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Table of Contents
Introduction …………………………………………………………….................
4
Humoral immunity in innate immune system ……………............
5
Cellular immunity in the innate immune system ……………........
6
Pattern recognition receptors (PRRs) in innate immunity ….....
9
Innate immunity influences adaptive immunity ………………....... 11
Concluding Remarks ……………………………………………………............. 11
References ………………………………….………………………….................. 12
3
Introduction
I
mmune system refers to the cells and molecules responsible for immunity, which is a collection of mechanisms
within an organism. Healthy individuals protect themselves against diseases by means of an immune system within
the body, that functions by identifying and killing a wide variety of pathogens, such as viruses, bacteria, and parasitic
worms, as well as tumor cells. The immune system distinguishes foreign material from the organism's normal cells and
tissues. Two layers of defense systems are found in organisms, the innate immune system and the adaptive immune
system. The innate (also called natural or native) immune system is a front line of defense providing an immediate, but
non-specific response found in all plants and animals.[1] A second layer of protection possessed by all vertebrates is
provided by the adaptive immune system, which is also called acquired or specific immunity. The adaptive immune
system has improved recognition of the pathogen and retains specific responses in the form of an immunological
memory that allows the host to mount faster and stronger attacks upon subsequent encounters with pathogens.[2] Both
the innate and adaptive immune systems are comprised of both cellular and soluble components (known as humoral
immunity) by which they carry out their protective function, but they differ in a number of ways (Table 1).
The innate system is thought to constitute an evolutionarily older defense strategy, based on the fact that non-vertebrate
organisms use immune systems similar to the vertebrate innate immune system. The major functions of the vertebrate
innate immune system include:
1) Recruiting immune cells to sites of infection and inflammation, through the production of specialized chemical
mediators, such as cytokines and chemokines.
2) Activation of the complement cascade to identify bacteria, activate cells, and to promote clearance of dead cells or
antibody complexes.
3) The identification and removal of foreign substances present in organs, tissues, the blood and lymph, by specialized
white blood cells.
4) Activation of the adaptive immune system through a process known as antigen presentation. Both humoral and
cellular components of innate immunity are required for these protective functions.
Table 1 : Features of the immune system
Innate immune system
Adaptive immune system
Non-specific response
Antigen-specific response
Immediate maximal response
Lag time between exposure and maximal response
Broad receptors recognize PAMPs (Pathogen –associated
molecular patterns)
Narrow specific receptors recognize a particular epitope
Receptors are PRRs (Pattern recognition receptors)
Receptors are B-cell (BCR) and T-cell (TCR) receptors
Relatively stereotypic
Highly specialized
No memory of prior exposure
Memory of prior exposure
In all forms of life
Vertebrates only
Components
4
Physical & chemical barriers (Skin, mucosal epithelia &
antimicrobial substances, e.g. defensins)
Cutaneous & mucosal immune system secreted antibodies
Humoral immunity: Complement
Humoral immunity: antibodies
Cellular immunity: Phagocytes, NK cells
Cellular immunity: Lymphocytes
Humoral immunity in innate immune system
O
nce infectious agents have breached the anatomical barriers and penetrated tissues, acute inflammation is
stimulated and is typically manifested by symptoms of redness, swelling, heat, pain, and possible dysfunction of
the organs or tissues involved. Humoral factors play an important role in inflammatory edema and the recruitment of
phagocytic cells. These humoral factors (see: Table 2) are found in serum or they are formed at the site of infection.
Table 2 : Humoral Factors in the innate immune system
Humoral components
Effector function
Complement, Mannose-binding lectin
Opsonization, enhanced phagocytosis, inflammation
Coagulation
Chemotactic agents for phagocytic cells, inflammation
Platelets
Antimicrobial substance, e.g. beta-lysin
Lactoferrin and Transferrin
Iron binding, limiting bacterial growth
Lysozyme
Peptidoglycan hydrolysis, breaking down the cell wall of bacteria
Fibronectin
Opsonization and phagocytosis
Interferons
Antiviral proteins
Interleukin-1
Fever, Opsonization
TNF
antiviral, phagocyte activation
Defensins
Antibacterial, antiviral proteins
The complement system is the major humoral component of innate defense mechanism
mention.
