chapter 3

_, ...
Innate Iin,nunity .'
I' ~
I ~

r ( ,--,.../
·,\~
,
-
V [ RT E BR.\ TE s ARI, PROlTl.' TFn IW T \\'O SYS1T.~1S OF

i_mn~.~nit,·: innJte ~nd Jd.1pt_i,·l\ ~m_rnte immunit_y

-. on sists ot the deknses Jg,1mst 111kct1on th::i t a1e
read~_-for immediate activation prio,-'.to Jttack by a pathoge11.)
The mnate immune system includes physical, chemical, and
cell ub r barri~rs. The main physicafbarriers are skin and mu-
Maffopllllgc (pink) and mo11ocyte (purple) bind
cous membranes. !=hemical barriers include the acidity of the
and plwgocytose bacteria. f Dennis Kunkel
stomach contents and specialized soluble molecules that pos-
sess antimicrobial activit)> The cellular line of innate defense Microscopy/Dennis K,mkel./
comprises an array of cells with sensitive receptors that detect
m icrobial products and instigate a counterattack. The re- • Anatomical Barriers
sponse to inYasion by a microbial agent of infection that over-
comes the initial barriers of skin and mucous membranes is
.
• Connections Between Innate and Adaptive
rap id, typically initiating within minutes of invasion. Immunity
Despite the multiple layers of the innate system, some
Pathogens mav evade the innate defenses. On call is a second • Inflammation
system~ calledI'" adaptive immunity (or acqmre · d rmmum
· 'ty)I'\
. '.:__J • Soluble Molecules and Membrane-Associated
which is indu'ced by exposure to microbes and counters ~n-
Receptors
fection with a specific response tailor-made to the attacking
pathogen in the form of a large populati~n of Ban~~ lym- ■ Toll-like Receptors
pho01es that specifically recognize the mvad_:!) Ra1smg an
adapt iYe response takes time-as much as ~ wee~ or ~ore ■ Cell Types of Innate Immunity
before it is full y effective0,daptive immumty displays t_he
■ Signal Transduction Pathways
henomenon of immunological memory, and once t~i~-
p d b a part1cu . 1ar Pathogen ' future ~e~osures - · ..·elicit
-- · ■ Ubiquity of Innate Immunity
ge~e y often more vigorous respons~ ecog_ri1tion of
quicker a~d d . d b antibodies and T cell receptors, the
invaders 1s me iat~ . Y -t~-These molecules are prod-
" . » O f adapti ve 1mmurn y ·
sensors f .
es wi th an extraor dinary feature: they. undergo.
ucts .fi o gen . .fi t·on- genetic recombmat1on- A large and growing body of research has reveakd that ai
· d d1 vers1 1ca 1
modi 1cat10_ n an. erate a urnqu . e, gigantic population of sen-• innate and adaptive immunit y have co-evolwd, a high de·
in th e host to gen , . nvadcrs. The processes ot gree of interaction and interdependt·111:e h,1s arisen betwt'cn
h lookout ior I . ..
tinel s on t c . f immun ological d1vers1ty are the two systems. In fact, if a pathogen completely evades the
modification and generat1odn9o first line of defense, the innate immune system, the response
dl·scussed 111 • Ch pters 5 an ·
a . t anciml dC'frosl' of verte- of the adapti ve immune system may be quite feeble. Recog·
, . · 1s th e~ ., . . . .
ri:... nate immunity , rm of rnnate 1mmun1t y has nit ion by the innall' immune system sets the stage for an ef·
~ . • bes· some 1° • . . fective adaptive immune response.
brates aga 111st micro I .' II 'tr ant s and animals. Adaptive
b l found in all mu ~ · d . Thi s chapll'r describes the components of the innate
ee1 d 1·n Jawe ver tebrati·s "' and. is a much . more
.1111mu1,it y evolve · vent10n . t h··an innate immunity. InI ver-d 1mm~ne system-ph ysical and physiologic barriers, solubk
111 chemical agents, and several types of cells and their re.:eptors--
r •rent evolutionary. umt. y con1 plements a well-deve . oped
t , · adaptive 1mm . , b)e _ compares mnate an and illustrates h?w they act together to defend against infecti 00·
tdn,1 tD, . mumt y. Ta 3, 1
, , , !l' l11
of innate tm
. , We conclude with an overview of innate im munity ac ross the
. . in1mun 1t }- phyla of animals and plants.
. 11 l.q it I\ l
52
 ( " • , r 1 , J 53
INNATE IMMU NIN

TAB LE 3- 1 Innate and adaptive imm unit y

Attri bute
Innate Immunity Adaptive Immunity ( fa~ fl.V~' vt }
D1y1
Minutes/houn
Response time
Highly speci fic; discriminate1 even minfl!'
Speci fic for mole cules and mole cular
Specificity differ ences in molecular structure; details of
patterns associated with pathogens
microbial or nonm icrob,al ~tructure recognrzed
with high speci ficity
Highly div!rse; 1 very large number of
Alimited number of germ line- receptors arising from g,~ ic rtcombinat ion
Diversity
encoded receptors
of receptor genes
Persistent memory. with faster response
Memory responses
None
of greater magnitude on subsequent infection
ff
Very good; occasional f1ilurn of wlf/rlOl'IW
Self/nonself discrimination Perfect; no microbe-specific discrimina tion result in autoimmune disea se
patterns in host
Antibodies
Soluble components of blood Many antimicrobial peptides
or tissue fluids and proteins
T cells, Bcells, antigen-presenting cells
Major cell types Phagocytes (monocytes, macrophages,
neutrophils), natural killer (NK) cells,
dendritic cells

pathogenic organ-
fleas, and sand flies), which can introduce
ozoan that causes
Anatomical Barriers isms into the body as they feed. The
in
prot
hum ans by mosquitoes
immunity are the malaria, for example, is deposited
The most obvious components of innate when they take a blood meal, as is the viru s causing West
-ski n and mucous
external barriers to microbial invasion Nile fever. Similarly, the bubonic plague bact
erium is spread
epith elia that line
membranes, which include the mucosal by the bite of fleas, and the bacterium
that caus es Lyme
enita l tracts and
the respiratory, gastrointestinal, and urog disease is spread by the bite of ticlcs.
ogen of the exte-
s
insulate the body's interior from the path In place of skin, the alimentary, respiratory,
and urogenital
of two distinct lay-
rior world (Figure 3-1 ). The skin consists tracts and the eyes are lined by mucous
membranes that
a thicker layer, the
ers: a thin outer layer, the epidermis, and consist of an outer epithelial layer and an
underlying layer of
tiers of tightly
dermis. The epidermis contains several connective tissue. Many pathogens enter
the body by pene-
l layer consists of
packed epithelial cells. The outer epiderma trating these membranes; opposing this entr
y are a number
protein called
mostly dead cells filled with a waterproofing example, saliva,
ective tissue and of nonspecific defense mechanisms. For
keratin. The dermis is composed of conn away pote ntial invaders
ceous glands, and tears, and mucous secretions wash
contains blood vessels, hair follicles, seba iral subs tances. The
elia prov ide a kind of living and also contain antibacterial or antiv
sweat glands. Skin and epith epith elial cells of mu-
inner domains of ·viscouffluid called mucus, secreted by
"saran wrap" that encases and protects the anis ms. In the
But these anat omical barri- cous membranes, entraps foreign microorg
the body from the outer world. bran e is cove red by
pers. They also mount ac- lower respiratory tract , the mucous mem
ers are more than just passive wrap cell mem bran e. The
hesiz ing and deploying cilia, hairlike protrusions of the epithelial
tive biochemical defenses by synt mucus-e ntra pped
icrob ial activ ity. Among synchronous movement of cilia propels
peptides and proteins with antim every meal, we in-
microorganisms from these tracts. With
' I
hum an skin, recen t re-
the many such agents produced by they must run a
l prote in with pote nt gest huge numbers of microorganisms, but
search has identified psoriasin, a smal antimicrobial com -
ia coli. This findi ng gauntlet of defenses that begins with the
antibacterial activity against Escherich the mouth and in-
is human skin re- pounds in saliva and in the epithdia of
answered a long-standing question: Why dige stive enzymes found
sistant to colonization by E. coli despite cons
tant exposure to cludes the hostile mix of acid and
of bioc hemical and
it? As shown in Figure 3-2, incubation of
E. coli on human in the stomach. In addition to the amy
mus t compete for
skin for as little as 30 minutes specifically
kills the bacteria. anatomical defenses, pathogenic microbes
geni c organisms
(Other bacterial species are generally less
sensitive.) The ca- the body's resources with the many nonpiltho
e norm al flora,
pacity of skin and epithelia to produce a wide
variety of an- t~at colonize the mucosa! surfaces. Thes
ent, gene rally out-
timicrobial agents is important because brea
ks in the skin highly adilpted to their internal environm
and nece ssary
from scratches, wounds, or abrasion provide
routes of infec - com~ete path~gens for attachment sites
ogenic microbes nutrients on epithelial surfaces.
tion that would be readily exploited by path e the defenses of
if not defended by biochemical means. The
skin may also be Some organisms have evolved ways to evad
virus (the agent
penetrated by biting insects (e.g., mosquito
es, mites, ticks, mucous membranes. For example, influenza
 p ~ II. T I

INTRODUCTION

Innate 111edia11l11ms prolc l·tlnK "kin/c pithd lum

Skin
Antimkrohial pcptll kS, fall y adds In schum
Mouth and upper
E111.yml·s, antimicrobial peptidc·s, and sweep ing
allmc:ntary canal of
surfa1.:c hy diret:tional now of fluid toward stoma
ch
Stomach
Low pH , digcst iw enzymes, antimicrobial peptid
es,
fluid flow toward intcMinc
Sk in- --- Small Intestine
Digestive enzymes, antimicrobial peptid es,
fluid flow to large intestine
large intestine
Nonna! intestinal flora compe te with invading
microbes, fluid/feces expelled from rectum
Airwa y and lungs
Cilia sweep mucus outward, cough ing, sneezing
expel mucus, macrophages in alveoli of lungs

Airway

lung

Epithelial lining of
airway and lung

Epithelial lining of
alimentary canal

Stomach

~-- --- --L arg e

intestine
t---------Small
intestine

FIGURE 3-1 Skin and epithelial barriers to

-------------Rectum
infection. The skin and mucosa! epithelial layers
are defended against microbial colonization by a
variety of mechanisms: chemical (enzymes,
antimicrobial peptides, pH), mechanical {cilia,
fluid flow). and cellular (alveolar macrophages) .

thJt causes flu) has a surface molecule that enabl

es it to which interact ':ith _certain glycoproteins or glycolipids
attach firmly to cells in mucous membranes of the only
respira- expressed by ep1thehal cells of the mucous membrane of
tory tract , preventing the virus from being swept out par-
by the ticular tissues l Figure 3-3). For these reasons and others
~ ih.sll'd epitheli.sl cells. The organism that
causes gonorrhea some tissues a~e susceptible to invasion by partic
h,~ ,urf,.ct projections that bind to epithelial cells ula;
in the pathogens, despite the general effectiveness of protec
mu,ou~ 111 ,mbr.tne of the uro~t'nital tract. Adher tive
ence of epithelial barriers. When this happens, the receptors
h..a, ll'l l., hi mu,·ou~ mem brai~ _is gt>nerally m~dia of
ted ~: ~nat~ immuni~y P~Y the ~n_tial roles of detecting
hJ11 l1l..t· J'h•truMuns on the' h.sdtriwn called ftmbraat tht
or pill. mfe1:t10n and tnggermg an eftecttvt defense ag.1inst it.
 INN/\lf IMMll,Uf'( r •1 A ' r I I I SS

lnnn1l~lillll

j .111 m;mn"

