Chapter 4

Innate Immunity
Xulong Zhang
Department of Immunology,
School of Basic Medical Sciences,
CMU
2023.9.11
Contents
Overview of Innate Immunity
Functions of Innate Immune Responses
Comparative Features of Innate and Adaptive Immunity
Evolution of Innate Immunity

Recognition of Microbes and Damaged Tissue by the Innate Immune System

Cellular Pattern Recognition Receptors
Toll-Like Receptors
Cytosolic Receptors for Pathogen-Associated Molecular Patterns and Damage-Associated Molecular Patterns,
Other Cell-Associated Pattern Recognition Receptors
Cellular Components of the Innate Immune System
Epithelial Barriers, Phagocytes, Dendritic Cells, Cytokine-Producing Innate Lymphoid Cells, Natural Killer Cells,T
and B Lymphocytes With Limited Antigen Receptor Diversity, Mast Cells
Soluble Effector Molecules of Innate Immunity
The Complement System, Pentraxins, Collectins and Ficolins

The Inflammatory Response

The Major Proinflammatory Cytokines of Innate Immunity
Sequence of Events in Inflammation: Vascular Changes and Leukocyte Migration Into Tissues, Ingestion and Killing
of Microbes by Activated Phagocytes
Role of Macrophages in Tissue Repair
Systemic and Pathologic Consequences of Inflammation
The Antiviral Response
Stimulation of Adaptive Immunity
Mechanisms that Limit Innate Immune Responses
Summary

2
Overview of Innate Immunity
Characteristic:

 Always present

 Ready to combat microbes

 Provide early defense

 Nonspecific

 Limited memory

 Linked with adaptive immune

 Many types of cells and soluble

molecules are involved

3
Functions of Innate
Immune Responses
The first line of defense against infections

Serves several essential functions that protect us against microbes

and tissue injury.

Barrier epithelia (epithelial cells and other tissue cells): block microbial entry;
Physical and chemical defenses
Tissue-resident sentinel cells (macrophages, mast cells, and DCs):
Major components detect microbes that have breached epithelia and initiate host responses
of the innate Leukocytes (neutrophils, monocytes (macrophages in tissues), NK cells:
immune system enter the tissues from the blood and eliminate microbes that have invaded
through epithelia and also remove damaged host cells, also initiates the
process of tissue repair

Plasma proteins: combat microbes within and outside the circulation.

4
Mechanisms

infection in tissues
damaged or dead cells
accumulations of abnormal substances

inflammation
prevent virus replication

The two major types of protective promote killing of infected cells

reactions of the innate immune Initiate innate immune responses, stimulate adaptive
system are inflammation and immune responses and can influence the nature of the
antiviral defense adaptive responses

remove damaged host cells, also initiates the

process of tissue repair

5
Comparative Features of Innate
and Adaptive Immunity
Innate immunity Adaptive immunity
Rapidly
do not require prior exposure to the develop over several days as clones of
microbe naive antigen-specific lymphocytes
present in sufficient quantities even expand and differentiate into functional
before infection effector cells.

Nonspecific specificity
PAMP/DAMP Diversity --TCR/BCR
fully functional or quickly become Clone selection
activated
little or no memory：no Memory: repeated exposure to a
appreciable change in the quality microbe enhances the
or magnitude of the response upon rapidity, magnitude, and effectiveness
repeated exposure of adaptive immune
responses.

6
Comparative Features of Innate
and Adaptive Immunity
固有免疫应答 适应性免疫应答
参与细胞 皮肤黏膜上皮细胞、巨噬细胞、中性粒 αβT 细 胞 （ 包 括 Th1 细 胞 、 Th2 细 胞 、
细胞、肥大细胞、树突状细胞、NK细胞、Th17 细 胞 、 Tfh 细 胞 、 Treg 细 胞 、 CTL
ILC2、NKT细胞、γδT细胞、B1细胞 等）、B2细胞

效应分子 补体、细胞因子、抗菌蛋白、酶类物质、特异性抗体、细胞因子、穿孔素、颗粒酶、
穿孔素、颗粒酶、FasL FasL

作用时相 即刻～96小时 96小时后

识别受体 模式识别受体/有限多样性抗原识别受体 特异性抗原识别受体（胚系基因重排后产
（胚系基因直接编码），较少多样性 生），具有高度多样性
识别特点 直接识别PAMP/DAMP及靶细胞表面某 识别APC表面MHC分子提呈的抗原肽或
些特定表位分子或CD1提呈的脂类/糖脂 FDC表面捕获的抗原分子，具有高度特异
类抗原，具有泛特异性 性
作用特点 募集活化后迅速产生免疫效应，有限的 经克隆选择、增殖分化为效应细胞后发挥
免疫记忆功能 免疫作用，具有免疫记忆功能，可发生再
次应答
维持时间 较短 较长
7
Evolution of Innate Immunity

Phylogenetically the oldest part of the immune system.

Defensins, Toll like receptors, NF-κB: about 750 million years ago
Adaptive immune system developed about 350 to 500 million years ago

850 genes that are directly related to innate immune responses

575 for adaptive immunity.