CLASSICAL PATHWAY
MB-LECTIN PATHWAY
ALTERNATIVE PATHWAY
Antigen:antibody complexes
(pathogen surfaces)
Mannose-binding lectin binds
mannose on pathogen surfaces
Pathogen surfaces
C1q, C1r, C1s
C4
C2
MBL, MASP-1, MASP-2
C4
C2
C3
B
D
[3, 4]
and deserves further
C3 convertase
C3a, C5a
Peptide mediators
of inflammation,
phagocyte recruitment
C3b
Binds to complement
receptors on phagocytes
Opsonization of
pathogens
Terminal
complement components
C5b
C6
C7
C8
C9
Membrane-attack
complex,
lysis of certain
pathogens and cells
Removal of
immune complexes
Figure 1a
Overview of the main components and effector actions of complement
5
The complement system is a that attacks the surfaces of
foreign cells. The term "complement" was introduced by
Paul Ehrlich in the late 1890s, who described it is
something in the blood which "complements" the cells of
the immune system in the killing of pathogens. The
complement system is made up of over 25 different
serum small proteins and protein fragments, including
serum proteins, serosal proteins, and cell membrane
receptors. These proteins are synthesized mainly in the
liver, and they account for about 5% of the globulin
fraction of blood serum. Complement proteins circulate
in the blood in an inactive form. Elements of the
complement cascade can be found in many species
evolutionarily older than mammals including plants,
birds, fish , some species of invertebrates[5], as well as in
humans. The complement system is not adaptable and
does not change over the course of an individual's
lifetime; as such it belongs to the innate immune system.
However, it can be recruited and brought into action by
the adaptive immune system .
After complement proteins initially bind to microbes,
they activate their protease activity, which in turn
activates other complement proteases, and so on. This
produces a catalytic cascade that amplifies the initial
signal by controlled positive feedback.[6, 7] The cascade
results in the production of peptides that attract immune
cells, increase vascular permeability, and opsonize (coat)
the surface of a pathogen, marking it for destruction.
This deposition of complement can also kill cells directly
by disrupting the plasma membrane barrier.[3]
Functional protein classes in the
complement system
Binding to antigen:antibody complexes
and pathogen surfaces
C1q
Binding to mannose on bacteria
MBL
Activating enzymes
C1r
C1s
C2b
Bb
D
MASP-1
MASP-2
Membrane-binding
proteins and opsonins
C4b
C3b
Peptide mediators of inflammation
C5a
C3a
C4a
Membrane-attack proteins
C5b
C6
C7
C8
C9
Complement receptors
CR1
CR2
CR3
CR4
C1qR
Complement-regulatory proteins
C1INH
C4bp
CR1
MCP
DAF
H
I
P
Cd59
Figure 1b
Functional protein classes in the
Three biochemical pathways activate the complement
complement system.
system: the classical complement pathway, which
initiates complement activation via binding to specific
antibodies; the alternative complement pathway, which
activates via direct binding to pathogen surfaces; and the mannose-binding lectin pathway, which is homologous to the
classical complement pathway, but involves a protein that binds to mannose residues and other sugars on multiple
pathogens.[5] Figure 1a & b diagrammatically show the major players in all three complement activation pathways of
vertebrates [the diagrams are adopted from Janeway CA, Jr. et al (2005). Immunobiology., 6th ed., Garland Science].
Cellular immunity in the innate immune system
T
he cellular component of the innate immune system consists of a number of white blood cells (WBC), also known as
leukocytes, which includes: Natural killer cells, mast cells, eosinophils, basophils, and phagocytic cells, including
macrophages, neutrophils and dendritic cells. They are all derived from CD34+ pluripotent hematopoietic stem cells
present in the bone marrow.[8] See Table 3 for characteristics of cellular components involved in the innate immune
system.
6
Since leukocytes are able to move freely, part of the inflammatory response is their recruitment to sites of infection.
These cells are the main line of defense in the non-specific immune system by interacting, identifying, capturing cellular
debris, foreign particles or invading microorganisms, and eliminating the pathogens that might cause infection.[5]
Phagocytic cells in the innate immune system utilize a number of processes to carry out their function, including
chemotaxis to sites of infection, production of chemicals, enzymes, chemokines and cytokines that initiate inflammation
and other immune responses, as well as induce apoptosis and engulf infected cells. [5, 8, 11]
In addition, macrophages and dendritic cells also serve as professional antigen-presenting cells (APCs) that display a
fragment of foreign antigen complexed with MHC II molecule on their surface. Cells from adaptive immune system,
such as T cells, recognize and interact with the antigen-class II MHC molecule complex on the membrane of the antigen
presenting cell. An additional co-stimulatory signal such as B7 is then produced by the antigen presenting cell, leading
to activation of the T cell which triggers adaptive immunity. [8, 11]
Neutrophils, eosinophils and basophils are classified together as granulocytes. Neutrophils are the most common
leukocyte type in the blood and are the major responders to inflammation and infection. Eosinophils and basophils
along with mast cells are often associated with allergic reactions, but normally carry out protective response in killing
pathogens such as parasites.