FIGURE 3-3 Electron micrograph of rod-shaped f . coiib«teria

Fresh culture pl;nes

l '"'"b"'
adhering to surface of epithelial cells of the urinary~ {From N
Sharon and H. Us, 1993, Scientific American Z68{1 ):85;courtesy of K.. Fi,jira.J

S. aureus E.coli
host capable of precisely discriminating between self I host J
II \ I \\ and nonself (pathogen ). These molecular sensors recognize
broad structural motifs that are highly conserved within a
, ,, microbial species (and are usually necessary for survival ) but
' I \ are generally absent from the host. Because they recognize

I ,.. particular overall molecular patterns, such receptors are

called pattern recognition receptors (PRRs), and when such
patterns are found on pathogens, they are called l!athogeb

~
"
associated molecular patterns (PAMPs). The PA.MPs recog-

a. ~
... 'I
FIGURE 3-2 Psoriasin prevents colonization of skin by f. coli.
nized by PRRs include combinations of sugars, certain
proteins, particular lipid-bearing molecules, and some nu-
cleic acid motifs. The restriction of innate recognition to
molecular patterns found on microbes focuses the innate svs-
Skin secretes psoriasin, an antimicrobial protein that kills f. coli.
tem on entities that can cause info:tion rather than s~b-
Fingertips of a healthy human were inoculated with Staphylococcus
aureus (5. aureus) and £. coli. After 30 minutes, the fingertips were stances that are merely nonself, such as artificial hip joints. In
pressed on a nutrient agar plate and the number of colonies of 5. aureus
contrast, antibodies and T cell receptors, the sensors of adap-
and E. coli determined. Almost all of the inoculated f . coli were killed;
tive immunity, recognize finer details of molecular structure
most of the 5. aureus survived. {Photograph courtesy of Nature lmmunol-
and can discriminate with exquisite specificity between anti-
ogy;from R. Glaser et al., 2005, Nature Immunology 6:57-64.} ge~~ featuring only slight structural ditfrrmces. Typically, the
ab1hty of pattern recognition receptors to distinguish be-
tween self and nonself is flawless, because the mokcular pat-
tern targeted by the receptor is produced only by the
pathogen and never by the host. This contrasts sharply with
Connections Between Innate the o~casi_onal re~ognition of self antigl·ns by receptors of
V adaptive 11nmun1ty, a potentially dangerous malfunction
and Adaptive Immunity from which autoimmune disl·ases may arise.
Once a pathogen breaches the nonspecific anatomical and . Detection of pathogen-asso ciated molecular patterns by
physiologic barriers of the host, infection and disease may s~luble_and membrane-bound mediators of innate immu-
ensue. The immune system responds to invasion with two ~1ty brings •~wltipl_c components of immunity into play. The
critical functions: sensors detect the invader, and an elaborate soluble mediators include initiators of the complement sys-
response mechanism attacks the invader. The first detection tem, s_uch as mannose-binding lectin (MBL) and C-reactive
event of the immune response occurs when the invader in- protein (~RP). If the pathogen bears PAMPs recognized by
kracts with soluble or membrane-bound molecules of the these mediators, the complement system (see Chapter 7) will
 56
INTRODUCTION

i ll OVERVIEW FIGURE 3-4: Effectors of Innate Immune

Responses to Infection
• ... - ... ... .. 4 ... ... . . - .. - ............. -

Path ol(t'n-a!ls1Kia ll'd

molcn1lar pall crn,
l'hal(1x·~tes
(l'AM P~)
(ll('Ul l'llphil~.
llla~' l'llJ)) UJ(CS) , \ .
y
f , '.:.':,

PAMPli recol(ni zed

by pattern rccnp.nition peptide,
recepton. (PRRs) Pathogen ~

~
{\°(:J
.,., -\
/ I
C-reactive :> , / /
protein (CRP) ,.,. ,,..,.,

~
Mannose- I /
binding Complement ' ,
Followed by
lectin (MBL) proteins
secretion of
Phagoqwsis Membrane
intlmunatioo-
damage kills
promoting ,...._
pathogen
~"tooncs and
chemokines 0

0
0

Opsonization
Opsonized
promotes
pathogen
phagocytosis

Innate initiation of
adaptive response
• Dendritic cell PRRs
recognize PAMPs
l CRP, MBL, complement
proteins activate complement

Complement destroys
membrane, stimulates
• Microbial antigens inflammation, attracts
displayed on class I neutrophils and other
and Il MHC molecules cells

~
• Dendritic cells
migrate to lymph
n9(1es

• Antigen presentation
Tcell and costimulation
mobilizes adaptive
response

Microbial invasion brings many effectors of innate immunity into play. they phagocytose and kill infecting microorganisms. During the action
Entry of microbial invaders through lesions in tpithelial barriers gentr- of these cellular and molecular effectoo, additional inflammatory sig-
ates inflammatory signals and exposes the invaders to attack by dif- nals are gentrated that intensify the response by bringing more
ferent effector molecules and cells. Microbes recognized by C-reactivt phagocyt,s and soluble mediatoo (CRP, MBL and complement) from
· (CRP) or mannose-binding lectin (MBL) are bound by thest the bloodstream to the site of infection. Dendritic cells internalize mi-
protein
· · and complement-activating molecules. Some pathogens, crobial components, mature, and present microbial peptides on MHC
opsonizing .
n-bearing fungi, can activate complement. which can molecules. Dendritic cells then migrate through lymphatic vessels to
such as zymo sa .
, . . or opsonization, marking the pathogen for phago- nearby lymph nodes, where they present antigen to T cells. Anti _
cause direct 1ys, 5 . activated Tcells ~hen initiate adaptive immune responses against8:e
. hils and macrophages. Inflammatory signals cause
cytosis by neut~ macrophages and neutrophils to bind to the walls pathogen. Cyt~nes produced during innate immune responses also
phagocytes sue as te and move to the site of infection, where support and direct the adaptive immune responses to infection.
of t,tood yessels, extravasa ,
 INNATE IMMUNITY C H AP . E R 3 59

be activated. One part of the comp lemen t system is a collec

tion of protei ns that, '¥hen activated, form aggreg ates th
bes,
at
- hood that the invader will be phagocytose d by
and neutrophils. (a ntibod
· · Ant1bo
.
d1es
y-mediated uptake, a t ,
also collaborate with the co,
Aus~
hil
p~~ch holes in the cell memb ranes of targeted micro sornza t10n ).
· a bout th e lys,s• of path ogemc . micro· dh must
killing the cells by lysis. The comp lemen t system also in- •
system to b rmg
te th e 10,ect1 · I d
· c · on 1s c eare , some of the B and T cell~ gent.·rmg .ere
cludes serum glycop rotein s that, when activated, promo . . .
;
uptake of micro organ isms by phagocytes (opsonizati
on) . durmg the adaptive phase of the respon se w,JJ persist in 1
ve host for long period s in the form of memo ry T and memo ry~
The comp lemen t system straddles the innate and adapti
cells. Future infections by the pathogen will then be met by
lemen t, a
immu ne systems: the activa tion cascad e of comp
specific for the pathog en and ca-
leading to opson izatio n or lysis of invade rs, can be activa ted ready reserve of lymphocytes
either by molecules that recognize PAMPs (innat ~) or
by pable of mounting a rapid response.
n antige ns.fa This thumbnail sketch introduces the major players in the
anti~? dies (adaptive) bindin g to specific foreig .
add1t1on, some of the bypro ducts of comp lemen t activa
tion innate immu ne system and its linkage to the adaptive system
comp onents and
promo te inflam matio n and thereby bring leukocytes to the The rest of this chapter will describe the
site of infect ion, launc hing anoth er layer of response. mechanisms of the innate immu ne system in more detail.
-
The invaded tissue's imma ture dendritic cells and macro
y of recept ors, includ ing the most im-
phages have a variet
the
porta nt group of innate receptors discovered to date:
detect micro bial produ cts.
Inflammation
Toll-like receptors (TLRs), which
the When patho gens breach the outer barrie rs of innate
Thus far 12 of these receptors have been described for ing
reacts with a specif ic immu nity-s kin and muco us mem brane s-the attend
mouse and 11 for huma ns; each TLR can induc e a comp lex cascad e of
ors. which are de- infection or tissue injury
microbial produ ct. These versatile recept y respo nse. Inflam matio n
and events known as the inflammator
scribed in detail in a later section, allow dendritic cells se to tissue damag e, or it
ens. Sig- may be acute, for example in respon
macrophages to detect a broad spectr um of pathog as
- may be chronic, leading to pathologic consequences such
nals initiat ed at the TLRs of macrophages stimulate phago n can.:e rs (see
are arthritis and the wasdllg associated with certai
cytic activity and produ ction of chemical agents that the
d micro bes. Activa ted macro phage s also Chapter 13). The acute inflam mator y response combats
toxic to phago cytose ses that result
ines, early stages of infection and initializes proces
secrete a class of molecules know1_1 collectively as cytok ed
growt h-fact or-lik e protei ns that in the repair of damaged tissue. The hallmarks of a localiz
which are horm one- or ns
to induc e specif ic cell activi- inflammatory response were first described by the Roma
comm unica te via cell receptors
almost 2000 years ago: swelling (Latin = tumor ) , redne
ss
y
ties (see Chap ter 12). Like hormo nes, the cytokine$ modif mark of
cells and tissues . For (rubor), heat (calor) and pam (dolor). An additi onal
the behav ior and physiology of target in tlie secon d centu ry by the physic ian
as inflammation added
example, activated macro phage s secrete cytokines such io laesa). Withi n minut es after
necro- Galen is loss of function (funct
interl eukin -I (IL-I) , interl eukin -6 (IL-6), and tumor ter
- tissue injury, · there is an increase in vascular diame
sis factor alpha (TNF-cx), which induc e and suppo rt inflam rise of blood volum e in the
(vasodilation), resulting in a
mator y responses. area. Higher blood volume heats the tissue and causes
it to
Imma ture dendr itic cells at the site of infection internalize ses, leadin g to leak-
lym- redden. Vascular permeability also increa
and process the antigen, matur e, and then migrate to pil-
of antige n to T cells is age of fluid from the blood vessels, particularly at postca
phoid tissue, where their present~tion n of fluid
immu ne respon se to lary venules. This results in · an accum ulatio
the key step in initiating an adaptive -
en . (edema) that swells the tissue. Within a few hours , leuko
pathogen invasion. This activity is therefore a bridge betwe and
itic cells cytes adhere to endothelial cells in the inflamed region
the innate and adaptive systems of immunity. Dendr of capilla ries and into the tissue
n pass throug h the walls
also secrete a variety of cytokines that promo te inflammatio
spaces, a process called extravasation (Figure 3-5). These
and help direct the host's adaptive immu ne response. e
leukocytes phagocytose invading patho gens and releas
All of the innate immu ne functions occur early in the to the inflam mator y
pop- molecular mediators that contri bute
course of infection, prior to the generation of significant cells.
cells and patho gen-sp ecific response and the recrui tment and activation of effector
ulations of pathogen-specific T
in- Among the mediators are low molecular weight regulatory
antibodies from B cells. However, cytokines released by cells mes
of subseq uent protei ns of the cytokine family menti oned above. Cytok
volved in the innate response affect the nature cells and variou s other cells in
- are sei.l eced by white blood
adaptive immu ne responses to the infection. The major molec li and play major roles in
ne the body in response to stimu
ular and cellular effectors employed by the innate immu ne
In regula ting the devel opme nt and behav ior of immu
system to attack infection are summarized in Figure 3-4. 13) are a major
immu ne system can defeat and clear an effector cells. Chem okine s (see Chap ter
many cases, the innate their
a co- subgr oup of cytokines whose signat ure activity is
inft'ction by itself. When it canno t, the patho gen faces cells
ne system . Durin g the capacity to act as chemoattractants (agents that cause
ordinatt"d attack by the adaptive immu ).
destro y pa~o - to move towar d highe r conce ntrati ons of the agent
1d.lp1ive respo n~. cytotoxic T cells detect and attrac tants are chemo kines. Other im-
the capaci ty However, not all chemo
~r•» lurking i.n hu~I c.ells, and antibodies neutraliz.e t
portan t chemoattractants are the byproducts of comp lemen
of tht> UJ\',.Jt'r to inft'\.1 other cells while increasing the likeli-
 58