8
Recognition of Microbes and Damaged
Tissue by the Innate Immune System
Innate immune system recognizes only
about 1000 products of microbes and
damaged cells relatively limited set of
molecular structures
Essential for survival of the microbes:
dsRNA, LPS, LTA
Pathogen-associated
molecular patterns (PAMPs)
Detects the presence of infection but
not the specific pathogens.
核酸类nucleic acids that are unique to or more abundant in
microbes than in host cells, such as double-stranded RNA
found in replicating viruses and unmethylated CpG DNA
sequences found in bacteria
糖类complex lipids and carbohydrates that are synthesized
by microbes but not by mammalian cells, such as
lipopolysaccharide (LPS) in gram-negative bacteria,
lipoteichoic acid in gram-positive bacteria, and
oligosaccharides with terminal mannose residues found in
microbial but not in mammalian glycoproteins.
蛋白类features of proteins that are found in microbes, such
as initiation by N-formylmethionine, which is typical of
bacterial proteins
9
PAMP

TABLE 4.2 10
 DAMP

Cell damage caused by infections indicate sterile injury to cells: such as chemical toxins, burns,
trauma, or loss of blood supply.
generally not released from cells dying by apoptosis.

innate immune system also recognizes endogenous molecules,

called damage-associated molecular patterns (DAMPs)

a subset of DAMPs and are

sometimes called alarmins

TABLE 4.2 11
 PRR
innate immune system uses germline-encoded invariant receptors to recognize
microbial and other products

The cellular receptors for PAMP/DAMP are called pattern

recognition receptors (PRR).

Expressed by phagocytes (primarily macrophages and

neutrophils), DCs, epithelial

Present in different locations in cells, and soluble molecules

in the blood and mucosal secretions

On the surface, in phagocytic vesicles, and in the cytosol of

various cell types, all of which are locations where microbes
or their products may be present

Activate signal transduction pathways that promote the

antimicrobial and proinflammatory functions

Soluble PRR molecules are responsible for facilitating the

clearance of microbes by enhancing uptake into phagocytes or
by activating extracellular killing mechanisms.

FIGURE 4.1 Cellular locations of pattern recognition receptors of the innate immune system 12
PRR

TABLE 4.3 13
PRR

TABLE 4.3 14
PRR

Receptors of the innate Genes encoding receptors of

immune system adaptive immunity
encoded by inherited (germline) genes somatic recombination of gene segments
in the precursors of mature lymphocytes.

Low diversity: 100 different receptors High diversity: millions of variations of

belonging to several protein families immunoglobulins [Igs] and T cell
receptors)

Low specificities: distinguish only High specificities: distinguish between

classes of microbes, or only damaged antigens of different microbes of the
cells from healthy cells, but not same class and even different antigens of
particular species of microbes or cell one microbe
types.

15
PRR

TABLE 4.1 16
The innate immune system does not react against normal, healthy
cells and tissues.

WHY?

normal cells do not produce ligands for innate immune receptors

these receptors are located in cellular compartments where they do not

encounter host molecules they could recognize

regulatory proteins expressed by normal cells prevent activation of

various components of innate immunity.

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Cellular Pattern Recognition Receptors

Phagocytes, especially
macrophages, and DCs express
the widest variety and greatest
number of these receptors.

FIGURE 4.1 Cellular locations of pattern recognition receptors of the innate immune system 18
Toll-Like Receptors

between 16 and 28 leucine-rich repeats

(conserved LxxLxLxxN motifs)

recognize microbes in different cellular locations

structurally diverse

products of all classes of microorganisms

endogenous molecules whose expression or location

indicates cell damage：TLR2 and TLR4

FIGURE 4.2 Structure, location, and specificities of mammalian Toll-like receptors 19

Toll-Like Receptors

TLR recognition of microbial ligands results in

the activation of several signaling pathways

Receptor-PAMP----TIR----Adaptor-----Kinase------
transcription factors (NF-κB, interferon response
factor 3 (IRF3), and IRF7)----- induce the
expression of genes important for inflammatory
(inflammatory cytokines (e.g., tumor necrosis
factor [TNF] and IL-1),) and antiviral responses
(interferon (IFN)-α and IFN-β,)

sense pathogens outside cells or in endosomes

CYTOSOL？

FIGURE 4.3 Signaling pathways and functions of Toll-like receptors 20

Cytosolic Receptors for
PAMP/DAMP

PRR that detect PAMP or DAMP in the cytosol:

viral gene translation and viral particle assembly

NOD-like receptors, retinoic acid–inducible

gene (RIG)-like receptors, and cytosolic DNA
sensors
Promote inflammation or type I IFN production

The formation of enzyme complexes called

inflammasomes, which proteolytically generate a
biologically active inflammatory cytokine IL-1β
from an inactive precursor and also may induce
cell death.

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NOD-Like Receptors (NLR)

a family of more than 20 different cytosolic

proteins recognize PAMPs and DAMPs recruit
other proteins to form signaling complexes
that promote inflammation.