Natural killer (NK) cells also known as large granular lymphocytes (LGL) because they resemble lymphocytes in their
morphology, except that they are slightly larger and have numerous granules in their cytoplasm contain special proteins
such as perforin and proteases known as granzymes.[5] They can be identified by the presence of CD56 and CD16 and a
lack of CD3 cell surface markers. NK cells can nonspecifically kill viral infected cells and tumor cells by releasing
perforin that forms pores in the cell membrane of the target cell through which the granzymes and associated molecules
can enter, inducing apoptosis of infected cells and preventing the spread of virus. [22] The killing becomes more efficient
upon exposure to IL-2 and IFNγ, wherein NK cells become lymphokine-activated killer (LAK) cells, which are capable of
killing malignant cells. Continued exposure to IL-2 and IFNγ enables the LAK cells to kill transformed as well as
malignant cells. It should be noted that anti-viral infection reactions and tumor surveillance of NK cells are not
inflammatory responses.
For a long time, researchers questioned how NK cells can distinguish a normal cell from a virus-infected or malignant
cell. Now we know that NK cells have two kinds of receptors on their surface – a killer activating receptor (KAR) and a
killer inhibiting receptor (KIR). When the KAR encounters its ligand, a killer activating ligand (KAL) on the target cell,
the NK are capable of killing the target. However, if the KIR also binds to its ligand then killing is inhibited even if KAR
binds to KAL. The ligands for KIR are MHC class I molecules. So, as long as a target cell expresses class I MHC molecules,
it will not be killed by NK or LAK cells even if it expresses KAL. Normal cells constitutively express MHC class I
molecules on their surface, however, virus infected and malignant cells down regulate expression of class I MHC. Thus,
NK and LAK cells selectively kill virus-infected and malignant cells while sparing normal cells. [29-32]
Cells capable of killing foreign and altered self target cells in a non-specific manner are also granted a name, Killer (K)
cells. NK cells, activated macrophages and eosinophils belong to this group of cells. Killer cells that carry Fcγ receptors
like NK and macrophages for IgG antibodies and Fcå receptor like eosinophils for IgE antibodies can mediate antibodydependent cellular cytotoxicity (ADCC). In ADCC, bound antibodies direct the K cells to the target cells, initiating cell
killing. These cells play an important role in the innate immune system. [22]
g
d
T cells are here counted in innate immune system because they exhibit characteristics that place them at the border
between innate and adaptive immunity. One on hand, γδ T cells may be considered a component of adaptive immunity
in that they rearrange TCR genes to produce junctional diversity and develop a memory phenotype. However, the
various subsets may also be considered part of the innate immune system where a restricted TCR or NK receptors may
be used as a pattern recognition receptor. [23-28]
7
Table 3 : Cellular components involved in the innate immunity system
Cell
Function
Product
Location
Reported Markers
Reference
Activation
Receptors
Mast cells
against pathogens, wound
healing, allergy and
anaphylaxis,
histamine heparin
connective
tissue and
mucous
membranes
CD9, CD33,
CD43, CD45,
CD54, CD117
(c-kit, SCF
receptor),
HLA-class I,
IgE
[9-10]
IgE:allergen
attachment
FcåRI
Moving to the
areas between
cells in pursuit
of invading
pathogens.
Fcg
Rs,
CD11c,CD14,
CD16/CD32,
CD68, CD82,
CD163 HLADM, MHC
class
[5, 18, 19]
LPS, LBP
IFNg
, MSP, IL4, IL-13,
MHC class II, Fcg
receptors (I-III),
B7-1, B7-2,
Scavenger
receptors,
Complement
receptors,
MSPR,TLR4,
IFNg
Rs, CXCRs,
IL-4Ra, IL-13Ra1
b
2-integrins, Fcg
receptors, lselectin,
complement
receptor 1 (CR-1),
C5a receptor,
decay-accelerating
factor (DAF),
intercellular
adhesion
molecule-1
(ICAM-1) and
ICAM-3
recruits neutrophils and
macrophages,
chemokines, or
chemotactic
cytokines
dilates blood vessels
Macrophages
Large phagocytic cells,
chemotaxis,
phagocytosis
destroy bacteria
through respiratory
burst, inflammation,
apoptosis, antigen
presentation
chemokines/cytoki
nes (IL-8, Rantes,
MIP1a, MIP1b,
MIP-2, IP-10, IFNã,
IL-1a, IL-1b, TNF,
IL-6, IL-12, TGFb,
PDGF, FGFb,
VEGF, IGF), Fas
Ligand
oxidizing agents
including hydrogen
peroxide, free
oxygen radicals and
hypochlorite,
Defensins and the
serine proteases
neutrophil elastase
and cathepsin G
the first cells to
arrive at the site
of an infection.
