated by ox-LDL itself and by angiotensin II, endothelin, cytokines, and shear stress.[pm]

not assigned

human SR-PSOX recently described scavenger receptor cloned from human macrophages

modified from here

 Complement Receptors  Fc receptors  Immune Cytokines  Immunoglobulins  Interferons

Toll-like receptors

Toll-like receptors show homology with the Drosophila Toll protein and the human interleukin-1 receptor family, and are transmembrane proteins that recognize extracellular or endosomal pathogen-associated molecular patterns. The specificity of Toll-like receptor signaling is due to adaptor proteins containing Toll–interleukin 1 receptor (TIR) domains. Five TIR adaptors display activating functions: MyD88, Mal, TRIF, TRAM, and SARM.

The TLR family is characterized by the presence of leucine-rich repeats (which mediates ligand binding) and a Toll/interleukin-1 receptor-like domain (which mediates interaction with intracellular signaling proteins). Most identified TLR ligands are either conserved microbial products that signal the presence of an infection, or endogenous ligands that might signal other danger conditions. TLRs trigger signals evoking synthesis and secretion of cytokines and activation of host defenses through NF-κB, MAP kinases, and costimulatory molecules.



adaptor proteins

TLR1 triacyl lipoproteins MyD88/MAL
TLR2 lipoproteins; G+ peptidoglycan; lipoteichoic acids; fungi; viral glycoproteins MyD88/MAL
TLR3 double-stranded RNA (viruses), poly I:C TRIF
TLR4 lipopolysaccharide (LPS); viral glycoproteins MyD88/MAL/TRIF/TRAM
TLR5 flagellin MyD88
TLR6 diacyl lipoproteins MyD88/MAL
TLR7 small synthetic compounds; single-stranded RNA MyD88
TLR8 small synthetic compounds; single-stranded RNA MyD88
TLR9 unmethylated CpG DNA MyD88
TLR10 unknown unknown
TLR11 profilin MyD88
TLR12 unknown unknown
TLR13 unknown unknown

Labels: , , , , , , , , , , , , , ,

. . . since 10/06/06