C-terminal leucine-rich repeat domain that

senses the presence of ligand

a central NOD (nucleotide oligomerization

domain, also called NACHT) domain required
for NLR proteins to bind to one another and
form oligomers
an N-terminal effector domain, which
recruits other proteins to form signaling
complexes
NLRB: uses the effector domain;
NLRC: uses CARDs domain
NLRP: uses pyrin domains
FIGURE 4.4 NOD-like receptors 22
NOD1 and NOD2

EXPRESSION: mucosal epithelial cells and phagocytes

NOD1 recognizes a glycosylated tripeptide called
diaminopimelic acid (DAP), derived mainly from gram-
LIGAND: bacterial cell wall peptidoglycans.
negative bacterial peptidoglycan, whereas NOD2
recognizes a distinct molecule called muramyl
dipeptide (MDP), derived from both gram-negative and
gram-positive peptidoglycans.

Both NOD1 and NOD2 appear to be important in

innate immune responses to bacterial
Certain NOD2 gene polymorphisms: defective innate
responses against commensal and pathogenic
organisms in the intestine, gain access to the intestinal
wall, they may trigger chronic inflammation: Crohn’s
When oligomers of NODs recognize their ligands, a disease; gain-of-function mutations of NOD2 that cause
conformational change occurs that allows the CARD increased NOD signaling and NF-κB activation lead to a
effector domains of the NOD proteins to recruit systemic inflammatory disease called Blau syndrome.
multiple copies of the kinase RIP2, forming a signaling
complex that has been called the NOD signalosome.

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Cytosolic DNA Sensors and
the STING Pathway

Cytosolic DNA sensors (CDSs)

PAMP: intracellular
detect double stranded microbes
(ds) DNA in the cytosol The STING (stimulator of IFN genes) pathway

STING independent pathways: RNA polymerase 3

DAMP: host DNA
damage AIM2

distinguish and react to microbial or damaged activates the RIG-I pathway

self DNA and not normal self DNA is partly
related to the location of most of the DNA
sensors in the cytosol
forms an inflammasome
initiate antimicrobial responses,
including type I IFN production and
autophagy

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cGAS-STING Pathway

cytosolic dsDNA activates the enzyme cGAS (cyclic

guanosine monophosphate–adenosine
monophosphate [GMPAMP] synthase), which
generates a signaling molecule called cGAMP
(cyclic GMP-AMP).
DAI (DNAdependent activator of IFN-regulatory factors)
and IFI16 (interferon inducible protein 16).
cGAMP bind STING, inducing a
conformational change

translocation from the endoplasmic

reticulum to the Golgi apparatus.

STING activates the TBK1 kinase

phosphorylates and activates the IRF3

transcription factor, leading to type I IFN gene
expression and autophagy
Autoinflammatory Syndromes
25
RIG-Like Receptors

RIG-like receptors (RLRs) are cytosolic sensors of viral RNA

RIG-I (RIG-I will only recognize RNA with a 5′ triphosphate moiety, RIG-I can recognize uncapped
short single-stranded RNA or dsRNA) and MDA5 (recognizes long dsRNA (1 to 6 kb), MDA-5 can
recognize dsRNAs with or without a 5′ cap)

recruited to the outer mitochondrial membrane

by the MAVS (mitochondrial antiviral signaling)
protein

MAVS polymerizes

phosphorylation and activation of IRF3 and

IRF7, as well as NF-κB,

production of the antiviral type I IFNs

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Inflammasomes

Inflammasomes are multiprotein enzymatic

complexes that form in the cytosol

Either when sensor proteins in the cytosol directly

recognize microbial products or when sensors detect
changes in the amount of endogenous molecules or
ions in the cytosol

Most inflammasomes (so-called canonical

inflammasomes) are composed of oligomers
of a sensor, caspase-1, and an adaptor

Produce proteolytically active caspase-1

inflammation mediated by IL-1β and IL-18

Pyroptosis
27
Inflammasomes

Inflammasomopathies or IL-1β–activation syndromes

Excessive amounts of endogenous substances deposited in tissues: cholesterol crystals

within macrophages in atherosclerosis, free fatty acids and lipids in adipose tissue in
obesity-associated metabolic syndrome and type 2 diabetes, and β-amyloid in Alzheimer’s
disease. Gout is a painful inflammatory condition deposition of monosodium urate crystals
in joints.

Calcium pyrophosphate crystals: inhalation of silica and asbestos

gain-of-function mutations: familial Mediterranean fever, caused by mutation of the MEFV

gene, which encodes pyrin.

mutations in NLRP3 (also known as cryopyrin) are called cryopyrin-associated periodic

syndromes (CAPS).

IL-1 antagonists
MCC950

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Other Cell-Associated Pattern
Recognition Receptors

CLRs：C-Type Lectins Receptors for Microbial Carbohydrates Ca -dependent manner

Mannose Receptor (CD206); Dectin-1 (CD369) Dectin-2 and Mincle; Langerin (CD207) and DC-SIGN
(CD209)

recognize carbohydrates on the surface of microbes

facilitate the phagocytosis of the microbes

Secretion of cytokines
promote inflammation and subsequent adaptive immune responses

Scavenger Receptors

scavenger receptor A (SR-A) and CD36: mediating the uptake of oxidized lipoproteins into cells.
bacterially derived lipoteichoic acid and diacylated lipopeptides.