CD11b, CD15,
CD66, CD66b,
Ly-6G (for
mouse)
[11, 12, 17]
IL-8, IFNg
C5a,
most abundant
type of
phagocyte
phagocytic cells,
chemotaxis,
phagocytosis, destroy
bacteria through
respiratory burst
Dendritic cells
[Myeloid
dendritic cells
(mDC),
Plasmacytoid
dendritic cells
(pDC)]
phagocytic cells,
phagocytosis, antigen
presentation (TH cell
activators) serving as a
link between the innate
and adaptive immune
systems
Cytokines (IL-12
by mDC, IFN-a by
pDC)
Skin
(Langerhans
cells), mucosa
CD1a, CD11c,
CD40,
[8, 13, 16]
MHC class II, B7s,
TLRs, LTb
Rs
TLRs, BDCA-2,
BDCA-3, BDCA-4,
CD40，LTb
Rs
Basophils
against parasites, allergic
reactions (such as asthma)
histamine
Infectin site
Ly-6G (for
mouse)
[5, 21]
FcåR TLR
Eosinophils
killing bacteria and
parasites, allergic
reactions
toxic proteins and
free radicals
Infectin site
Cd15, Ly-6G
(for mouse),
CD67
[11, 20]
FcåR
Natural killer
cells, or large
granular
lymphocytes
attack and destroy tumor
cells, and virally infected
cells by inducing
apoptosis
perforin and
granzymes,
cytokines (IFNã,
IL-4)
Infectin site
Human: CD16,
CD56,
CD94/NKG2A/B
Mouse: Ly49,
NK1.1/NK1.2
[5, 22, 2932]
IFNa
/b
, IL-2,
IFNã, IL-12,
Cd1d
FcR, KAR, KIR,
CD94/ NKG2,
Ly49, LIR
g
d
T cells
bridge between innate
and adaptive
responses
abundance in
the gut
mucosa
g
d
TCR, CD94,
Vg
9/Vd
2
[23-28]
PRR: Vg
9/Vä2
g
d
TCR, CD94,
Vg
9/Vä2
Neutrophils,
8
reactive oxygen
species,
Cathepsins,
lysozyme, PLA2,
iNOS, MMPs (1, 2,
7, 9, 12),
SCF receptor (ckit, Cd117)
TLR 2 & TLR 4
(mDC), TLR 7
& TLR 9 (pDC)
The markers
BDCA-2,
BDCA-3, and
BDCA-4 for
discriminate
among the
types
Pattern recognition receptors (PRRs) in innate immunity
P
hagocytic cells have a variety of receptors on their cell membranes that recognize distinct molecular patterns on
infectious agents. There are three groups of PRRs: 1) Secreted PRRs, 2) Phagocytic receptors and 3) Toll-like
receptors (TLRs). Secreted PRRs are molecules that circulate in blood and lymph system such as complement.
Phagocytic cells have a receptor for the 3rd component of complement, C3b. The binding of C3b-coated bacteria to this
receptor results in enhanced phagocytosis and stimulation of respiratory burst. Phagocytic cells also have surface
receptors that bind the pathogen for engulfment, such as Fc receptors and Scavenger receptors. Toll-like receptors are
cell surface or intracellular transmembrane receptors that bind to pathogens or other pathogen-associated material and
initiate signaling leading to the release of cytokines. These receptors were so-called Toll-like receptors due to their
homology to receptors first discovered and named in Drosophila. [33] Macrophages and dendritic cells have a set of Tolllike receptors that recognize broad types of PAMPs on infectious agents. Binding of infectious agents to Toll-like
receptors recruits intracellular adapter molecules that propagate a signal. Four adapter molecules are known to be
involved in TLR signaling. These proteins are known as MyD88, Tirap (also called Mal), Trif, and Tram.[7, 8, 37-39] The
adapters activate other molecules within the cell, including certain protein kinases (IRAK1, IRAK4, TBK1, and IKKi)
that amplify the signal. The TLRs will then identify the nature of the pathogen and turn on an effector response. These
signaling cascades direct the expression of various cytokine genes and the release of inflammatory cytokines (IL-1,
TNF-alpha and IL-6) by phagocytes, ultimately leading to the induction or suppression of genes that orchestrate the
inflammatory response. In all, thousands of genes are activated by TLR signaling, and collectively, the TLRs constitute
one of the most powerful and important gateways for gene modulation. Figure 2 diagrams the signaling pathway of
TLRs.