I
• J. l 1 IN1RODUCTION

T\ss ul.'
U:llll:111,l'

T," ue d.1m.1~c cam,c:~ rck.1sc \

nf, A~a l·t,vc and chcm ot:K l ic
facto n- that tri)1..Q.cr a local
in<.-rea.-.c in hloo d How and
~) Phagocyt e s and anti bac te rial
,:api llary pen neah ility exud ate dest roy bact e ria
l\al·ter y i ¾
l r - - - - -- -- ~ 1 ~ 0 0
~ -\\ o ~ ¾
Pem, eabl e capillarie s allow an
infl ux of fl uid (exu date ) and cells ° o 0
Phag ocyt es mig rate to site of
Exud ate
infla mma tion ( chem otax is)
(com plem ent,
0

D• 0

Cap illar y
D

0J

Neu trop hils and

o ther phagocytes

Extr avas ation

FIGURE 3-5 Recruitment of macroph

ages and antimicrobial
agents from the bloodstream. Bacterial and phagocytes (first neutrophils and then
entry through wounds initi- macrophages and mono-

---
- - - .
ates an inflammatory response that bring cytes) to the site of infec tion. - · ~
~
s antimicrobial substances

Ca) (b)

Bacterium beco mes

attac hed to mem bran e
evaginations called
pseu dopo dia

Bacterium is inge sted ,

forming phag osom e

Phagosome fuses with

lysosome

LyM>somal enzymes
di.:est captul't'd material

DiKeslion prod ucts are

relea.'i<'d from cell ·
FIGURE 3-6 (a) Electron microgra
ph of macrophage (center, soluble factors secreted by the macropha
, pink) attacking Escherichia coli (green).
The bacteria are phagocy- ge. The red sphere is an
erythrocyte. (b) Steps in the phagocyto
tos ed as descn'bed 1·n part b' and breakdown products are secreted.The Denn
sis of a bacterium. {Part a.
is Kunkel Microscopy/Denn isKunkel.}
. ...
monocyte (purp le, top left) has been recruited to the 111c1 mty by
 INNAT[ IMMUNITY c 11 A , r 1 1 J
59

(C5a, 0,1 ) and v.irious N-fn rmyl pl'pl idl's prod11rnl hy 1hc n_n 1hc1r mrr y, hl'Min~ in mind rh.it ,,th t r lt uk, Kytr, uw
breakdown nf h,Kk rial proll'ins dur in~ ;lll inkl 1i1111 . Hi nd in~ \lll11l.1r nm h,11mm,. hrr,1v,1 ,at11 ,n prt\('n r, th( neu rrophil
of chl·mokinl's nr ot hn dwnHM lt r,1da111s 1(1 rcn·p1n1s on lhl' wilh a n11111l)(' r of formid .t hlc d 1;1J k n l(t'1 . ~, r,r, rhf'Y mu,r
membrane nf nrn trophil cdls lriµ~c rs .i n ,:h 1iv,11i11~ sig n,11 rr((lg11i n· the infl.m1rJ r nrlothel111 m; thry mu,t ~dhne
th,11 induces a rnnform,llinn.1I (h,111gc in a m11kll1 k of 1hr , 1ro11gly ~o th.ti thfy ;ire nrrf ,w,.pr aw,1y t,y th.- fkiw,n~
t1l·utrophil llll'mhr,inc (,llll'll intcgrin, i1K rl'a~i n~ it s affinit y blood; ;1 11 d while dingin g to tht" vewl w,ill, tht nr.urr,,phtl,
for intercdlular adhrsion molrcules (ICAM !i) on th l· cndn- mml prnctr,ite the r ndothrli.il l.1yr r and ~in A<v,.. ,,, rflt
thdium . Althou~h thl'rl' are m.,i"· diffcrrnl dmnoattra( - underlying 1im1e.
tants. d1cmnki nl'S arc thl' most ·important and vcrsatik Ncutroph il exl ravd~Jtion cJn he d1vidt d ,nr,, fr,ur ,,~P"·
regul.,tl)rs of kuklK)'tc tr,,tfo:, seb :ti vcly controlling the ( t ) rolling, (2) activarion t,y chfmndttr.i, r.i nt ,t1m1Jlu,. 1 } 1
adhesilm, chet111)taxis, and activation of a variety of lcuko- arrest and adhesion, and (4) tr .rn~nd,,rhtl ,.il rn1gr .1h,,n
(~"te subpopulations. Inflammatory dwmokin cs arc typi(a ll y (Figure 3-7a). In the fir,t ,tep, neutrophil~ .tttJch '°'~ly tr,
indu(ed in response to infection or the response of cells 10 the endothelium by a low-affinity interaction betwetn
proinflammatory (inflammation -promoting) cytokincs. gl yco prntcins-mucins on the neurmphil, 1(lect1m on t~
Chemokines cause leukocytes to move into various tissue cndothclial cell (fi gure 3-7b). Jn the ah~ncc of add,r,ondl
sites by inducing the adherence of these cells to the vascular signals, the weak interac tion~ tethering the neutroph,I to rhe
endothelium lining the walls of blood vessels. After endothelial cell are quickly broken by shearing forces .AS
migrating into tissues, leukocytes move by chemotaxis the circulating blood sweeps pa.~t the cdl. ~ regjon, oft~
toward the higher lo,alized concentrations of chemokines at neutrophil surface successively bind and break free, the MU-
the site of infecti~n. Thus, targeted phagocytes and effector trophil tumbles end over end along the surface of rh~
l~mphocyte populations are attracted to the focus of the endothelium.
inflammation. ' As the neutrophil rolls along the endothelium, it ffi.JY'
A major role' of the cells attracted to the inflamed site is encounter chemokines or other chemoattracunts th.1t have
phagocytosis of invading organisms. Elie Metchnikoff de- arisen from the site of an inflammatory procas. Sub<iequmt
scribed the process of phagocytosis in the 1880s and ascribed to interaction between integrins and ICA.\ls stabiliza adhesion
it a major role in immunity. He hypothesized that white blood of the neutrophil to the endothelial cell, enabling the cell to
cells engulfing and killing pathogens were the major effec- then force its w_ay between cells of the endothelium.
tors in immunity, more critical, in his judgment, than defenses
mediated by serum components (antibodies). Metchnikoff was
correct in assigning a critical role to the process of phagocyto- Soluble Molecules and Membrane-
sis, and we now know that lack of this function leads to se- Associated Receptors
vere immunodeficiency. The general process of phagocytosis of
bacteria is shown in Figure 3-6. The microorganism is en- The innate immune system is multifaceted, utilizing a vari-
gulfed and lysed within the macrophage, and the products of ety of soluble molecules as well as cell membrane-bound re-
lysis are discharged. These products include molecules car- ceptors as its effectors. Certain of the soluble molecules are
rying PAMPs, which alert cell receptors to the presence of produced at the site of infection or in_iury and act locally.
the pathogen. The assembly of leukocytes at sites of infec- These include antimicrobial peptides such as ddt"nsins and
tion, orchestrated by chemokines, is an essential stage in the cathelicidins as well as the interferons. an important group
focu~ response to infection. of cytokines with antiviral action, discussed belvw md more
Finally, some signals generated at sites of inflammation fully in Chapter 12. Other soluble effectors are produceJ .it
are carried systemically to other parts of the body, where they distant sites and arrive at their target tissues vic1 the blooJ-
induce changes that support the innate immune response stream. Complement proteins and acute ph.iSc.' protems fall
(discussed below in the section describing the acute phase into this group. The nature of thl'Sc.' l'tltctors .ind tht"ir con-
response). tributions to host defense are discussed bt'low.

Leukocyte extravasation is a highly regulated, Antimicrobial peptides contribute to the

multistep process innate defense against bacteria and fungi
The tightly regulated process of extravasation is responsible Peptides with antimicrobial ai.'livity have been isolated from
for the migration of leukocytes from the bloodstream to sites sources as diverse as humans, frogs, flies, nematodes, and
of infection. As an inflammatory response develops, various several species of plants (T.ihle 3-2). The early evolution and
cytokines and other inflammatory mediators act on the retention of this defensive strategy, coupled with the identi-
endothelium of local blood vessels, inducing increased fica~ion of more than 800 different antimicrobial peptides,
expression of cell adhesion molecules (CAMs). The affected testifies to their effectiveness. They range in size from six to
epithelium is said to be inflamed or activated. Since neu- 59 ~mi_no ~cid residues, and most are positively charged
trophils are generally the first cell type to bind to inflamed (cataonac),_hke the magainins found in the skin of frogs and
endothelium and extravasate into the tissues, we will focus the defensms present in humans and other species. Human
60 tNTRO[)lJCllON

\ll RnlhnJl .1rhl '"\ tr.1, a~.11k1n

A,tiutlon Arrr~I/ ·uralion

Tran,<·ncl1Jthdla I m,,.,
adht'sion

Endothelium

(h) lnitiati,,n of cxtm.isatio n

'.'\ctn.rorhil

Chemokine ~
or other W
chemoattractant T

1 \__ _ _ _ _-,
Selectin-mucin Chemokines/
interaction s chemoattractants
mediate rolling induce change
in integrins