Formyl-Peptide Receptors甲酰肽受体(FPR1)

29
Cellular Components of the
Innate Immune System

The main functions of the cells of the innate immune system:

1. serve as barriers against infections,

2. act as sentinels to detect microbes and damaged cells in tissues

3. perform effector functions that eliminate microorganisms.

4. critical for stimulating subsequent adaptive immune responses

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 Epithelial Barriers

Intact epithelial surfaces form physical barriers：

skin and the mucosal surfaces of the gastrointestinal,
respiratory, and genitourinary tracts.

PHYSICAL ROLE：specialized epithelial cells form

tight junctions: preventing the entry of microbes

Mucus, a viscous secretion containing glycoproteins

called mucins, is produced by respiratory,
gastrointestinal, and urogenital epithelial cells and
physically impairs microbial invasion.

ciliary action

antimicrobial peptides: defensins and the

cathelicidins

FIGURE 4.7 Epithelial barriers 31

Phagocytes

macrophages and neutrophils

疾病中显示作用：The essential role that phagocytes play in innate immune defense

against microbes is demonstrated by the high rate of bacterial and fungal infections in
patients with low blood neutrophil counts caused by bone marrow cancers or
chemotherapy and irradiation for cancer (which destroys immature cells in the bone
marrow) and in patients with inherited deficiencies in the functions of neutrophils and
macrophages.

introduced these cell types in Chapter 2,

32
Dendritic Cells

Dendritic cells rapidly and efficiently detect invading microbes because of their location in
tissues and their expression of numerous pattern recognition receptors for PAMPs and
DAMPs.

Secrete inflammatory cytokines that promote recruitment of additional leukocytes from the
blood.

Plasmacytoid subset of DCs is a major source of the antiviral cytokines type I IFNs,
produced in response to viral infections.

Important bridge between innate and adaptive immunity.

33
Cytokine-Producing
Innate Lymphoid Cells
The feature of ILCs that makes them potentially
bone marrow–derived cells with lymphocyte important for early host defense is that they are
morphology always resident in epithelial barrier tissues, poised
to react against microbes that breach those barriers.
from the same common lymphoid precursor that gives
rise to B and T cells
work in a temporally coordinated way, with ILCs
being the early innate participants, activated by
produced cytokines similar to those made by helper T alarmins in infected tissues, and the helper T cells
cells but lacked TCRs appearing later as part of adaptive immunity.

Three subsets of ILCs, called ILC1, ILC2, and ILC3,

produce different cytokines and express different The actions of ILC1s, NK cells, and Th1 cells are
transcription factors, analogous to the Th1, Th2, and sometimes grouped under type I immunity。ILC2s
Th17 subsets of CD4 + T lymphocytes and Th2 cells are type II immunity, and ILC3s and
Th17 cells comprise type III immunity.

34
 ILC

ILC1s produce IFN-γ and express the transcription factor T-BET,

like Th1 cells. ILC2s produce mainly IL-5 and IL-13. and express
the transcription factor GATA3, like Th2 cells. ILC3s produce IL-
22 and/or IL-17 and express the transcription factor RORγt, like
Th17 cells.

ILC1s are likely important for defense against intracellular

microbes. ILC2s are important for defense against helminthic
parasites, and they also may contribute to allergic diseases.
ILC3s are found at mucosal sites and participate in defense
against extracellular fungi and bacteria, as well as in
maintaining the integrity of epithelial barriers. Lymphoid tissue–
inducer (LTi) cells are a subtype of ILC3s, which, in addition to
secreting IL-17 and IL-22, also express the membrane molecule
lymphotoxin and secrete TNF, both of which are required for the
normal development of lymphoid organs

35
Natural Killer Cells
NK cells are cytotoxic cells that play important roles in innate immune responses, mainly
against viruses and intracellular bacteria.
CD56+ CD3- Most human blood NK cells also express CD16, an IgG Fc receptor

FUNCTION：killing infected cells, similar to the adaptive immune CTLs killer cells.
cytoplasmic granules
No primer activation
Secrete IFN-γ and thus resemble ILC1s

ILC1: in tissue, not in blood and lymphoid organs

NK : in blood 5%-20% of lymphocytes, rare in lymphoid organs, rich in liver and placenta

36
Functions of Natural Killer Cells

The effector functions of NK cells are to kill infected cells Perforin/granzymes apoptosis?
and to produce IFN-γ, which activates macrophages to
destroy phagocytosed microbes
FasL
NK Vs CTLs: granule exocytosis releases these proteins
adjacent to the target cells.

