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, C5aR	C3a, C4a, C5a	granule release from mast cells, contraction of smooth muscle

 Fc receptors  Immune Cytokines  Immunoglobulins  Interferons

Cytokines

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/tissue	Target cell	Functions
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
Interleukins
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

FcR relative binding	expressed on	activity
Fcγ RI (CD64) IgG1 ~200	macrophages, neutrophils, eosinophils, dendritic cells	Uptake Stimulation Activation of respiratory burst Induction of killing
Fcγ RII-A (CD32) IgG1~4	macrophages, neutrophils, eosinophils, platelets, Langerhans cells	Uptake Granule release from eosinophils
Fcγ RII-B2 (CD32) IgG1~4	macrophages, neutrophils, eosinophils	Uptake Inhibition of stimulation
Fcγ RII-B1 (CD32) IgG1~4	B cells, mast cells	No uptake Inhibition of stimulation
Fcγ RIII (CD16) IgG1~1	NK cells, eosinophils, macrophages, neutrophils, mast cells, FDCs	Induction of killing by NK cells
Fcε RI IgE~20,000	mast cells, eosinophils, basophils, FDCs	Secretion of granules Eosinophilic attack of parasites such as Schistosoma mansoni
Fcα RI IgA1, IgA2~20	macrophages, neutrophils, eosinophils	Uptake Induction of killing

Immunoglobulins

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	humoral	cellular
IgG - γ - Gamma monomers	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 monomer	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

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

Type	Receptor	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) IFNGR1 and IFNGR2	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	actions
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	action
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
dSR-C1	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.

receptor	ligand	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