7 ( ) Neutrophil rolling and extravasation. (b) Cell

FIGURE a
... __ . 3-molecules and chemokines involved. . in neutrophil. neutrophil activate a signal transduction pathway, resulting in a con-
adr~,on . .15 d. ted by transient binding of select1ns on formational change in integrin molecules that enables them to adhere
extravasation. RotLing me ,a cins on the neutrophil. Chemokines firmly to intracellular adhesion molecules on the surface of Mdotht-
lar endothelium to mu h
the vascuchemoattractants that bind to a specific receptor on t e lial cells.
or other

. . . pept1'des , 29 to 35 amino acid residues

cat1on1C h
defem1m are . . . t cysteines that form two to t rec Antimicrobial peptides often work by disrupting microbial
h .th six mvanan d' . al
in lengt , WI bl· . g relatively rigid three- 1mens1on membranes. How these compounds discriminate between
disulfide bonds, sta_ I izm 'd variety of bacteria, including
They kill a w1 e . microbial and host membranes is a matter of current
structures. Streptococcus pneumomae, E. coI'1, research interest. Although membrane disruption is a major
St aphylococcus aur~us, d Hemophilus influenzae. Neu-
d rugmosa, an h h mechanism of action, antimicrobial peptides also produce a
Pseu omonas. ae h f h
rces o t ese peptides, butt. ere are
h .ot er variety of intracellular effects, such as inhibiting the synthe-
hils are nc sou 11 crete defensins mto t e mtes- sis of DNA, RNA, or proteins, and activating antimicrobial
trop as well: paneth ce s : ancreas and kidney release
enzymes that lyse components of the microbe. Antimicro-
s~urces d epithelial cells of ~eef!sins kill microb~ ~apid!y,
une, ~
defensms I~ . to the serum.
. minutes. Even
slow-acting anhm1crob1al
bial pept!des attack not just bacteria and fungi but viruses as
well, havmg been shown to effectively target the Jipoprotein
typically ~1th1_~hin 90 minutes. envelope of some enveloped virUSes such as influenza virus
pt'ptl'des kill w1 and some herpesviruses. The breadth of these activities, their
 INNATE IMMIJNll'Y c w A, , I I f 61

TABLE 3-2 Some antimicrobial peptides

Typical producer specil!S• Typical microbial activ~
Peptide

Human (found In paneth cells Antibacterial

Defensin family
cx-Defensins of intestine and in cytoplasmic
granules of neutrophils)
Antibacterial
~-De~nsins Human (found in epithelia and
other tissues)
Antibacter ial
Cathelicidins Human, bovine
Antibacterial; antifungaf
Magainins Frog
Antibacterial
Cercropins Silk moth
Antifungal
Drosomycin Fruit fly
Antibacterial; antifungal
Spinigerin Termite
the typical producer but is produced by many different ~e. Also. -
•1n many cases, production of the indicated antimicrobial peptide or family is not limited to
activity than the typical one indicated.
mffl'I~ of the indicated peptide or family may have broader antimicrobial

proven antimicrobial effectiveness, and the increasing emer- pentraxins, which bind ligands in a calcium-dependent r~-
gence of resistance to existing antibiotics has stimulated tion. Among the ligands recognized by CRP are a pol},-saccha-
investigation of the suitability of antimicrobial peptides for ride found on the surface of pneumococcal species and
therapeutic use. However, questions remain about their in phosph oryfc~ which is present on the surface of many
vivo stability, toxicity, and efficiency when administered in a fuicrobes. C-reactive protein bound to these ligands on the
clinical setting. Concerns have also been raised about the surface of a microbe promotes uptake by ph.lg01.--ytes and
danger that bacteria might rapidly acquire resistance to these activates a complement-mediated attack on the microbe. (The
antimicrobials if they are used widely, undermining an Clinical Focus box on p. 66 discusses the link between CRP's
essential tier of innate immunity against infection. For these role in inflammation and heart disease. ) Mannose-binding
reasons, antimicrobial peptides are not yet in clinical use. lectin is an acute phase protein that recognizes mannose-
containing molecular patterns found on microbes but not
on vertebrate cells. Mannose-binding lectin, too, directs a
Proteins of the acute phase response complement attack on the microbes to which it binds.
contribute to innate immunity
During the 1920s and 1930s, before the introduction of antibi- Innate immunity uses a variety of receptors
otics, much attention was given to controlling pneumococcal to detect infection
pneumonia. Researchers noted changes in the concentration of
several serum proteins during the acute phase of the disease, A number of pattern recognition molecules have b«n identi-
the phase preceding recovery or death. The serum changes fied; several examples appear in T.ible 3-3. The Toll-likt' l\'\:'e(>-
were collectively called the acute phase response (APR), and tors are perhaps the most important of these anJ .ire diS(uS&\.i
the proteins whose concentrations rose or fell during the acute below. Others are present in the bloodstrt',un and tissue tluids
phase are still called acute phase response proteins (APR pro- as soluble, circulating proteins or bound to the membranes of
teins). The physiological significance of many APR proteins is macrophages, ncutrophils, and dt•ndritk cdls. MBL and CRP,
still not understood, but we now know that some, such as com- discussed above, are solublt' pattern recognition rn:eptors that
ponents of the complement system and C-reactive protein, are bind to microbial surfaces, promoting phago"·ytosis or m.iking
part of the innate immune response to infection. The acute the invader a likdy target of complement-mediated Iysis. Yet
phase response (discussed fully in Chapter 13) is induced by another solullle receptor of the innate immune svstem,
signals that travel through the blood from sites of injury or lipopolysaccharide-binding protein (LBP), is an imp~rtant
infection. The liver is one of the major sites of APR protein ~art of the syst~m that recognizes and signals a response to
synthesis, and the proinflammatory cytokines TN F-cx, IL- I, hpopolysacchande, a component of the outer cell wall of
and IL-6 are the major signals responsible for induction of the gram-negative bacteria. NOD proteins (from nucleotide-
acute phase response. Production of these cytokines is one of binding vligomerization domain) are the most recent group of
the early responses of phagocytes, and the increase in the level re~eptors found_to play roles in innate immunity. These pro-
of C-reactive protein and other acute phase proteins such as teins are cytosolic, and two members of this family, NOD J and
complement contribute to defense in several ways. C-reactive NOD2, recognize products derived from bacterial peptidogly-
protein belongs to a family of pentarneric proteins called cans. NODI binds to tripeptide products of peptidoglycan
 r A R l IN TRODUCTION
62

TABLE 3 - 3 Receptors of the innate immune system

L---
Rec
_ e_p_t_o_r_(_lo_c_a_t_io_n_)_ _ _ _ _ _ _ _ _Taf'Re-t (source) Effect of recognition
I -· - - - - - - - · - - - - - - - - - - - - - - - ~ - -- - : ~ -,
Compleme-nt (bloodstream. Microhi.:il cPII w;i ll compone-nt \ Complement activation, opsonization,
t issue fluids) ly~is

Mannose-binding lectin (M~L) Mannose-containing microbial carbohydrates Complement activation, opsonization

(bloodstrNm, tissue fluids) (cell walls)

C-~i~ protein (CRP) Phosphatidylcholine, pneumococcal polysaccharide Complement activation, opsonization

(bloodstream. tissue fluids) (microbial membranes)

lipopolysac:charide (LPS) receptor;• Bacterial lipopolysaccharide (gram -negative Delivery to cell membrane
LPS-binding protein (LBP) bacterial cell walls)
(bloodstream, t issue fluids)

Toll-like rec-ept~ (cell surface Microbial components not found in hosts Induces innate responses
or internal compart~nts)

NOD' fam ily receptors Bacterial cell wall components Induces innate responses
(intracellula r)

Scavenger receptors (SRs) Many targets; gram-positive and gram-negative Induces phagocytosis or endocytosis
(ceU membrane) bacteria, apoptotic host cells ~

• LPS is bound at the a!ll membrane by a complex of proteins that includes CD14, MD-2, and a TLR (usually TLR4) .
t N~ti~inding oligomerization domain.

breakdown, and NOD2 recognizes muramyl dipeptide, de-

rived from the degradation of peptidoglycan from gram-
positive bacterial cell walls. Pattern recognition receptors

, . found on the cell membrane include scavenger receptors (SRs)

that are present on macrophages and many types of dendritic
cells. SRs are involved in the binding and internalization of
gram-positive and gram-negative bacteria as well as the phago-
cytosis of apoptotic host cells. The roles and mechanisms of
J scavenger receptors are under active investigation.

Toll-like Receptors
The protein Toll first attracted attention during the 1980s,
when researchers in Germany found that devdoping flies
could not establish a proper dorsal-wntral axis without Toll.
( Toll, referring to the mutant flies' hizarrdy scrambled
anatomy, means "weird" in German slang.) Toll is a trnns-
membrnne signal receptor protein; rdated molecules with
roles in inn,1te immunity came to be known as Toll-like re-
ceptors (TLRs). Three recent discoverit·s ignited an explo-
sion of knowledge about the central role of TLRs in innate
immunity. The first observation came from the fruit fly. In
1YlJ6, Jules Hoffman and Bruno Lemaitre found that muta-
tions in Toll, previously known to function in fly develop-
, al infection In a fruit fly (color) with • ment, made flies highly susceptible to lethal infection with
GURE 3 - 8 severe fung i nal-transduction pathway required Aspcrgillus fumigatus, a fungus to which wild-type flies were
Fl utation in the s g l ptide drosomycln. {Electron immune (1-'igure 3-8). This landmark experiment convinc-
disabling m h ·s of the antifunga pe 996 Cell 86:973; courtesy of ingly demonstrated the importance of pathogen-triggered
for the synt es• 8 Lemaitre et al.. 1 , immune responses in a nonvertebrate organism. A year
dapted from . J
micrograph a . .hi of Strasbourg.
' • nffman, LJn,verS/.J
 INNATE IMM UNITY c H ,. , r, • J 63

Bac tt'rial ct'll ( E. coli) <di w;1 II orjt;t11l1;11J11n

w- --- 1.ip,,pol>\:,in h.,ri1£r
frmJ,11,,,unJ

' , , :, _-, , '· ,11 jl

1 1• 1- "; ,- 111
I
c '11frr
, , 1: ' , , _,.I'/~ (~ m('mhw,c:
, : : ,. r. , ,
\ · Prp!i<lt ,wyc :ni