Early in the course of a viral infection, expanded and LT-a，TNF-a

activated by recognition of activating ligands on the
infected cells and by the cytokines IL-12 and IL-15

CTLs can become fully active, which usually takes 5 to 7

days. NK cells also may be important later in the course of
viral infection by killing infected cells that have escaped
CTL-mediated immune attack by reducing expression of
class I major histocompatibility complex (MHC) molecules.
NK cell–derived IFN-γ increases the capacity of
macrophages to kill phagocytosed bacteria, direct the
differentiation of naive T cells into Th1 cells
FIGURE 4.9 Functions of natural killer cells 37
2020 May 29;368(6494):eaaz7548. doi: 10.1126/science.aaz7548.
 Subsets

Some human NK cells do not express CD16, nor are they cytotoxic, but they do produce abundant IFN-γ.

Cytokines can enhance the functional responses of NK cells: IL-12, IL-15, IL-18, and type I IFNs

39
 Activating and Inhibitory
Receptors of Natural Killer Cells
Distinguish infected and stressed cells from healthy cells

Balance between signals that are generated by activating and inhibitory receptors, germline DNA–encoding
Activating receptors recognize ligands on infected and injured cells, and the inhibitory receptors recognize
ligands on healthy normal

FIGURE 4.10 Functions of activating and inhibitory receptors of natural killer cells. 40
Activating receptors on NK cells

Recognize a heterogeneous group of Ligands, mainly

on cells that have undergone stress, are infected with
microbes, or are neoplastic

1. Killer cell Ig-like receptors (KIRs)

2. C-type lectins：lectin-like NK cell–activating

receptor is NKG2D-DAP10----MIC-A/B, ULBP family，
increased by cellular stress

3. antibody-dependent cell-mediated cytotoxicity:

CD16 (FcγRIIIA): low-affinity receptor for IgG
antibodies IgG1 and IgG3

immunoreceptor tyrosine-based activation motifs (ITAMs),

FIGURE 4.11 Structure and ligands of receptors of natural killer cells 41

Inhibitory receptors on NK cells

Inhibitory receptors of NK cells recognize class I MHC molecules, which are cell surface
proteins normally expressed on all healthy nucleated cells in the body

Normal cells express class I MHC molecules, and many viruses and other causes of cell
stress lead to a loss of cell surface expression of class I MHC

NK inhibitory receptors:
1. KIR family inhibitory KIRs bind a variety of different class I MHC molecules.
2. lectin-like, such as the CD94/NKG2A heterodimer, which recognizes HLA-E.

immunoreceptor tyrosinebased inhibition motifs (ITIMs)

FIGURE 4.11 Structure and ligands of inhibitory receptors of natural killer cells 42
NK receptors

43
Missing self and induced self

Nat Immunol. 2020 Aug;21(8):835-847. 44

Nat Rev Drug Discov. 2022 Aug;21(8):559-577. 46
iNKT, γδT, MAIT, B1 cells

T and B Lymphocytes With Limited Antigen Receptor Diversity

Lymphocytes express antigen receptors that are structurally the same as those of T and
B cells, but these receptors have very little diversity.

T cells with limited antigen receptor diversity include invariant natural killer T (iNKT)
cells, γδ T cells, mucosa-associated invariant T (MAIT) cells

B cell subsets that produce antibodies with a limited set of specificities include B-1 cells
and marginal-zone B cells.

47
Soluble Effector Molecules of
Innate Immunity
the humoral branch of innate immunity
early defense against pathogens that enter the circulation or are present outside host cells at
some stage of their life cycle.

The major components of the humoral innate immune system are the complement system,
collectins, pentraxins, and ficolins

By binding to microbes, they act as opsonins and enhance the ability of

macrophages and neutrophils to phagocytose the microbes.
two major ways
After binding to microbes, soluble mediators of innate immunity promote
inflammatory responses that bring more phagocytes to sites of infections and they
may also directly kill microbes.

48
The Complement System
Complement activation involves proteolytic cascades
Enzymatic cascades result in tremendous amplification of the amount of proteolytic products
These products perform the effector functions of the complement system.

opsonize microbes

promote the recruitment of

phagocytes to the site of
infection directly kill the
microbes

FIGURE 4.12 Pathways of complement activation

49
The Complement Activation
classical pathway: C1q to detect antibodies bound to the surface of microbes, serine
proteases, called C1r and C1s, become active and initiate a proteolytic cascade. one of
the major effector mechanisms of the humoral arm of adaptive immune responses

The alternative pathway: C3 directly recognizes certain microbial surface structures, such as
Recognition of bacterial LPS. Because microbes lack these regulatory proteins, the spontaneous activation
molecules on can be amplified on microbial surfaces. distinguish normal self from foreign microbes on the
microbial surfaces basis of the presence or absence of the regulatory proteins.

lectin pathway: mannose-binding lectin (MBL), which recognizes terminal mannose residues on
microbial glycoproteins and glycolipids, similar to the mannose receptor on phagocytes. two
zymogens called MASP1 (mannose-associated serine protease 1 or mannan-binding lectin-
associated serine protease) and MASP2, with functions similar to those of C1r and C1s

50
 The Complement Activation

晚期adaptive immunity
阶段启动

早期innate immunity
阶段启动

正反馈放⼤信号，此处的C3b放⼤
了凝集素途径的C3b作⽤

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The Complement Activation

sequential recruitment and assembly of additional complement proteins into protease complexes

C3 convertase cleaves the central protein of the complement system, C3, producing C3a and C3b

C3b molecules can deposit on the surface of a microbe within 2 or 3 minutes. C3b serves as an
opsonin to promote phagocytosis of the microbes.

