NK-T cells, MAIT cells, ?d T cells, B-1 cells, and

marginal-zone B lymphocytes all respond to infections

in ways that are characteristic of adaptive immunity

(e.g., cytokine secretion or antibody production) but

have features of innate immunity (rapid responses, limited diversity of antigen recognition).

Complement System

The complement system is a collection of circulating

and membrane-associated proteins that are important in

defense against microbes. Many complement proteins are

proteolytic enzymes, and complement activation involves

the sequential activation of these enzymes. The complement

cascade may be initiated by any of three pathways (Fig. 2.14):

• The alternative pathway is triggered when some

complement proteins are activated on microbial surfaces and cannot be controlled, because complement

regulatory proteins are not present on microbes (but

are present on host cells). The alternative pathway is

a component of innate immunity.

• The classical pathway is most often triggered by antibodies that bind to microbes or other antigens and

is thus a component of the humoral arm of adaptive

immunity.

• The lectin pathway is activated when a carbohydrate-binding plasma protein, mannose-binding

lectin (MBL), binds to its carbohydrate ligands on

microbes. This lectin activates proteins of the classical pathway, but because it is initiated by a microbial

product in the absence of antibody, it is a component

of innate immunity.

Activated complement proteins function as proteolytic enzymes to cleave other complement proteins. Such

an enzymatic cascade can be rapidly amplified because

each proteolytic step generates many products that are

themselves enzymes in the cascade. The central component of all three complement pathways is a plasma protein called C3, which is cleaved by enzymes generated

in the early steps. The major proteolytic fragment of C3,

called C3b, becomes covalently attached to microbes

and is able to recruit and activate downstream complement proteins on the microbial surface. The three pathways of complement activation differ in how they are

initiated, but they share the late steps and perform the

same effector functions.

The complement system serves three main functions

in host defense:

• Opsonization and phagocytosis. C3b coats microbes

and promotes the binding of these microbes to phagocytes by virtue of receptors for C3b that are expressed

on the phagocytes. Thus, microbes that are coated

with complement proteins are rapidly ingested and

destroyed by phagocytes. This process of coating a

microbe with molecules that are recognized by receptors on phagocytes is called opsonization.

• Inflammation. Some proteolytic fragments of complement proteins, especially C5a and C3a, are chemoattractants for leukocytes (mainly neutrophils

and monocytes), and they also are activators of endothelial cells and mast cells. Thus, they promote movement of leukocytes and plasma proteins into tissues

(inflammation) at the site of complement activation.

• Cell lysis. Complement activation culminates in

the formation of a polymeric protein complex that

inserts into the microbial cell membrane, disturbing

the permeability barrier and causing osmotic lysis.

A more detailed discussion of the activation and

functions of complement is presented in Chapter 8,

where we consider the effector mechanisms of humoral

immunity.

Other Plasma Proteins of Innate Immunity

Several circulating proteins in addition to complement

proteins are involved in innate immune defense against

infections. Plasma MBL recognizes microbial carbohydrates and can coat microbes for phagocytosis or activate the complement cascade by the lectin pathway, as

discussed earlier. MBL belongs to a family of proteins

called the collectins, because they are structurally similar

40 CHAPTER 2 Innate Immunity

Initiation of

complement

activation

Late steps

C3a

Effector

functions

C3a:

Inflammation

C3b:

opsonization

and

phagocytosis

C6-9:

Lysis of

microbe

C5a:

Inflammation

Microbe

Antibody Mannose

binding

lectin

Alternative

pathway

Classical

pathway

Lectin

pathway

C3b

C3b

C3b is

deposited

on microbe

Complement

proteins form

membrane

attack complex

Early steps

MAC

C6-9

C5a

C5 C5b

C5b

B C3 C2 C4

C2 C4

C3b C3

C3b C3

C3 C3b

Fig. 2.14 Pathways of complement activation. The activation of the complement system (the early steps)

may be initiated by three distinct pathways, all of which lead to the production of C3b. C3b initiates the late

steps of complement activation, culminating in the formation of a multiprotein complex called the membrane attack complex (MAC), which is a transmembrane channel composed of polymerized C9 molecules

that causes lysis of thin-walled microbes. Peptide by-products released during complement activation are

the inflammation-inducing C3a and C5a. The principal functions of proteins produced at different steps are

shown. The activation, functions, and regulation of the complement system are discussed in more detail in

Chapter 8.