,' ,/~~1 lr
,, ''I '\
ln~r
'' ' "///A J mcmnr.,nc

FIGURE 3-9 lipopolysaccharide (LPS) in the cell wall of E.coli. LPS is a powerful stimulus of innate
immunity. {Photograph from Gary GauglerMsuals Unlimited.}

later, in 1997, Ruslan Medzhitov and Charles Janeway dis- the TLR. The intracellular domain of TIRs is called the TIR
co\'ered that a certain human protein, identified by ho- domain, from Toll/ JL-1 receptor, referring to the similarity
mology between its cytoplasmic domain and that of Toll, between the cytoplasmic domains ofTIRs and the comparable
activated the expression of immune response genes when region of a receptor for IL-1, an importan t regulatory
transfected into a human experimental cell line. This
human protein was subsequently named TLR4. This was
the first evidence that an immune response pathway was Leucine-rich repeats (l.RRs)
consen ed between fruit flies and humans. In 1998, proof
1

that TLRs are part of the normal immune physiology of

mammals came from studies with mutant mice conducted
in the laboratory of Bruce Beutler. Mice homozygous for Exterior
the fps locus were resistant to lipolysaccharide (LPS), also domain
known as endotoxin, which comes from the cell walls of
gram-negative bacteria (Figure 3-9). In humans, a buildup
of endotoxin from severe bacterial infection can cause
septic shock, a life-threatening condition in which vital
organs such as the brain, heart, kidney, and liver may fail.
Each year, about 20,000 people die of septic shock caused
by gram-negative infections, so it was striking that some
mutant strains of mice were resistant to fatal doses of LPS.
DNA sequencing revealed that the mouse lps gene encoded
a mutant form of a Toll-like receptor, TLR4, which dif- Cell membrme
fered from the normal form by a single amino acid. This
,-:z=-. -- Box l
work provided an unequivocal demonstration that TLR4 ~ -lllt---- Hoxl
is indispensable for the recognition of LPS and showed TtR domain
that TLRs do inde~d play a role in normal immunophysi- • - •- ttox j
ology. In a very few years, the work of many investigators
has determined that there are many TLRs. So far, 11 have
been found in humans and 12 in mice. FIGURE 3-10 Structure of a Toll-like receptor (TLR). Toll-like re-
Toll-like receptors are membrane-spanning proteins that ceptors have an exterior region that contains many leucine-rich re-
share a common structural element in their extracellular peats (LRRs), a membrane-spanning domain, and an interior domain
region, repeating segments of24 to 29 amino acids containing called the TIR domain. The ligand-binding site of the TLR is found
the sequence xLxxLx.Lxx (xis any amino acid and Lis leucine). among the LRRs. The TIR domain interacts with the TIR domains of
These structural motifs are called leucine-rich repeats (LRRs; other members of the TLR signal-transduction pathway; three highly
Figure 3-1 0 ). All TLRs contain several LRRs, and a subset of consl!rved sequences of amino acids called box 1, 2, and 3 are essen-
the LRRs make up the extracellular ligand-binding region of tial for this interaction and are characteristic features ofTIR domains.
64 P A R T I INTRODUCTION

R,Kterfa\ l;ram-\'\\,sith-c <,ram n1·11,.1 1lvr l'l ~l(l'll a1n l

FIGURE 3-1 1 Toll-like receptors and
p.lrasitr!- ha,-t<'ria an,\ harlrria h.trtr rla their ligands. TLRs that interact with ex-
hm11,i tracellular ligands reside in the plasma
-~ ~ -, membrane; TLR.s that bind ligands gener-
Cell~ ated within the cell are locali zed to intracel-
m~h ra~
,-;::::. lular membranes. Some TLRs form dimers
-~
i
\
Ou
11..Rl TI.Rl
with other TLRs; TLR4 dimerizes with itself
(and TLRS might do so). Other TLRs may
function as monomers, or dimeric partners
TI.Rl TI .R6 TI.R4 TI.M TI.R'; TLR";?
l may yet be discovered.
Yiral Yiral Viral Hacterial
dsR.~A ssRl~A ONA elements

r'

I
I

\ 1lJl3 11.R~ TI.RS TI.R9

\ Internal
\ com partm ent

1Uls liga nds Target micr obes

TIJll Tria q1 lipop eptid es Mycobacteria
TIJl2 Pcpti dogly cans Gram-positive bacte ria
GPl-linked prote ins Tryp anoso mes
Upop rotei ns Mycobacteria
z,-mosan Yeasts and other fungi
TIJl~ Double-stranded RNA (dsRNA) Viruses
11Jl4 lJ>S Gram-negative bacte ria
F-protcin Respiratory syncytial virus (RSV)

nas Flagcllin • Bacteria

Diaq1 lipopeptidel Mycobacteria

ZylDOWl Yeasts and fungi
TUlr Mnglc-ttrandc:d RNA (1sRNA) Viruses

1l..R8 Singk-11trandt'd RNA (1hRNA) Viruses

TIJl9 C:p(i unmrthybtcd dlnudrotidc1 8aclr
rial l>NA
l>inuckOlidn
Hcr pc• ~ tnkc tlon Somr hrrpr svlru srs

TIJll 0,11 Unknown llnknown

mole cule . As show n in Figure 3-10 , TIR repertoire of hiohly c

dom ains have three
onse
complete set of TLRs presentrved h
ci
· ns high ly cons erve d amo ng all mem
reg10 , bers of the TlR • . pat ogen mole cule s Th
, ·1 alled boxes l, 2, and 3, that serve as b' d ' · c a b road variety of viruse b mam ou • e
1am1 y, IIc m mg sites 1or . fu se or hum a
S, acte na
. I r prot eins part1.c1pa
• · · h · 1· tozoa. The set of hum an TLRs • ng1,. n can d etect
tmg m t e s1gna mg pat hways and even som e ro-
intra ce u a have been determined a
me diate d. by TLR
Func t_ions av
h es.been dete rmin ed for nine of the
11 TLRs
rf whose func tions d
the ligands that bind :ar in Figure
pathogens: a virus could are indispens
p
3-11 It . an ligan ds
Strikingly, each TLR detects a distinct abie ,: nota ble that
present in hum ans. not function . h mpo nent s of
wit out .
Its nuclt>ic
 INNATE IMMUNITY C H A , T E It 65

acid, gram-negative bacteria ca nnot be constructed without The roles of the major cell types in innate immunity are
their LPS-c~ntaining walls, and fungi must incorporate the highlighted in Figu re 3- 12.
polysacchande zymo_sa n in their celJ walls. Pathogens simply
do no! hav~ t~e option of mutating to forms that lack the Neutrophils are specialized for phagocytosis
e~sential building blocks recognized by TLRs. As shown in
Figure 3-l l , TLRs that recognize extracellular ligands are and killing
~ound on the_surface of cells, whereas those that recognize Neutrophils are the first cells to migrate from the blood to
mtracellula~ ligands, such as viral RNA or fragments of DNA sites of infection, and they arrive with a vast array of weaporu
from bacteria, a~e localized in intracellular compartments. to deploy against infecting agents. They are essential for the
. Sever~! Toll-like receptors, TLRs l, 2, 4, and 6, operate as innate defense against bacteria and fungi . Although phagocy-
~1mers (m some cases, additional proteins are incorporated tosis is the neutrophil's main weapon against invaders, other
~n the com~lexes formed). One of this set, TLR4, pairs with mechanisms contribute to the containment and elimination
itself (forming a homodimer), and the others form com- of pathogens. Neutrophils display several Toll-like receptors
plexes with another TLR (heterodirners). Partners have yet to on their surfaces. TLR2 allows them to detect the peptidogly-
be found for TLRs 3, 7, 8, and 9, which may act as monomers, cans of gram-positive bacteria, and TLR4 detects the lipo-
and some data suggest that TLRS may exist as a homodimer. polysaccharide present on the cell walls of gram-negative
The pairing of TLRs affects their specificity. TLR2 coupled microbes. In addition to TLRs, there are other pattern recog-
with TLR6 binds a wide variety of molecular classes found in nition receptors on the surface of the neutrophjl.
microbes, including peptidoglycans, zymosans, and bacterial Although neutrophils are capable of direct recognition of
lipopeptides. When paired with TLRl, however, TLR2 recog- pathogens, binding and phagocytosis improve dramatjcally
nizes bacterial lipoproteins and some characteristic surface when microbes are marked (opsonized) by the attachment
proteins of parasites. TLR4 is the key receptor for most bac- of antibody, complement components, or both. Even in the
terial lipopolysaccharides. TLRS recognizes flagellin, the absence of antigen-specific antibodies, the complement pro-
major structural component of bacterial flagella. TLR3 rec- teins in serum can deposit protein fragments on the surface
ognizes the double-stranded RNA (dsRNA) that appears in of intruding pathogens that facilitate binding by neutrophils,
cells after infection by RNA viruses, and viral single-stranded followed by rapid phagocytosis.
RNA (ssRNA) is the ligand for TLR8 and TLR7. Finally, TLR9 In neutrophils, mo_nocytes, and macropiages, two addi-
recognizes and initiates a response to the DNA sequence CpG tional antir_nit:robial. devices,· oxidative ana -nonoxidative
(unmethylated cytosine linked to guanine). Unmethylated se- attack, contribute to a multipronged, coordinated, and
quences such as this are abundant in microbial DNA and highly effective defense. The oxidative arm employs reactive
much less common in vertebrate DNA. oxygen species (ROS) and reactive nitrogen species (Ri~S ).
The reactive oxygen species are generated by the NADPH
phagosome oxidase (phox) enzyme complex. Phagocytosed
microbes are internalized in vacuoles called phagosomes, in
Cell Types of Innate Immunity which reactive oxygen species are used as microbicides.
Innate immune responses typically involve the participation The oxygen cg_!'}~umed by phagocytes to support ROS
of many different cell types. Key actors are neutrophils, macro- production by the phox enzyme is provided by a metabolic
phages, monocytes, natural killer cells, and dendritic cells. process known as the respiratory burst, during which oxygen

Ncum>phila Macrophages Dendrltic cells Natur.d killer cells

Cell type

Phagcx:ytosis Ph.tgocytosii. Antigen present,.uion Lysis of vir-.tl-infected

Function
Reactive oxygen Jnlliunmatory Costlmulatory cc-Us
and nitrogen mc-di.lton e.ignals lnterfc.-ron
species Antigen pKsc-nl.ttion Rea,:tivc oxygen Macmphage activation
Antimicrobial Rc--..ctlve oxygen and spedes
peptides nitrogc-n species Interferon
Cytokincs Cytokines
Complement proteins
FIGU RE 3 • 1 2 The major leukocytes of innate immunity. Monocytes, not shown here, have many
of ttw same uipabiliti~s as macrophages.
 f l R 1 I

D CLINI C AL fOC US
( -Reactive Protein Is a Key
Marke r of Cardiovascular Risk
att-'<k \0 th-3t pr,v~ntatl'lf! th~rap1~ and
hf P,;tylfl ch;ing~ ( ¥1 ~ 1n,;t1t1Jtl'rl
Thf con~ct10n b-tw -~ tnflarnmat,on
and p\a<JI~ formation h~ led r~;w:hffl to
eram1ne inf\,1rnmatory markf!f'> ac; pr~o rs
of cardiovascular events. A rK~ stU't-j <:A
Ca:-~lovascular d1Sl'\\Se 1 is the that leukocytes are important in the devel- men and women meac;ured the blood ~
ll'ad1ng killer N'1 the United StatE's and Eu- opment of athero.-,clerotic p\ilques. In the of several markers of 1nf\.am mation. lf'lduding
rope, and only mfect,ous d1seasE' causes
initial stages of thE' disease, monocytes interteuk1n-6 (ll-6), soluble tumor r,,ecrCM
men deaths wortdwide. The most fre.quE'nt
adhere to the arterial walls and migrate factor alpha rKeptoo {TNF-o), and the
cause of cardiovascular disease is athero -
through the layer of endothelial cells and dif- acute phase response protein CRP In addition
sclerosis. the progressive accumulation of
ferentiate into macrophages. Scavenger re- to the inflammatory ~~ ;ust men-
lipids and fibrous eleme nts in the arteries.
ceptors on the macrophages bind lipoprotein tioned , the stu<tj also examined the l'TlOl'e tra-
Atherosdffl)sis is a comp lex disE'aSE' still far
particles and internalize them, accumulating ditional risk factor , cholesttrot. and its
frOITl completely understood. However, a
lipid droplets and assuming a "foamy" ap- related ~ LDl and HDL zThe risk a55(r
growing body of evidence identifies inflam -
pearance.These foamy macrophages secrete ciated with inflammatory f'N(i(ers was
mation as an important factor in the pro-
proteolytic enzymes, reactive oxygen species compared with the risk associated with
gi-e.s.sion of atherosclerosis. A connection
(ROS), and cytokines. The proteases degrade cholesterol-related markers. Thorough rne<:ll-
\ between inflammation, the immune system, the local extracellular matrix, which under-
and arte()' disease was first suggested by cal histories were taken, and the data were
goes some remodeling during repair pro- adjusted for the risk associated with the fol-
~ies in which animals were fed an