C3a, is released and stimulates inflammation by acting as a chemoattractant for neutrophils,

by inducing mast cell degranulation, and by directly increasing vascular permeability so that
plasma proteins and fluid leak into sites of infections.

C3b binds other complement proteins to form a protease called C5 convertase that cleaves C5,
generating a released peptide (C5a) and a larger fragment (C5b) that remains attached to the
microbial cell membranes. C5a exerts the same proinflammatory effects as C3a and is more potent.
C5b initiates the formation of a complex of the complement proteins C6, C7, C8, and C9, which are
assembled into a membrane pore called the membrane attack complex (MAC) that causes lysis of
the cells where complement is activated.

52
Complement associated
diseases

The complement system, activated by the alternative and lectin pathways, is an essential component
of innate immunity

Patients with deficiencies in C3 are highly susceptible to recurrent, often lethal, bacterial
infections. Genetic deficiencies in MAC cause increased susceptibility to only a limited number
of microbes, notably Neisseria bacteria, which have thin cell walls that make them especially
susceptible to the lytic action of the MAC.

The complement system also contributes to cell and tissue injury in many inflammatory and
autoimmune diseases.

53
Pentraxins
Acute-phase proteins elevated in the blood during acute inflammatory reactions, and their increased
production is part of the acute-phase response to infection and other insults.

a phylogenetically old group of structurally homologous pentameric proteins. Prominent members of

this family include the short pentraxins, C-reactive protein (CRP) and serum amyloid P (SAP), and the
long pentraxin PTX3. Both CRP and SAP bind to several different species of bacteria and fungi.

Plasma concentrations of CRP are very low in healthy individuals but can increase up to 1000-fold
during infections and in response to other inflammatory stimuli.

反应过程infections or injury----- phagocytes and DCs ----the cytokines IL-6, IL-1, and TNF---- synthesis by
liver cells----increased CRP---- CRP recognized phosphorylcholine on bacterial membranes or exposed on
apoptotic cells----activate complement by binding C1q and initiating the classical pathway.
自学PTX3 is produced by several cell types, including DCs, macrophages, and endothelial cells, in
response to TLR ligands and inflammatory cytokines, such as TNF, and may be considered an acute-
phase reactant. PTX3 is also stored in neutrophil granules and released as neutrophils die. PTX3
recognizes various molecules on fungi, certain bacteria, and viruses, as well as apoptotic cells, and
activates the classical complement pathway.
54
Collectins and Ficolins

Three members of this family serve as soluble effector molecules in the innate immune system; these
are MBL and pulmonary surfactant proteins SP-A and SP-D.
MBL

MBL, which is a soluble pattern recognition

receptor that binds carbohydrates with terminal
mannose and fucose

MBL also functions as an opsonin by binding to

and enhancing phagocytosis of microbes.

Low MBL levels result in increased

susceptibility to a variety of infections

55
 Ficolins
Ficolins are plasma proteins that are structurally similar to collectins.

Ficolins have been shown to bind several

species of bacteria, opsonizing them and
activating complement in a manner similar to
that of MBL. The ligands of the ficolins
include N-acetylglucosamine and the
lipoteichoic acid component of the cell walls
of gram-positive bacteria.

56
SP-A and SP-D

Surfactant protein A (SP-A) and surfactant protein D (SP-D)

自学They are found in the alveoli of the lungs, and their major functions are to maintain the
ability of alveoli to expand upon inhalation by reducing surface tension of alveolar fluid,
and as mediators of innate immune responses in the lung. They bind to various
microorganisms and act as opsonins, facilitating ingestion by alveolar macrophages.

57
The Inflammatory Response
The principal way is to stimulate acute inflammation, which is the accumulation of leukocytes, plasma
proteins, and fluid derived from the blood at an extravascular tissue site of infection or injury

Leukocytes and plasma proteins must be recruited

to extravascular sites of infection and injury, where
they perform the effector functions that kill
microbes and begin to repair damaged tissue.

Acute inflammatory responses begin with

recognition of microbial PAMPs or DAMPs from
injured host cells by tissue sentinel cells, mainly
macrophages, DCs, and mast cells. These
sentinels respond by secreting mediators that act
on small blood vessels in ways that promote
increased blood flow, delivery of plasma proteins,
and migration of leukocytes into the tissues.

FIGURE 4.14 Acute inflammatory response 58

The Major Proinflammatory
Cytokines of Innate Immunity

Produced mainly by tissue

macrophages and DCs,
• paracrine action
endocrine action
• Different cytokines have similar or
overlapping actions or are functionally
unique.
• The cytokines of innate immunity
serve several roles: inducing
inflammation, inhibiting viral replication,
promoting T cell responses, and limiting
innate immune responses.
• Most important proinflammatory
cytokines of the innate immune system
are TNF, IL-1 and IL-6 in acute
inflammation.

