Page 319 - Clinical Immunology_ Principles and Practice ( PDFDrive )

21

The Human Complement System: Basic

Concepts and Clinical Relevance

John P. Atkinson, Terry W. Du Clos, Carolyn Mold, Hrishikesh Kulkarni,
Dennis Hourcade, Xiaobo Wu

OVERVIEW: AN EVOLUTIONARY AND and likely consisted of three elemental proteins (C3 and two
HISTORICAL PERSPECTIVE proteases known as factor B and factor D). These three were
sufficient to generate a C3 convertase (splitting) enzyme and
The complement system arose early in evolution, possibly even also to form a feedback loop. The positive regulator of this
in single-cell organisms. In vertebrates, it features a proteolytic remarkable enzymatic feedback/amplification loop, known as
cascade to coat microorganisms with cleavage fragments that properdin, probably came later in evolution (as did lectins and
1-4
are recognized by receptors on phagocytic cells. This phenom- antibodies).
enon, known as opsonization, leads to immune adherence followed Later to arise in evolution is the membrane attack complex
by internalization. A related strategy employed by primates is (MAC, often called the terminal pathway) that is common to
to express a complement receptor on erythrocytes. In blood, all three cascades. The goal of its five sequentially interacting,
the opsonized pathogen becomes adherent to the abundant nonenzymatic proteins (C5b, C6, C7, C8, and C9) is also to
erythrocytes and then, like a taxi, is taken by them to the liver attach to and then alter the surface of a pathogen by membrane
and/or the spleen for transfer to monocytes and macrophages. perturbation, often ending in lysis. In humans, a deficiency of
In this manner, bacteria are both immobilized and prevented any one of these five proteins leads to meningococcal infections.
from traveling free in the circulation to such sites as the brain. Interestingly, properdin deficiency also predisposes to recurrent
To mediate opsonization, the complement system needed meningococcemia. Thus such infections likely drove specialization
to develop a system to transfer a plasma component onto the of this terminal wing of the complement system.
pathogen. Lectins and, subsequently in evolution, antibodies In contrast to the rapidly acting AP, a major limitation with
(Abs) faced this same challenge. Of note, both of the latter the lectin and Ab systems is that the triggers of these two pathways
eventually utilized the complement system (lectin pathway and are slow! It takes several days to ramp up synthesis of a particular
classical pathway [CP]) to “complement” their attachment lectin (acute phase type response) and at least a week to develop
strategies. In contrast to lectins and antibodies, the alternative an appropriate immunoglobulin M (IgM) and even longer for
pathway (AP) earlier solved this problem creatively through an IgG immune response. For a host with an opportunistic
development of a thioester bond in C3. C3’s homologous cousin, pathogen invading the bloodstream, this time delay for an adaptive
α 2 -macroglobulin, also utilizes cleavage of a thioester bond to humoral immune response is far from adequate. Consequently,
covalently attach to and thereby inactivate proteases. The parallels the complement system is often called the “guardian of the
are apparent—upon its generation following C3 activation, C3b intravascular space.” Once a “pumped” circulation developed in
can transiently (within microseconds) attach to nearby hydroxyl evolution, a rapidly acting, abundant, and nearly fail-safe system
or amino groups to form an ester or amide linkage, respectively. to prevent and stop “bugs” from entering, traveling, and dividing
This mechanism creates essentially an almost unbreakable bond in plasma was mandatory.
and places this complement fragment irreversibly on the patho- The second function of the complement system is to promote
gen’s surface (Table 21.1). the inflammatory response. This is primarily accomplished
To summarize, the major function of the complement system by the anaphylatoxins C3a and C5a. Upon cleavage of C3 to
is to modulate the membrane of a microbial target, leading to C3b (the major complement opsonin) and C5 to C5b (the trigger
immune adherence and internalization of the opsonized antigen. of the MAC), the ~10 kilodalton (kDa) C3a and C5a fragments
The target is selected by lectins in the lectin pathway and pre- are released, and these can engage their respective receptors
dominantly by antibodies in the CP. However, the ancient AP to initiate vascular and cellular changes, rapidly leading to a
does not feature selective or specific recognition. Instead, 1–2% proinflammatory state. These receptors are expressed on many
of C3 “ticks over” each hour, serving as a surveillance system. cell types, including endothelial, epithelial, and immune cells.
The activated C3b has a few microseconds to bind to a target, Upon receptor engagement, defensive strategies are initiated and
such as bacteria, or it will be inactivated by water. If C3b lands result in increased blood flow and stimulated phagocytes that are
on a pathogen, C3b can rapidly amplify to put several million now more efficient at binding and ingesting C3b-coated antigens.
copies of C3b on a single Escherichia coli in 2–3 minutes. If C3b Through these same interactions, the complement system
remains in the fluid phase, it is promptly inactivated by plasma instructs the adaptive immune response. Antigens decorated
regulators. If it binds to healthy self, it is inactivated by ubiqui- by complement proteins are taken up by monocytes, follicular-
tously expressed membrane complement inhibitors. To sum- dendritic cells (FDCs), B lymphocytes, and other antigen-
marize, the AP initially formed the original complement system presenting cells (APCs), resulting in an adaptive immune response

299