I atherosderosis-inducing diet and then the

walls of the ~eries were examined and
~ with those of control anima
ls.
cesses . The cytokines and ROS intensify
inflammation, and more cells and lipids mi-
grate into the newly forming plaque, leaving
the artery narrowed and more susceptible to
lowing medical history and lifestyle factcn
known to increase the risk of heart disease:
• Parental history of coronary heart
Light microscopy revealed that the arterial disease before age 60
blockage. Blocked arteries in the heart are
walls of the controls were free of leukocytes, called myocardial infarctions. They choke off • Excessive alcohol intake
; whereas many were found to be firmly at- blood flow to regions of the heart, denying • Smoking
tac:hed to the arterial walls of animals fed oxygen to the muscle served by the oc-
the atherosderosis-inducing diet This was • Obesity
cluded vessel-a "heart attack." In a signi-
surprising because arterial blood flow nor- ficant percentage of cases, the first heart • Inadequate physical activi ty
\ mally
pre-m,ts firm adhesion of leukocytes attack is fatal. It is therefore advantageous • Hypertension (high blood pressure)
\ to arterial walls. Further studies have shown to identify individuals at risk of a first heart
I • Diabetes

uptake by the cell increases severalfold. The ROS

include a tive assault. The inclusion of nonox.idative dd~nses
mix of , uperoxide anion (•0 - ), hydrogen peroxide in the ar-
2 (H 0 ), senal of neutrophils (and m,Kroph.tges) gre.1tly increa
and hypochloruu, acid (HOCl), the active comp 2 2 ses their
onent of defense against microbes. Nonoxidant defenses ,m:
hou!lehold bleach. The generation of ROS by neutr depll) yed
ophils when neutrophil granules fuse with ph,lgosome
and macrophages ~ triggered by phagocytosis, which s, adding
acti- their cargo of antimicrobial pt·ptides and prote
vatefl the NADl'H phagowme oxidase. The enzym ins to the
e complex mix. Among the protdns is the bach:rkid,tl/per
then produces , uperuxide (hgure 3-13 ). The other meability-
highly increasing protein (BPl) , a rem,trkable 55-kDa prote
toxic reactive oxygen 11>ecies (hydrogen perox in that
ide and hinds with high atlinity to LPS in the walls of gram
hypochlorous acid) are generated from 11uperoxide -negative
. bacteria and causes damage to the bacterium's inner
As shown in Figure 3-13, reaction of nitric oxide mem-
with brane. Other neutrophil granule agents include enzym
superoxide generates reactive nitrogen species. es (pro-
Thus, the teases and lysozyme, for example) that cause the
respiratory burst contributes to both ROS and RNS hydrolytic
produc- breakdown of essential structural components of
tion. The importance to antimicrobial defense of microbes.
NAl>PH The antimicrobial peptides include defensins and cathe
hagosome oxidase and its products, ROS and RNS, licidins,
f
rated by the dramatically increa~d susc_eptibilit~
is illus-
to fun~al
cationic peptides with a broad range of antimicrobial
activity.
d b cterial infection observed m patients afflicted
with
ahn ~ ranulomatous disease, which is caused Macrophages deploy a number
c romcg by a defec t
. h b'l'ty 11 of phox to generate ox1.d..
mng
.
specie s. of antipathogen devices
mt ea
thogens, such as the yeast can d'.J_
'"" atb·icans andh t e
So~e pas eus are not efficiently killed solely by oxida- Macrophages in a resting state are activated by a
bactenurn · aur ' variety of
stimuli. TLRs on the surfaces of macrophages
recogni,..e
 C H A P T E R 3 67
INNATE IMMUNITY

The study group was followed for six to whether statins lowered CRP levels and the established rote of CRP as an agent of
eight year5 and the number of nonfatal and whether patients with acute coronary syn- innate immunity and a mediator of in-
fatal heart attacks recorded. Of the marker5 dromes who had tower CRP values as a re- flammation, the finding that CRP levels
of inflammation studied, only CRP 1s. assoo.- sult of statin therapy would have a lower are useful in evaluating the risk of heart
ated with higher risk of coronary heart dis- risk of another heart attack than those pa- attack strengthens this hypothesis . The
ease. Comparing the predictive value of CRP tients who had higher CRP levels. The inves- finding that statin therapy, originally in-
levels in patients with different ratios of tigators found that administration of troduced to reduce cholesterol levels , also
(total chotesterot)/(HDL-bound cholesterol) statins produced impressive reductions in reduces the level of CRP is an unexpected
this inflammatory marker correlates with in~ CRP levels. The study also found that in benefit, one that supports the hypotheses
creased risk. Specifically, the study found those patients for whom statin treatment linking inflammation to cardiovascular
that high levels of CRP are a greater risk fac-
tor for patients with tower (total chotes-
lowered CRP levels to values of 2 mg/liter
or less, the rate of heart attack was signifi-
disease.
I
~
terol)/(HDL-bound cholesterol) ratios th~n
in patients with high ratios.
The past decade has seen the increasing
cantly lower than in patients where values
remained above this level, and there was a
striking parallel between lower CRP and
1 Cardiovascular disease includes strokes and

myocardial infarctions, or heart attacks.

2 HDL high-density lipoprotein, often imprecisely
,
use of a class of cholesterol-lowering drugs lower levels of LDL. referred to as "good cholesterol" and LDL low-
known as statins. These drugs inhibit Evidence of a link between cardiovas- density lipoprotein, often called "bad cholesterol"
cholesterol biosynthesis while also lowering cular disease and inflammation has been are complexes of cholesterol and protein. Elevated
LDL is a risk factor for cardiovasular disease.
inflammation. A recent study examined accumulating for many years. In view of

ctive
Statin treatment reduces serum levels of (-rea
two
protein (CRP). Subjects were tested with either
of
Pravasrarin of CRP
statins, pravastatin or atorvastatin. Reduction
P. M.
levels were striking and long term. {Adapted from
Ridker et al., 2005, New England Journal of Medic
ine 352: ZO.}
4 mont hs End ofsru dy

e + NADP
cans, and flag- L-arginine + 0 2 + NADPH ~ NO + L-citrullin
microbial components, such as LPS, peptidogly iNOS
released by
ellins, and cytokine receptors detect cytokines
tory respo nse. On activa-
other cells as part of the inflamma The enzyme is called inducible NOS to distin
guish it from
ocyti c activ ity, in-
tion, maaophages exhibit greater phag other forms of the enzyme present in the body
.
they secrete
creased ability to kill ingested mkrobes, and Nitric oxide has pote nt antim icrob ial activ ity and can
ss higher levels
mediators of inflammation. They also expre combine with superoxide to yield even more
potent antimi-
antigen to TH
of class II MHC molecules, which present crobial substances. Recent evidence indic ates that nitric oxide
colla bora tion between
cell s-an othe r important point of and substances derived from it account for much of the an-
Path ogens in-
the innate and adaptive immune srstems. timicrobial activity of macrophages against
bacteria, fungi,
in phagosomes
gested br m,Krophages are dfo:iently killed parasitic worms, and protozoa. This was impressiv
ely demon-
hy m,my of the same microbicidal agen
ts used by neu- inducible nitric
OX)'gen species strated using mice in which the genes encoding
trophil~. with rolt'S played by both reactive oxide reductase were knocked out. Thes e mice lost much of
re 3-13 ). An addi-
ilnd rt',h:tive nitrogen species (see Figu their ability to control infections by such
intracelluJar
neutrophils has
tional ~-ht'mi"·.al weapon of macrophages and pathogens as Mycobacteriwn tubercuwsis, the
bacterium re-
iated by recep-
hn-n " ·di i.tuJit'd. following aL"tivation, med sponsible for tuberculosis, and Leishma,iia majo
r, tht intra-
te cytokines,
to,, ,u, h •• Tl Rs or expoi.ure to appropria ceUular protowan parasite that cause s ki~h m.an i.uii.
dbl~ nitri c ox.id~ syn-
ph ..tt,11. rtn eAprc-» hit:h k\·ds of indu igts also
Besides killing and de-c1ring pathogt-ns, m.k:roph.
thti. aw tiNO ~). •n c-n, unr th.at oAidiLc-s L-arg
1 , ,truUuw ,nJ 11111'1( u.uJ.: (l\'0 1.
inint to yidd
-
pl.ty , role in the coordin.uion of othe r u-lb Mid
ti»u o of tht-
-- ..
 INTRO()\ll TIC'\N

- -----·- ·- --- -- -----

!'I \I ll'lt
ph~11,,-.,111r S11pc-ri,111<lr
Mvr l,,Pf'r•,-. i,l..iw
~\,- ''"r"'''"" 1nit1"l 111\mlllllV
.--➔

t'II · 11',l"'"''' r,.I" an .... •l l l ♦ fli'J ,

fl yptl(hlorilt
II :l ' : th\l"'1'1\1' rr"'\ llh·l ~111,i·r11lhlr fhd ro,trn (
'"" l 1h, r<" hl,"1". 1nt1>nl anion rx-rrntllk-

<I
<.hloriclf'
Ion

· ------·--·····-··----········ ············-·····\ ---········---·---------···

' , ::r..-_ __ _. (l N(KJ
········
/ Pc·roll ynilrilt
"', 1nn"' ,,,..tr\
'K l; OVU\'!lffl cl101udr·\
( ____________ ~ N()l
NO
O '\,. l l) - ~,~-,'N1nlt) ~ •trORffl diolti<k
Nilrtc oxldl"