CHAPTER 2 Innate Immunity 41

to collagen and contain a carbohydrate-binding (lectin)

domain. Surfactant proteins in the lung also belong to

the collectin family and protect the airways from infection. C-reactive protein (CRP) is a pentraxin (five-headed

molecule) that binds to phosphorylcholine on microbes

and opsonizes the microbes for phagocytosis by macrophages, which express a receptor for CRP. CRP also can

activate proteins of the classical complement pathway.

The circulating levels of many of these plasma proteins increase rapidly after infection. This protective

response is called the acute-phase response to infection.

Cytokines of Innate Immunity

In response to microbes, dendritic cells, macrophages,

mast cells and other cells secrete cytokines that mediate many of the cellular reactions of innate immunity

(Fig. 2.15). As mentioned earlier, cytokines are soluble

proteins that mediate immune and inflammatory reactions and are responsible for communications between

leukocytes and between leukocytes and other cells. Most

of the molecularly defined cytokines are called interleukins with a number, for example interleukin-1, but

several have other names, for example tumor necrosis

factor, for historical reasons related to how they were

discovered. In innate immunity, the principal sources

of cytokines are dendritic cells, macrophages, and mast

cells that are activated by recognition of microbes,

although epithelial cells and other cell types also secrete

cytokines. Recognition of bacterial cell wall components

such as LPS and peptidoglycan by TLRs and recognition

of microbial nucleic acids by TLRs, RLRs, and CDSs are

powerful stimuli for cytokine secretion by macrophages,

dendritic cells, and many tissue cells. In adaptive immunity, helper T lymphocytes are a major source of cytokines (see Chapters 5 and 6).

Cytokines are secreted in small amounts in response

to an external stimulus and bind to high-affinity receptors on target cells. Most cytokines act on nearby cells

(paracrine actions), and some act on the cells that

produce them (autocrine actions). In innate immune

reactions against infections, enough dendritic cells and

macrophages may be activated that large amounts of

cytokines are produced, and they may be active distant

from their site of secretion (endocrine actions).

The cytokines of innate immunity serve various

functions in host defense. Tumor necrosis factor (TNF),

interleukin-1 (IL-1), and chemokines (chemoattractant cytokines) are the principal cytokines involved in

recruiting blood neutrophils and monocytes to sites

of infection (described later). TNF and IL-1 also have

systemic effects, including inducing fever by acting on

the hypothalamus, and these cytokines as well as IL-6

stimulate liver cells to produce various proteins of the

acute phase response, such as C-reactive protein and

fibrinogen, which contribute to microbial killing and

walling off infectious sites. At high concentrations,

TNF promotes thrombus formation on the endothelium and reduces blood pressure by a combination of

reduced myocardial contractility and vascular dilation

and leakiness. Severe, disseminated bacterial infections sometimes lead to a potentially lethal clinical

syndrome called septic shock, which is characterized

by low blood pressure (the defining feature of shock),

disseminated intravascular coagulation, and metabolic

disturbances. The early clinical and pathologic manifestations of septic shock may be caused by high levels

of TNF, which is produced in response to the bacteria.

Dendritic cells and macrophages also produce IL-12 in

response to LPS and other microbial molecules. The

role of IL-12 in activating NK cells, ultimately leading

to increased killing activity and macrophage activation,

was mentioned previously. NK cells produce IFN-?,

whose function as a macrophage-activating cytokine

was also described earlier. Because IFN-? is produced

by T cells as well, it is considered a cytokine of both

innate immunity and adaptive immunity. In viral infections, a subset of dendritic cells, and to a lesser extent

other infected cells, produce type I IFNs, which inhibit

viral replication and prevent spread of the infection to

uninfected cells.

INNATE IMMUNE REACTIONS

The innate immune system eliminates microbes

mainly by inducing the acute inflammatory response

and by antiviral defense mechanisms. Different

microbes may elicit different types of innate immune

reactions, each type of response being particularly effective in eliminating a particular kind of microbe. The

major protective innate immune responses to different

microbes are the following:

• Extracellular bacteria and fungi are defended

against mainly by the acute inflammatory response,

in which neutrophils and monocytes are recruited

to the site of infection, aided by the complement

system.

IFN-?