Chapter 13
Innate and Adaptive Immunity
285
(approximately 1000) so the classes of pathogens recognized
by them are very diverse. Therefore, pathogens of very dif-
ferent biochemical composition are recognized by relatively
similar mechanisms by host PRRs, and no single class of
pathogens is sensed by only one type of PRR. Therefore, the
host genetic code allows for the unique receptors involved in
both innate and adaptive immunity to recognize fine details of
molecular structure.
The ability of the innate immune response to limit
microbes early in the infectious process results from the bind-
ing of pathogens to the PRRs on leukocytes, which in turn
initiates the signaling events that lead to complement activa-
tion, phagocytosis, and autophagy. Once initiated, white blood
cells, neutrophils, and monocytes migrate from the blood to the
tissues, along with other body fluids causing peripheral edema.
Blood monocytes mature into macrophages as they traverse
the tissues and join the macrophages and DCs already present
in the tissues. PRRs present on these cells become activated,
which amplifies the inflammatory response through enhanced
secretion of all chemical mediators including cytokines
and complement.
Toll-Like Receptors
The most studied PRRs associated with the innate immune
response are the
Toll-like receptors
(
TLRs
). TLRs derive their
name from the study of the
Drosophila melanogaster
toll pro-
tein, which is responsible for the resistance of
Drosophila
to
bacterial and fungal infections.
3,4
Structurally, TLRs are inte-
gral glycoproteins that possess an extracellular or luminal
ligand-binding site containing leucine-rich repeats and a cyto-
plasmic signaling toll/interleukin-1 (IL-1) domain.
17
Binding
of PAMP to a TLR induces a conformational change in the
receptor, which subsequently triggers intracellular signal
transduction and activation of cellular processes, such as acti-
vation of transcription factors such as nuclear factor
κβ
(NF-
κβ
). NF-
κβ
regulates the production of a number of proteins
that are important components of innate immunity. TLRs can
be found in most of the bone marrow cells including the mac-
rophages, DCs, neutrophils, T cells, B cells, and non–bone
marrow cells including epithelial and fibrocytes. Eleven dif-
ferent TLRs have been identified in humans, and they each
recognize distinct PAMPs derived from various microorgan-
isms including bacteria, viruses, fungi, and protozoa.
18
Human TLRs can be divided into subfamilies that pri-
marily recognize related PAMPs. TLR1, TLR2, TLR4, and
TLR6 recognize lipids and lipopolysaccharides (LPS),
whereas TLR3, TLR7, TLR8, and TLR9 recognize nucleic
acids.
18
TLRs can also be classified according to their cel-
lular distribution such that TLR1, TLR2, TLR4, TLR5,
TLR6, TLR10, and TLR11 are expressed extracellularly
and THR3, TLR7, TLR8, and TLR9 are mainly expressed in
intracellular compartments.
19,20
These receptors are involved
in responses to widely divergent types of molecules that
are commonly expressed by microbial, but not mam-
malian, cell types. For example, TLR4 is essential for
phagocytic recognition and response to the LPS present in
germline-encoded
pattern recognition receptors
(
PRRs
).
Upon PAMP recognition, PRRs come in contact with the
cell surface and/or send intracellular signals to the host that
trigger proinflammatory and antimicrobial responses includ-
ing the synthesis and release of cytokines, chemokines, and
cell adhesion molecules.
3
The PAMPs recognized by the host
PRRs are made up of a combination of sugars, lipid mole-
cules, proteins, or patterns of modified nucleic acids and are
essential to the functioning and infectivity of the pathogen.
Because the PAMPs are essential for the functioning of the
microorganism, mutation cannot help it avoid immune rec-
ognition. The human complement of PRRs is very extensive
Normal cell
NK cell
Inhibitory receptor
MHC-I self-recognition
peptide
Activating receptor
Ligands for
activating receptor
Inhibitory receptor
not engaged
Virus inhibits
MHC-I expression
Cell killing
No cell killing
Virus-infected cell
A
B
FIGURE 13.2
•
Natural killer (NK) cell receptors. (
A
) NK cells express
activating receptors that respond to ligands from virus-infected or injured
cells and inhibiting receptors that bind to the class I major histocompat-
ibility complex (MHC-I) self-recognition molecules expressed by normal
cells. Normal cells are not killed because inhibitory signals from normal
MHC-I molecules override activating signals. (
B
) In virus-infected or
tumor cells, increased expression of ligands for activating receptors and
reduced expression or alteration of MHC molecules interrupts the inhibi-
tory signals, allowing activation of NK cells and lysis of target cells.
