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structures are generally known as
pathogen-associated
molecular patterns
(PAMPs), and the receptors that rec-
ognize them as
pattern recognition receptors
(PRRs).
The recognized structures of PAMPs are essential
to the functioning and infectivity of the microbe. The
microbe cannot, therefore, evade innate immune rec-
ognition through mutation or a lack of production of
the molecules because they would not survive. Humans
inherit a limited number of germline genes for PRRs that
effectively recognize major groups of microbes. One such
receptor is the mannose-binding lectin (MBL), which is
present as a free protein in the blood plasma. Pathogen
recognition and discrimination of self from nonself by
the MBL is due to the particular orientation and spacing
of particular sugar residues, which are found only on
microbes and not on host cells.
The phagocytic cells of the innate immune system are
also equipped with several cell surface receptors that
recognize pathogen surfaces directly. Among these is
the macrophage-mannose receptor. This receptor binds
certain sugars found on the surface of many bacteria
and viruses, including HIV. A second set of phagocytic
receptors, called the
scavenger receptors,
were originally
defined as molecules that bind and mediate endocytosis
of oxidized or acetylated low-density lipoproteins (LDLs)
that do not interact with the conventional LDL receptor
(see Chapter 18). Macrophage scavenger receptors bind
a variety of microbes in addition to LDL particles.
Not all receptors that recognize pathogen-specific
molecules are phagocytic receptors. The binding of
pathogens to some receptors on leukocytes initiates a
series of signaling events that lead to the tissue changes
associated with acute inflammation. Stimulation of other
pattern receptors leads macrophages and dendritic cells
to display co-stimulatory molecules that enable them to
act as antigen-presenting cells to lymphocytes and initi-
ate an adaptive immune response.
Toll-Like Receptors
The best-defined activation pathway for the pathogen
sensors of innate immunity is a family of transmembrane
receptors called
Toll-like receptors
(TLRs). Interestingly,
the first protein to be identified in this family was the
Drosophila
Toll protein, which was found in the fruit
fly
Drosophila,
where it functions in embryonic develop-
ment as well as in protecting the fly from lethal fungal
infections.
Eleven different TLRs have thus far been identified,
each specific for different components of microbes
(Table 15-2). Although most TLRs are found on the
surface of the leukocytes, a few are intracellular,
where they recognize viruses and intracellular patho-
gens such a
Mycobacterium
. Because there are only
11 recognized TLR genes, the Toll-like receptors have
limited specificity compared with the antigen recep-
tors of the adaptive immune system. Despite this lim-
ited diversity, they can recognize elements of most
microorganisms.
Ligand binding to the TLR at the cell surface leads
to an intracellular cascade of events which ultimately
regulates the production of several proteins that are
important components of innate immunity. Alterations
in the structure of TLRs or mutations in the signaling
system associated with TLRs have been suggested to
play a pathologic role in disorders such as atherosclero-
sis, allergies, and certain autoimmune diseases.
Soluble Mediators of Innate
Immunity
Although cells of the innate immune system can commu-
nicate critical information about microbial agents and
self–nonself recognition through cell-to-cell contact,
soluble mediators are essential for many other aspects
of the response. Development of innate immunity and
regulation of the behavior of effector cells both depend
on the secretion of soluble mediators such as opsonins,
cytokines, and proteins of the complement system.
Opsonins
Various soluble molecules can tag microorganisms for
more efficient recognition by phagocytes. The coating
of particles, such as microbes, is called
opsonization,
TABLE 15-2
Types of Toll-Like Receptors (TLRs) andTheir Recognized Ligands
TRLs
Ligands
Type of Microorganisms
TRL1
Lipopeptides
Mycobacteria
TRL2
Peptidoglycan
Gram-positive bacteria
Lipoprotein
Mycobacteria
Zymosan
Yeast and other fungi
TRL3
Double-stranded RNA
Viruses
TRL4
Lipopolysaccharide
Gram-negative bacteria
TRL5
Flagellin
Flagellated bacteria
TRL6
Lipopolypeptide
Mycobacteria
Zymosan
Yeast and fungi
TRL7
Single-stranded RNA (ssRNA)
Viruses
TRL8
Single-stranded RNA (ssRNA)
Viruses
TRL9
CpG unmethylated dinucleotides
Bacterial DNA
TRLs 10,11
Unknown
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