Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

1302 Chapter 24: The Innate and Adaptive Immune Systems
If a pathogen is too large to be successfully phagocytosed (if it is a large parasite
such as a worm, for example), a group of macrophages, neutrophils, or eosinophils
(another type of leukocyte) will gather around the invader. They secrete
defensins and other damaging agents and release the toxic products of the respiratory
burst. This barrage is often sufficient to destroy the pathogen (Figure 24–6).
schistosome larva
eosinophils
Complement Activation Targets Pathogens for Phagocytosis or
Lysis
The blood and other extracellular fluids contain numerous proteins with antimicrobial
activity, some of which are produced in response to an infection, while
others are produced constitutively. The most important of these are components
of the complement system, which consists of about thirty interacting soluble
proteins that are mainly made continuously by the liver and are inactive until an
infection or another trigger activates them. They were originally identified by their
ability to amplify and “complement” the action of antibodies made by B cells, but
some are also secreted PRRs, which directly recognize PAMPs on microbes.
The early complement components consist of three sets of proteins, belonging
to three distinct pathways of complement activation—the classical pathway,
the lectin pathway, and the alternative pathway. The early components of all
three pathways act locally to cleave and activate C3, which is the pivotal complement
component (Figure 24–7); individuals with a C3 deficiency are subject to
repeated bacterial infections. The early components are proenzymes, which are
activated sequentially by proteolytic cleavage. The cleavage of each proenzyme
in the series activates the next component to generate a serine protease, which
cleaves the next proenzyme in the series, and so on. Since each activated enzyme
cleaves many molecules of the next proenzyme in the chain, the activation of the
early components consists of an amplifying proteolytic cascade.
Many of these protein cleavages liberate a biologically active small fragment
that can attract neutrophils, plus a membrane-binding larger fragment. The binding
of the large fragment to a cell membrane, usually the surface of a pathogen,
helps stimulate the next reaction in the sequence. In this way, complement activation
is largely kept confined to the cell surface where it began. In particular, the
large fragment of C3, called C3b, binds covalently to the surface of the pathogen.
Here, it recruits protein fragments produced by cleavage of other early complement
components to form proteolytic complexes that catalyze the subsequent steps in
the complement cascade. The early events in complement activation have diverse
functions: C3b‐binding receptors on phagocytic cells enhance the ability of these
cells to phagocytose the pathogen, and similar receptors on B cells enhance the
Figure 24–6 Eosinophils attacking a
parasite. Phagocytes cannot ingest large
parasites such as the schistosome larva
shown here. When the larva is coated with
antibody or complement components,
however, eosinophils (and other leukocytes)
can recognize it and collectively kill it by
secreting a large variety of toxic molecules.
(Courtesy of Anthony Butterworth.)
MBoC6 m24.54/24.07
15 µm
CLASSICAL
PATHWAY
antibody
binding
COATING OF
MICROBES
AND INDUCTION
OF PHAGOCYTOSIS
C1
C2
C4
LECTIN
PATHWAY
mannose
binding
MBL
MASP
C2
C4
CLEAVAGE OF C3
C5
C6
C7
C8
C9
PORE FORMATION
AND LYSIS
D
ALTERNATIVE
PATHWAY
pathogen
surfaces
B
RECRUITMENT OF
INFLAMMATORY
CELLS
STIMULATION OF
ADAPTIVE IMMUNE
RESPONSES
Figure 24–7 The principal stages in
complement activation by the classical,
lectin, and alternative pathways. In
all three pathways, the reactions of
complement activation usually take place
on the surface of an invading microbe, such
as a bacterium, and lead to the cleavage of
C3 and the various consequences shown.
As indicated, the complement proteins
C1 to C9, mannose-binding lectin (MBL),
MBL-associated serine protease (MASP),
and factors B and D are the central
components of the complement system.
The early components are shown within
gray arrows, while the late components are
shown within a brown arrow. The functions
of the protein fragments produced during
complement activation are indicated by
the black arrows. The various complement
proteins that regulate the system are
omitted.