AGURI 3- 13 Get~ ation of 1ntimlaobial mctivt oxygen and the products of this pathway, supemxide anion, can interact with a
rNctM ~ species. Within the confines of neutrophils and reactive nitrogen species (RNS} to produce peroxynitrite, anothtr RNS.
macrophages. ~ ~ transform molecular oxygen into highly NO can also undergo oxidation to generate the RNS nitrogen dioxide.
~~ CIC)~ spKtes (ROS) that ~ antimicrobial activity. One of

immUM and other supporting systems. They exert this influ- vated natural killer cells are also potent producers of a va-
ence by tM secntion of a variety of cytokines, including IL-1, riety of cytokines that regulate other cells of the imm une
Th""f-a, and ll-6. These cytokines are particularly adept at system and thereby shape and modify the body's ongoing
~ promotion of inflammatory responses, although each of and future defenses against the pathogen. It is notable that
~ agenu has a variety of effects. For example, IL-1 acti- NK cells produce interferon--y and TNF-a, two potent and
\'ilto lymphocyt~ and IL-1, IL-6, and TNF-a promote fever versatile immunoregulatory cytokines. These two
by affecting the thermoregulatory center in the hypothala- cytokines can stimulate the maturation of dendritk cells.,
mlli. These q 1olunes also promote the acute phase response the key coordinators of innate and adaptive immunity,
cfacu.sscd earlier and in Chapter 13. In addition to cytokines, discussed in the next section. Interferon--y is also a power-
acti\'ated macrophages produce complement proteins that ful mediator of macrophage activation and an important
promote inflammation and assist in eliminating pathogens. regulator of TH cell development, establishing a direct link
Although tht major site of synthesis of complement proteins between NK cells and the adaptive system.
ii tht liver, these proteim are also produced in macrophages
and other cell types.
Dendritic cells engage pathogens and invoke
NK cells are an important first line adaptive immune responses by activating
T cells
of defense against viruses and provide a key
activating signal to other cells Dendritic cells provide a brodder link between inndte and
ada_Ptive in:imun_ity th,m the other cells of innate immunity
Natural killer (NK) ull1 provide a first line of ddense by_ 1~teractmg with both TH cells a,id Tc cells. Mature den-
against many different viral infections. Using a system dis- dnuc cells are able to activate both TH and Tc cells because
cussed in Chapter 14 that allows them to distinguish be- they are able to present exogenous antigens on either MHC I
tween infected and uninfected host cells, NK cells target or MHC 11 and deliver strong costimulatory signals to the
and kill infected cells, which are potential sources of large T cells. As agents of innate immunity, immature dendritic
numbers of additional infectious virus particles. NK cell-
c~lls use a variety of ~~Rs, especially TLRs, to recognize
mediated lysis effectively eliminate, the infection or holds
pa~~ogens. The recognition causes the activation of den-
it in check until days later, when the adaptive immunt sys- ?nllc cells, whi~h then undergo a maturation process that
tem engages the infection with virus-specific cytotoxic T mdudes the increased production of MHC class II
cells and antibodies. However, some viral infections are
m~lecules and costimulatory molecules for T cell activation.
robably cleared completely by innate mechanisms such as (Like most nucleated cells, dendritic cells normally express
~K cells without any aid from adaptive immunity. Acti- class I MHC molecules.) Dendritic cells then migrate to
 INNATE IMMUNITY C 1-1 A , T E II J 69

lymphoid tissues, where they present antigen to both Ml IC da\S we examine a signaling pathway ( Figure 3-14) used by
II -dependent T helper (TH) cel ls and M HC cla,s I-depe ndent ~veral TIRs, which can serve as an a.ample for the signal-
T cytotoxic (Tc) cells. ing pa thways of other receptors of innate immunity listed in
T he dendr itic cell response is not limi ted to the vitall y Ta hie 3-3, all of which follow a similar outline. The pathway
important role of communication bt'twee n inn ate and d iSCU!,sed below result, in the induction of many of the sig-
adaptive immu nity. These versatile cell s al~o mount a direct nature featu re• of innate immunity, including the generation
assault on the pathogens they detect. Dendrit ic cells are ca- of infl am ma tory cytokine, and chemokinn, generation of
pable of generating the reactive oxygen species and nitric antim ic robial peptides, and so on.
oxide, and they have been reported to p roduce antimic ro- E. In itiation by interaction of signal with receptor: Microbial
bial peptides as well. Pathogens that suffer phagocytosis by products bind the C'X tracellular portion oft~ TLR rStt
dendritic cells a re therefore killed by many of th e same Figure 3- 10). On the cytoplasmic side, a ,eparate protein
agents used by macrophages. In addition, there is a subset of domain contains the highly c.on~ed TIR structural
dendritic cells, plasmacytoid dendritic cells, that are potent motifs found in signaling molecules of animals and
producers of type I interferons, a family of antiviral cy- plants. The TIR domain offers binding sites for other
tokines that induce a state in virally infected cells and other
components of the pathway.
nearby cells that is incompatible with viral replication. A
critical activity of viruses is expression of their genomes in ■ Signal-induced assembly of pathway components/
host cells. Engagement of TLRs on plasmacytoid dendritic involvement of an adaptor molecule: Adaptor proteins,
cells with foreign nucleic acid triggers production of the themselves containing TIR domains, interact with the
type I interferons that block viral replication. Other subsets TIR domain of TLRs. The most common a.daptOI'
of dendritic cells produce interleukin-12, TNF-a, and IL-6, protein for TIRs is My088, which p romotes the
potent inducers of inflammation. One of this group, IL-12, association of two protein kinases, JRAKl and IRAK-l.
plays a major role in shaping the T helper cell responses of ■ Protein kinase-mediated phosphorylatwn: The protein
adaptive immunity. kinase IRAK4, of the IRAK 1:IRAK4 com plex,
phosphorylates its partner, IRA.K l. The n~iy attached
phosphate provides a docking site on IR.U:1 for TR-\F6,
Signal Transduction Pathways which binds and then dissociates in co mpany with
Cell surface receptors receive the initial signals that activate IRAKl to fonn an intermediate IRAK 1:TR-\F6 com pla..
complex innate immune system responses. The next step, Another protein kinase, TAK l , _ioins this complex with
transmission of signals to the cell interior, or signal trans- several other proteins, resulting in the actnration of the
duction~ is a universal theme in biological systems and an TAKI kinase activity.
area of intense research in many fields beyond immunology. • Initiation of an enzyme cascade: TAK I is pivotal in the
Response to signals requires three elements: the signal itself, pathway because its protein kinase acti1ril)· allows it to
a receptor, and a signal transduction pathway that connects perform the phosphorylation-mediated actintio n of two
the detector to effector mechanisms. other signal transduction modules. One of these is the
mitogen-activated protein kinase l ~L\.P kin.i.se ) path~-.iy,
Signal---+ receptor---+
signal transduction ---+ effector mechanism and the other is the 1'FKB pathway (Stt below). ~L\.P
kinase pathways are signal-transducing el\Z)me 1.~ades
Thii general pathway is illustrated in Figure 1-6. found in many cell types and consen'l!'J ,Kross ~
In the case of innate immunity, the signal will be a mi- spectrum of eukaryotes from yeasts to humIDs. The end
crobial product, the receptor will be a PRR on a leukocyte, product of the cascade enters tht> nudeus ffld promotes
and the signal will be tran.duced by the interactions of spe- phosphorylation of one or more tr-.m~ription factors.
cific intracellular molecules. The effector mechanism-the which then affnt the cell q ·de or celluJ.ir ditl('renti,uion.
action that takes place as a con&equence of the signal-
results in the clearance of the invading organism. Signaling TAK I also phosphor)·l,ues the prott>in kinase IKK, which
and its consequences is a recurring theme in immunology. ii the key step in activating the NFKB pathway. NFKB is a
Some general features of signal tranduction pathways are powerful transcription factor who~ activity is inhibited bv
outlined here, followed by the example of , ignal tramduc- the unphosphorylated form of a cytoplasmic protein, IKB.
tion through TLRs. NFKB bound to unphosphorylated IKB is sequestered in the
cytoplasm. lKK phosphorylates IKB, causing the release of
Nh:B, which can then migrate to the nucleus.
TLR signaling is typical of signal transduction NFKB in the nucleus initiates the transcription of many
pathways genes necessary for the effector functions of innate immu-
TLJu and their roles in innate immunity were discovered nity. In vertebrates, NFKB-dependent pathways generate
only recently, yet the major signal transduction pathways cytokines, adhesion molecules.. and other effectors of the
~d by these receptors have already been worked out. Here innate immune response. NFKB also plays a role in some key
 70 P A It T I
INTRODUCTION

l ~ - - - - - - - - --- 7
JR,\ K-i phoc;phory lalc" IRAK I . c rratinjl a
hindin~ ,11c for TRM-6

11U F6

1 3

I
C)
~ TAKl (Orl')
The JRAKI -TRAf6 comp kx dis'KXiate~ and
activates the protein kina~ TAK I compkx

• TAKI (ON) The active TAK I activates two distinct signaJ

~
transducti on pathways

.,--._,_
·~ ---- ---- ---- ---- -,
TAKI phosp~- wcs IKK to activate the TAKI also phosphory lates and acti~.ate5
,r icB path•·a~-: Du( then phosphocyiates a componen t of the MAP kinase O UPK)
IKB. a ~ ir to rdcasc :\'FKB pathway

~ MAPkinas es

l
l
,m~
J
(±)
lW~ MAPK pathway-
dc-1lt·nuc-nt

6a1-- ----- ---- ---- --. (,h,;- - - - - - - - - - -- - -

The freed NfKB tramlocai ~ from the
l'ht' MAPK l"ast·a t
qtopla."m into the nudcu.,. where it o .. . . l t' rt'sults in tr.insl<X·ation
t a tr-,Ulsl·npUonal Jl'tivat or .,__
serves u a tr,m!l(.'riptimu.1 u ·tivator for ., . ,u>m tht"
q loplasm Into tht' nudt'us .
NFKB-dep cndcntgen es tr,msnipti on of MAP . • where n activates
K-dt'pendent genes

FIGURE 3-14 A typical TLR signal transduction pathway. Abbrevia- tumor-necrosis-factor-receptor-ass . ed

tions: MyD88, myeloid differentiation primary-response protein BB; growth-factor-13-activated k' ociat factor 6; TAKl, transforming-
inase 1. MAPK . .
IRAK. IL-1R-associated kinase; IL-1R, interleukin-1 receptor; TRAF 6, ki
nase; IKB, inhibitor of nucle c ' • mitogen-act1vated protein
ar ,actor NFKB; IKK, IKB kinase.
 INNATE IMMUNITY C H A P T l R 3 71