59
 最常⻅的三聚体，另⼀个是Fas
Tumor Necrosis Factor
TNF is a mediator of the acute
inflammatory response to bacteria and
other infectious microbes.

TNF is also called TNF-α to distinguish it from

the closely related TNF-β, which is also called
lymphotoxin.
TNF=TNF-α

TNF-β=lymphotoxin-α（淋巴毒素）

TNF is produced mainly by macrophages, and

also by other cell types, including DCs and
mast cells.

FIGURE 4.15 Structure of the tumor necrosis factor (TNF) receptor with bound TNF 60
 急性炎症和慢性炎症的主要作⽤分⼦

Tumor Necrosis Factor

TNF has multiple local and systemic effects

that account for many of the reactions in
inflammation

TNF is a major contributor to inflammation

in several chronic inflammatory diseases,
and anti-TNF agents have become the
mainstay of treatment of many
of these diseases.

Septic shock, a life-threatening condition

resulting from severe infections, is
mediated in large part by TNF.

FIGURE 4.16 Local and systemic actions of cytokines in inflammation 61

Interleukin-1
IL-1 is also a mediator of the acute inflammatory
response
Myd88
A major cellular source of IL-1 is activated
mononuclear phagocytes, macrophages, neutrophils,
DCs, epithelial cells and endothelial cells.
IL-1 production usually requires two distinct signals, NF-kB
one that activates new gene transcription and
production of a 33-kD precursor pro–IL-1β
polypeptide and a second that activates the
inflammasome to proteolytically cleave the precursor 先表达出来前体 再通过炎性⼩体的活化，产
to generate the 17-kD mature IL-1β protein ⽣caspase-1切割前体

IL-1β gene transcription is induced by TLR, NLR, and

caspase-1再切割
RLR signaling pathways that activate NF-κB, whereas gasdermin D产⽣
pro–IL-1β cleavage is mediated by caspase-1, which is gasdermin在细胞膜打
孔，从⽽让IL-1出膜
activated by inflammasomes. IL-1β may be secreted
through membrane pores formed by gasdermin D.

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Interleukin-6

IL-6 is another important cytokine in acute inflammatory responses that has both local and systemic
effects. It induces the synthesis of acute-phase reactants by the liver and promotes the differentiation
of IL-17–producing helper T cells. IL-6 is synthesized by mononuclear phagocytes, DCs, vascular
endothelial cells, fibroblasts, and other cells in response to PAMPs and DAMPs and in response to IL-1
and TNF.

The IL-6 receptor/gp130 activates the transcription factor STAT3

IL-6 is a major contributor to inflammation in several human inflammatory diseases,

including rheumatoid arthritis, and antibodies specific for the IL-6 receptor are used to treat
some forms of arthritis.

63
 Other Cytokines Produced During Innate Immune Responses

IL-12 is secreted by DCs and macrophages

Stimulates IFN-γ production by ILC1s, NK cells, and T cells
Enhances NK cell– and CTL-mediated cytotoxicity
Promotes differentiation of Th1 cells.
与IL-23共⽤
异源⼆聚体 IL-12 exists as a disulfide-linked heterodimer of 35-kD (p35) and 40-kD (p40) subunits. the p40
subunit is also a component of the cytokine IL-23. Therefore, an antibody specific for p40 blocks
both IL-12 and IL-23 and thus inhibits the IL-12–dependent development of Th1 cells and the IL-
23– dependent development of Th17 cells. This antibody is approved for the treatment of
inflammatory bowel disease and psoriasis, which are caused by Th1 and/or Th17 cytokines.

IL-12 activates the transcription factor STAT4.

64
 IL-18 enhances the functions of NK cells, similar to IL-12.
Production of IL-18, like that of IL-1, is dependent on inflammasomes.

IL-15 stimulates growth and functions of ILC1s, NK cells, and some T cells. IL-15 is structurally
homologous to the T cell growth factor IL-2, and the heterotrimeric IL-15 receptor shares two subunits
with the IL-2 receptor.

IL-25, thymic stromal lymphopoietin (TSLP), and IL-33 are structurally unrelated cytokines produced by
epithelial barrier cells, as well as other cell types, which stimulate ILC2s, Th2 cells, and mast cells to
produce IL-4, IL-5, and IL-13.

Important for defense against helminths, but also contribute to allergic Disease
与DAMP功
能类似
IL-33 is constitutively expressed by barrier epithelial cells and stored in their nuclei. It is often called an
alarmin because it is rapidly released from damaged epithelial cells and then stimulates innate and
adaptive responses.

65
 Sequence of
inflammation
Sequence of Events in Inflammation: Vascular Changes and Leukocyte Migration Into Tissues

FIGURE 4.14 Acute inflammatory response 66

 Sequence of
inflammation
1. Recruitment of large numbers of neutrophils, followed by monocytes, from blood into tissues
typically occurs as part of the acute inflammatory response to infections and tissue injury.