Figure 2 : Signaling pathway of toll-like receptors
9
In mammals, there are about 13 TLRs reported so far[34-36], each of which, specializes in a subset of PAMPs. See Table 4 for
the summary of known Mammalian Toll-like Receptors.
Table 4 : Summary of Mammalian Toll-like Receptors
10
Receptor
Ligand(s)
TLR 1
triacyl lipoproteins
TLR 2
lipoproteins; gram positive
peptidoglycan; lipoteichoic
acids; fungi; viral
glycoproteins
TLR 3
Target Pathogen(s)
Adapter(s)
Location
MyD88/MAL
cell surface
Gram-positive bacteria (e.g.
Streptococci, Staphylococci),
Viruses
MyD88/MAL
cell surface
double-stranded RNA (as
found in certain viruses),
poly I:C
Viruses
TRIF
cell
compartment
TLR 4
lipopolysaccharide
(endotoxin); viral
glycoproteins
Gram-negative bacteria (e.g.
Salmonella, E. coli O157:H7)
MyD88/MAL/TRIF/TRAM
cell surface
TLR 5
flagellin
Mobile bacteria (e.g. Listeria)
MyD88
cell surface
TLR 6 (Forms a
heterodimer with TLR-2)
diacyl lipoproteins, certain
lipids
MyD88/MAL
cell surface
TLR 7
small synthetic
compounds; singlestranded RNA
ssRNA viruses (e.g. Influenza,
Measles, Mumps)
MyD88
cell
compartment
TLR 8
small synthetic
compounds; singlestranded RNA
ssRNA viruses (e.g. Influenza,
Measles, Mumps)
MyD88
cell
compartment
TLR 9
unmethylated CpG DNA
CpG DNA pathogen
MyD88
cell
compartment
TLR 10
unknown
unknown
cell surface
TLR 11 (not in human)
Profilin
MyD88
cell surface
TLR 12 (not in human)
unknown
unknown
unknown
TLR 13 (not in human)
unknown
unknown
unknown
Protozoans (Apicomplexa)
Innate immunity influences adaptive immunity
T
he innate immune system does not act separately from the adaptive immune system. In fact, the innate immunity
can trigger adaptive immunity. This can occur in several ways. 1) Macrophages and dendritic cells are phagocytes
that are also responsible for "presenting" antigens to T cells to initiate both cell-mediated and antibody-mediated
adaptive immune responses. 2) The interaction of PAMPs and TLRs on dendritic cells causes them to secrete cytokines,
including interleukin 6 (IL-6), which interfere with the ability of regulatory T cells to suppress the responses of effector T
cells to antigen. 3) Pathogens coated with fragments of the complement protein C3 are not only opsonized for
phagocytosis but also bind more strongly to B cells that have bound the pathogen through their BCR. This synergistic
effect enables antibody production to occur at doses of antigen far lower than would otherwise be needed. 4) B cells are
also antigen-presenting cells that function similarly to macrophages and dendritic cells. They bind antigen with their
BCRs and engulf it into lysosomes, where the digested fragments are incorporated into class II MHC molecules, which
are then presented to T cells. In addition, B cells also have TLRs. When a PAMP such as LPS binds the TLR, it enhances
the response of the B cell to the antigen.
All in all, adaptive immunity is not possible without the assistance of the mechanisms of innate immunity.
Concluding remarks
T
he innate immune system, as a first line of defense against pathogens, involves a diverse collection of
molecules and mechanisms that include chemicals, enzymes, cytokines, chemokines, and effector cells
(see tables 1-4). Overall, many different cellular processes are involved, including cell signaling via receptors,
phagocytosis, targeted cell killing, and apoptosis. BioLegend provides a variety of reagents, antibodies, and
tools for study of the innate immune system including leukocyte phenotyping, cytokine and chemokine
measurements, receptor detection, measurement of apoptosis and cell signaling molecules.
11
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