signal transduction pathwars of T and 13 cells and is th ere- imm unit y. The accumu latin g eviclence lcacls to th e conclu-
fore also important in ad.1ptive immunit y. sion th at some sys tem of immunit y protec ts all multicellular
Activation of TLR signaling pathways has many effects. It organisms from microbial infection and exploitation. The
promotes the e:-..pression of genes that co ntribute to genome of th e sea squirt, Ciona intestinalis (Figure 3- 1Sa),
inflJmmation , induces ch.111ges in anti gen-presenting cells encodes many of lhe genes associated wi th innate immunit y,
that make them more efficien t at antigen presentation, and including those for compl ement -like lectins and Toll -like
causes the synthesis and export of intercellular signaling receptors. Jn fruit flies, a pathway involving a member of
molecules that affrct the brhavior of leukocytes and other the NFKB family is triggered by gram-negative bacterial
c_e~s- Engagemen t of TLRs ca n increase the phagocytic ac- infections, leading to the production of dipter~n, a potent
t1n ~ of m_acrophages and neutrophils and change their antibacterial peptide. In addition to these pathways,
physiology m ways that increase thrir ability to kill and clear Drosophila and other arthropods have a variety of other
pathogens. In nonvertebrate systems, TLR signaling activates strategies of innate immunity, which include the activation
a \'ariety of effective systems of immunity. Most, but not all, of.£!.Ophenoloxidase cascades that result in the deposition of
TLRs employ the signal transduction pathway schematized melanin around invading organisms. The tomato, Lycopersi-
in Figure 3-14. TLR3 uses a pathway that is independent of con esculentum (Figure 3-lSb), like other plants, has evolved
MyD88, and TLR4 uses both the pathway described above a repertoire of innate immune defenses to protect itself
and the ~fyD88-independent pathway employed by TLR3. against infection. These include generation of oxidative
bursts, raising of internal pH, localized death of infected
regions, and the induction of a variety of proteins, including
enzymes that can digest the walls of invading fungi (chiti-
Ubiquity of Innate Immunity nases) or bacteria (a-1,3 glucanase). Plants also respond to
A determined search for antibodies, T cells, and B cells in infection by producing a wide variety of antimicrobial pep-
organisms of the nonvertebrate phyla has failed to find any tides, as well as small nonpeptide organic molecules, such as
traces of these signature features of adaptive immunity. Yet phytoalexins, that have antibiotic activity. Mutations that
despite their prominence in vertebrate immune systems, it ..._disrupt syntfiesis of phytoalexins result in loss of resistance
would be a mistake to conclude that these extraordinary to many plant pathogens. In some cases, the response of
molecules and versatile cells are essential for immunity. The plants to pathogens even goes beyond a chemical assault to
interior spaces of organisms as diverse as the sea squirt (a include an architectural response, in which the plant isolates
chordate without a backbone), fruit fly, and tomato do not cells in the infected area by strengthening the walls of sur-
contain unchecked microbial populations. Careful studies of rounding cells. Table 3-4 compares the capabilities of im-
these organisms and many other representatives of nonver- mune systems in a wide range of multicellular organisms,
tebrate phyla have found well-developed systems of innate both animals and plants.

(b)
(.a)

flCiURE 3- 15 Innate Immunity in species extending across the plant kingdom, the tomato. {Part a. Gary Bell/Getty Images; part b,
lun1dom1. (a) Sea squirts, nonvertebrate chordates. (b) A member of George Glod, SuperStock.)
 ----- --
72 P A R T I
INTRODUCTION

TABLE 3-4 Immunity in multicellular organisms

Invasion-
Induced
protective Pattern Anti-
enzymes Anti- rand B
Innate Adaptive recognition Graft bodies
microbial cells
Taxonomic immunity immunity and enzyme rejection
peptides receptors
Phagocytosls
group (nonspecific) (specific) cascades
- -
- + - + + -
Higher plants +
+ - -
Invertebrate animals ? 7
Porifera + - ? +
(sponges) + - -
? ?
Annelids + - ? +
-
(earthworms)
+ ? -
Arthropods + - + + +
(insects,
crustaceans)
Vertebrate animals + + +
+ + Equivalent +
Elasmobranchs + + agents
(cartilaginous
fish;e.g~
sharks, rays)
+ + +
Teleost fish and + + + Probable +
+
bony fish (e.g.,
salmon, tuna) +
+ + +
Amphibians + + + + +
+ + + +
+ + + ?
Reptiles + + +
+ + + 7 + +
Birds + +
+ + + + +
Mammals + + +

KEY: + =definitive demonstration; - = failure to demonstrate thus far; ? = presence or absence remains to be established.
System," in Fundamental Immunology, 5th ed., W. E. Paul (ed.),
SOURCES: M. J. flajnik, K. Miller, and L Du Pasquier, 2003, "Origin and Evolution of the Vertebrate Immune
Lippincott, Philadelphia: M. J. Flajnik and L Du Pasquler, 2004, Trends In Immunology 25:640.

■ Inflammation increases vascular permeability, allowing sol-

SUMMARY uble mediators of defense such as complement, mannose-
• Two systems of immunity protect vertebrates: innate immu- binding lectin (MBL), C-reactive protein (CRP), and later
nity, which is in place or ready for activation prior to infec- antibodies to reach the infected site. In addition, inflamma-
tion, and adaptive immunity, which is induced by infection tion caus~s migration of phagocytes and antiviral cells by
and requires days to weeks to respond. extravasation and chemotaxis to the focus of infection.
• The receptors of innate immunity recognize pathogen- ■ Antir:riicrobial peptides are important effectors of innate im-
associated molecular patterns (PAMPs), which are molec- mum~ and h_ave be~n found in a broad diversity of species.
ular motifs found in microbes. In contrast, the receptors of They. kill a. wide. vanety of microorganisms , often worki ng
.
adaptive immunity recognize specific details of molecular bYdisruptmg m1crob1al membranes.
structure.
■ Many cytokines are generated by the in t .
• The receptors of innate immunity are encoded in the host tern These cytokines me . 1d nae immune sys-
. u e type I · rfi
germ line, but the genes that en_c ~e antib~ies and T cells, antiviral effects and oth h mte erons that have
ers sue as TNF d.
the signature receptors of adaptive 1mmumty, are formed by that exert powerful effe t -a an mterferon--y
a process of genetic recombination. c s on other cells and
• Certain cytoki •d organs.
. nes m uce an acute h
~ Adaptive immune responses display memory, whereas in- during which several an1·un1crob1al . ~ ase response, a process
•
nate responses do not. from the liver to the bloods proteins are released
. . nd mucous membranes constitute an anatomi- MBL, CRP, and compleme ~;ea;, ~ong these proteins are
Theskma . a· · · .
• that is highly euecuve m protecting against
caJ barner • The innate immun ' w ic can act to kill microbes.
e system emplo .
infection. ceptors (PRRs) to d..t- · , . ys pattern recognition re-
~"'~l m,ection 1i U
0 1:L.
• • 11\C' receptors (TLRs )
' INNATE IMM UN ITY C H ,. ' T I • 3 73

a_re an important ca tegory of PRRs; e,Kh TlR dctc...ts II clis-

tmct subset
. of. p.:ithogens, a, noJ t h e cnt1n.
tect a w1de v.1nety, of v ,ruses,
· h ,h . .· f
. · repertoire can dc-
.
.tllJII Useful Web Sites
. let 1a, un~•• and pr11to1rn1.
http://www.nc.bi .nlm.nih.gov/PubMed/
• Phag~~s use a v,uicty of stratq,tics to kill p..itho~cns. These
strategies mdu~e cyto lvtic proteins. antimicmhial peptides, l'uhM n l, the N;itiona l l.1br.u y of Med,ci~ d.1raha~ of
more th,m J'l million puhl1c.at1001, '" the world ', mr,'lt
an~ the_generat,on ofrcactivt' oxygen species ( RO~ ) and re -
compre h emive hihlio~raphic. dilt.:iha~ fr,r h1oln~ic.al and
actJ\'e mtrogen spedes ( RNS ).
hinmerlica l literature. It ;, al~o highly u~r friendly.
• Dendritic
• •
cells are
.
a key
• •
cellular bri leIge h e,...,-veen ad .ipt1vc
· an d
mn~te immumty. M1erohial components acquired during http://cpmcnet.columbia.edu/dept/currk-p.athotGgy/
pathology/pathology/pathoatla§/GP_t_rnenu.htmt
~e mnate n:sponse by dendritic cells are brought from th e
site Image!! are .~hown of the major intlammatory cell, involved
. of mfectJon to l)'lnph nod cs, an d nucro · b.,aJ antigens · are in acu te and chronic inflammation, a, well a, example, of
d,s~la):<l on l\fHC molecules and presented to T cells, re- specific inflammator y disease,.
sulting m T cell activatJ·on a n d an a d apt1ve
· immune
· response.
http://animaldiversity.ummz.umich.edu/sit.e /
• TLRs use signal-transduction pathways common to those
Index.html
fou_nd ~h~ughout the plant and animal kingdom. TLR sig- The Animal Oivenity Web ( ADW >, ba~d at the
~alm~ initiates events that enable cells to control and clear University of Michigan, is an excellent and comprehensrve
mfect1ons. database of animal classification as well as a sourc~ of
• Innate immunity appeared early in the evolution of multi- information on animal natural history and distribution.
cellular organisms and has been found in all multicellular Here is a place to find information about animals that are
plants and animals examined. Adaptive immunity is found not humans or mice.
only in vertebrates.

References ~ Study Questions

Akira, S., and K. Takeda. 2004. Toll-like receptor signaling. Na- CLINICAL Focus Q U ESTION Comment on the roie of inflam-
ture Reviews Immunology 4: 499. matory processes in the development and progression of
Basset, C., et al 2003. Innate immunity and pathogen-host in- atherosclerosis. How might inflammation raise CRP levels?
teraction. Vaccine 21: s2/12. 1. Innate immunity collaborates with adaptive immunity to pro-
Beutler, B., and ET. Rietschel. 2003. lnnate immune sensing and its tect the host. Discuss this collaboration, naming key points of
roots: the story of endotoxin. Nature Reviews Immunology 3: 169. interaction between the two systems.

Bulet, P., R Stocklin, and L. Menin. 2004. Antimicrobial peptides: 2. What are the hallmark characteristics of a localized intlamma-
from invertebrates to vertebrates. Immunological Reviews 198: 169. tory response? How do these characteristics contribute to the
mounting of an effective innate immune response?
Fang, F. C. 2004. Antimicrobial reactive oxygen and nitrogen
species: c.oncepts and c.ontroversies. Nature Reviews Microbiol- 3. Use this list to complete the statements that follow. Some
terms may be used more than once.
ogy 2: 820.
Iwasaki, A., and R Medzhitov. 2004. Toll-like receptor control of Interferon Antimicrobial ~ptid~
the adaptive immune responses. Nature Immunology 5: 987. NO TLR8
TLR2 NADPH ph.igosome ox.iJ~
Lemaitre, B. 2004. The road to Toll. Nature Reviews Immunology
TNF-cx Antibody
4: 521.
NK cells PAMPs
Medzhitov, R., et al. 1997. A human homologue of the Toll pro-
tein signals activation of adaptive immunity. Nature 388: 394.
TLR4 oi
NOD Complement
O'Neill, A. J. 2005. Immunity's early warning system. Scientific Class I MHC molt'cult's Class 111\,lHC molecules
American 292: 38. Phagocytosis CRP
Pai, J. K., et al. 2004. Inflammatory markers and the risk of coro- iNOS T cell rect>ptors
nary heart disease in men and women. New England /ourm,I of Costimulatury molt'.'cules Innate immunity
Medicine 351: 2599. Adaptive immunity APR
Poltorak, A., et al. 1998. Defective LPS signaling in C3Hej and PRRs ROS
C57BUIOScCr mice: mutations in TLR4 gene. Science 282: 2085. TLR7 RNS
Ridiker, P. M., et al. 2005. C-reactive protein and outcomes after Dendritic cell TLR9
statin therapy. New England Journal of Medicine 352: 20. TH Tc
Ulevitch, R. J. 2004. Therapeutics targeting the innate immune Arginine Proinflammatory cytokines
~yi.tt'.'m. Nature Reviews Immunology 4: 512. MBL NADPH