2. Postcapillary venule endothelial cells increase surface expression of adhesion molecules for leukocytes.

Expression of E-selectin and ligands for integrins, including intercellular adhesion molecule 1 (ICAM-1) and vascular
cell adhesion molecule 1 (VCAM-1) are induced by TNF and IL-1 activation of transcription factors, including NF-κB.

3. TNF and IL-1 also stimulate various cells to secrete chemokines, such as CXCL8 and CCL2, which
bind to receptors on neutrophils and monocytes, respectively.

The result of increased selectin, integrin, and chemokine expression is an increase in neutrophil and monocyte
adhesion to endothelial cells and transmigration through the vessel wall.

67
Ingestion and Killing of Microbes
by Activated Phagocytes
Neutrophils and ingest microbes into vesicles by the
process of phagocytosis and destroy these microbes

氧依赖途径：直接杀伤病原微⽣物
• Reactive oxygen species (ROS). convert molecular
oxygen into ROS, which are highly reactive oxidizing
agents with free radicals that destroy microbes
氧依赖途径：直接杀伤病原微⽣物
Nitric oxide (NO). inducible nitric oxide synthase (iNOS).
iNOS catalyzes the conversion of arginine to citrulline,
and freely diffusible NO gas is released.
⾮氧依赖途径：不直接杀伤，⽽是酶促作⽤
• Proteolytic enzymes. One of the important enzymes in
neutrophils is elastase, a broad-spectrum serine protease
known to be required for killing many types of bacteria.
Another important enzyme is cathepsin G.
⾮氧依赖途径：捕获作⽤
Neutrophil extracellular traps (NETs), including
lysozyme, elastase, and defensins.
FIGURE 4.17 Phagocytosis and intracellular destruction of microbes. 68
Role of Macrophages in
Tissue Repair

Classically activated macrophages are microbicidal

and promote inflammation early in the reaction, and M2抗炎，起到组
alternatively activated macrophages promote tissue M1促炎，早期起效 织修复/纤维化的
作⽤，晚期起效
repair later.

Macrophages clear dead cells and secrete growth

factors that promote regeneration and angiogenesis.

Macrophages also secrete TGF-β and other cytokines

that stimulate collagen synthesis by fibroblasts, thus
promoting the formation of scar tissue to replace the
damaged parts.

FIGURE 10.10 Classical and alternative macrophage activation 69

Systemic and Pathologic Consequences of
Inflammation

Sepsis
Septic shock systemic inflammatory response
syndrome (SIRS).

TNF, IL-1, and IL-6 produced during the

innate immune response to infection or
tissue damage have systemic effects
that contribute to host defense and are
responsible for many of the clinical
manifestations of infection and
inflammatory disease

FIGURE 4.16 Local and systemic actions of cytokines in inflammation 70

The Antiviral Response

The major way by which the innate immune system

blocks viral infections is to induce the expression of
type I IFNs, whose most important action is to inhibit
viral replication.

TLRs, NLRs, RLRs, and CDSs, generate

signals that stimulate IFN-α and IFN-β gene
expression in many different cell types.

FIGURE 4.18 Biologic actions of type I interferons. 71

Stimulation of
Adaptive Immunity

第⼀信号 TCR
负责瞄准
The innate immune response provides
signals that function in concert with 第⼆信号
antigen to stimulate the proliferation and 负责开枪
differentiation of antigen-specific T and B
lymphocytes

two-signal hypothesis

72
 佐剂：成分是LPS、CpG等，活化各类TLR，让固有免疫应答⼤量活化，从⽽进⼀步促进adaptive
Adjuvants immunity

stimulating innate immune responses at the site of antigen exposure that

promote subsequent adaptive immunity.

Many adjuvants in experimental use are microbial products that engage TLRs, such as killed
mycobacteria and LPS. The most commonly used adjuvant in human vaccines is alum, which is
composed of either aluminum hydroxide or aluminum phosphate, and may work by causing
inflammasome activation. CpG, the ligand for TLR9, is used in some hepatitis B virus vaccines. Among
their important effects, adjuvants activate DCs to express more major histocompatibility molecules that
are part of the antigen (signal 1) that T cells recognize, increase the expression of costimulators (signal 2)
and cytokines needed for T cell activation, and stimulate migration of the DCs to lymph nodes where T
cells are located.

73
Mechanisms that Limit Innate
Immune Responses IL-10，TGF-β最常⻅的负向调节信号

The magnitude and duration of innate immune responses are regulated by a variety of
inhibitory mechanisms that limit potential damage to tissues.

Alternatively activated macrophages make more IL-10 than classically activated macrophages.

IL-10 is a cytokine that is produced by and inhibits activation of macrophages

and DCs.

competitive inhibitor of IL-1 called IL-1 receptor antagonist (IL-1RA).

There are numerous negative regulatory signaling pathways that block the activating signals
generated by pattern recognition receptors and inflammatory cytokines.
SOCS
PIAS
SHP1

74