Antigen Presenting Cells (APCs)
377
known receptors are phagocytic receptors
that stimulate ingestion of pathogens. One
of these receptors is the mannose receptor
(MR). The MR is also expressed on DCs,
but not on monocytes or neutrophils. The
MR is a C-type lectin that binds speciFc
arrays of terminal mannose or fucose
residues of glycoproteins and glycolipids,
as they are found on the surface of many
bacteria and some viruses, including the
human immunodeFciency virus (HIV).
Mammalian equivalents contain termi-
nal sialic acid or N-acetylgalactosamine,
which is why the MR recognizes microbes
and not host cells. Bacterial carbohydrates
are also bound by the glucan receptor.
Another receptor is the scavenger receptor
(CD36). Originally, this receptor was found
to bind to aberrant low-density lipoproteins
(LDLs
)tha
tareunab
letobetakenupv
ia
the LDL receptor. Today it is known that
CD36 is involved in removal of old red
blood cells and in recognition and removal
of pathogens.
Moreover, macrophages express several
types of ±c
γ
receptors suitable for bind-
ing the ±c portion of IgG antibodies.
During a humoral response, soluble IgG
molecules coat the microbes and thereby
promote phagocytosis by macrophages.
Host proteins such as IgG that promote
phagocytosis of microorganisms, such as
bacteria, are called
opsonins
.±u
r
the
rop
-
sonins are fragments of the complement
factor C3 and plasma proteins, such as F-
bronectin, Fbrinogen, C-reactive protein,
or the mannose-binding lectin. They coat
microbes early in the course of an infec-
tion before speciFc antibodies are available
and bind to receptors, such as the integrins
α
v
β
3
and Mac-1 (CD11b/CD18).
A third class of receptors that binds
microbial components induces effector
molecules that mediate initiation of an in-
nate immune response. The best-deFned
activation pathway of this type is triggered
through the family of Toll-like receptors.
The name for these receptors reflects the
fact that their extracellular regions are ho-
mologous to the protein Toll of the fruit fly
Drosophila. In this invertebrate, Toll trig-
gers the production of antifungal peptides
in response to fungal infection. In mam-
mals, a Toll-family protein called
Toll-like
receptor 4
, or TLR-4, signals the presence
of the gram-negative cell-wall component
LPS, also named
endotoxin
.Thepo
lysac
-
charide moieties of LPS vary strongly
between bacterial strains and are major
antigens in inducing an adaptive immune
response. The lipid moiety, by contrast,
is conserved and is a good example of a
molecular pattern recognized by the innate
immune system.
The LPS recognition system of macro-
phages consists of 3 components: (1) a
plasma protein, termed
LPS–binding pro-
tein
(LBP); (2) CD14, which binds LPS
boundtoLBP
;and(3
)TLR
-4
,thes
igna
l
-
transducing receptor. Circulating LPS is
captured by LBP, whereupon the LPS-LBP
protein binds to CD14. Upon dissociation
of LBP, LPS-CD14 engages TLR-4 lead-
ing to activation of the macrophage. This
is accomplished via a signal transduction
pathway sharing structural homology with
the type-I IL-1 receptor pathway. Both IL-1
and LPS stimulate activation of the tran-
scription factor N±-
κ
B, leading to cytokine
secretion and activation of inflammation.
Another mammalian Toll-like receptor,
TLR-2, signals the presence of another
set of bacterial components that mainly
include proteoglycans of gram-positive
bacteria. TLR-2 and TLR-4 induce similar
but distinct signals. Macrophages are also
able to sense the intracellular presence
of bacterial DNA. Bacterial DNA con-
tains
unmethylated
cytidine–guanidine
sequences, the so-called CpG nucleotides.
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