Page 319 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 24

COMPLEMENT AND IMMUNOGLOBULIN BIOLOGY LEADING TO

CLINICAL TRANSLATION

David J. Araten, Robert J. Mandle, David E. Isenman, and Michael C. Carroll

This chapter is divided into four parts. The first part details the Structurally, C1q consists of a central core with six radiating arms.
current understanding of the activation and biology of the comple- Each arm possesses a triple helical structure similar to collagen that
ment system and how it links innate and adaptive immunity. The is capped at the end with a head region consisting of a quaternary
second part focuses on immunoglobulins and their importance in assembly of the globular domains from each of chains A, B, and C.
protecting against disease. The third part discusses immunoglobulins C1q, largely through ionic interactions, links the C1 complex to the
as therapeutic agents, and the fourth part discusses therapies, includ- antibody molecule. In addition to its capacity for binding to antibody
ing monoclonal antibodies, that target the complement system. molecules, C1q possesses the capability to bind directly to the surfaces
of some microorganisms and apoptotic cells, not unlike mannan-
binding lectin (MBL; see lectin pathway discussion, later).
THE COMPLEMENT SYSTEM: AN OVERVIEW Associated with C1q are two molecules each of C1r and C1s. In
unactivated C1, C1r and C1s are proenzyme serine esterases. Upon
Complement refers to a family of distinct proteins that play a pivotal binding of C1q with an array of target-associated immunoglobulin
role in host defense against infection. In the 1880s, the serum factors G (IgG) Fc regions, or directly to surface molecules of the pathogen,
involved in host response to pathogens were placed into two catego- a conformational change occurs that leads to reciprocal autoactivation
ries based on sensitivity to heat. Whereas the heat-stable component, of the associated C1r molecules. The active form of C1r then cleaves
antibody, was recognized as being specific for the invading pathogen its associated C1s to generate an active serine protease.
and arose after immunization, the heat-labile (>56°C [133°F]) frac- Activated C1s is responsible for cleaving C4 and C2, the next two
tion displayed nonspecific killing activity. The heat-labile fraction proteins in the complement pathway. Cleavage of C4 yields two
acted to complement the antibody-mediated lytic killing of targeted fragments: C4a and C4b. C4b possesses a highly reactive thioester
organisms. 1–3 group that allows it to bind covalently to molecules in the immediate
In addition to its lytic role in the effector arm of the antibody vicinity of its active site. Only a small proportion of the C4b produced
response, the complement system serves several other functions. First, binds to proteins or carbohydrates on the targeted surface; the rest is
components of the complement system are involved in clearance of inactivated by reaction with water in the surrounding milieu. This
targeted microorganisms by the process of opsonization. Opsonization helps to prevent inadvertent C4b binding to surrounding host cells.
is the coating of a particle with proteins that facilitate phagocytosis of C2, the next substrate in the CP cascade, is susceptible to cleavage
the particle by tissue macrophages and activated follicular dendritic by C1s. Upon association with C4b, C2 is cleaved by activated C1s
4,5
cells (FDCs) as well as binding by receptors on peripheral blood cells. into two fragments: C2a and C2b. C2a, which is now an active serine
Second, complement promotes inflammation by releasing small protease, remains bound to C4b, thereby confining it to the targeted
peptide fragments from complement proteins. These peptides cause surface. C4b2a is termed the C3 convertase, an enzymatic complex
mast cell degranulation, smooth muscle contraction, and directed that is responsible for binding and cleaving C3, the next component
migration (chemotaxis) of motile cells to sites of inflammation. 6,7 in the cascade. The function of the C3 convertase is to cleave large
Complement can be activated via three distinct pathways: classical, numbers of C3 molecules to produce C3b and C3a. Nascently
lectin, and alternative. Although all depend on different molecules for activated C3b, similar to C4b, also possesses a highly reactive thioester
their initiation, eventually they converge to generate the same set of bond, allowing a portion of the nascent C3b to covalently bind to
effector molecules. Each of these pathways is described here (Fig. 24.1). the targeted surface (opsonization of the target) and thereby mark it
for phagocytosis. The activated thioester in the bulk of the nascent
C3b becomes water hydrolysed and can no longer bind to a target.
Classical Pathway By contrast, all of the C3a fragment remains in solution, where it
initiates a local inflammatory response.
The classical pathway (CP), so called because it was the earliest An Ig-independent mechanism for activation of C1q has been
13
studied arm of the complement system, directly links the innate and identified. The lectin protein Sign R1, which is expressed on a subset
acquired immune systems. There are nine proteins in the CP. As a of macrophages within the outer marginal zone sinus of the spleen, is
matter of terminology, each CP component protein is designated capable of capturing to the surface of the marginal zone macrophage
with an uppercase C followed by a number. Fragments of these both C-polysaccharide–containing bacteria and C1q. The recruited C1
proteins generated by cleavage during the complement cascade are becomes activated and propagates the CP to deposit C3b on the cap-
designated with a lower-case letter suffix (e.g., C3a, C3b). In general, tured bacterium. Recently, Sign R1 was identified on the surface of
the smaller product arising from a proteolytic activation step is given resident dendritic cells (DC) in draining lymph nodes and shown to
13a
the fragment designation “a,” and the larger product is designated be important in capture and transport of inactivated influenza virus.
“b.” The sole exception to this rule is for the naming of the C2 This novel pathway provides an alternative innate recognition of
proteolytic activation fragments, where, for historical reasons, the pathogens leading to activation of the CP of complement.
larger fragment is C2a and the smaller one is C2b.
C1, the first component of the CP, binds and is activated by the
Fc portion of the antibody molecule. C1q is a macromolecule Lectin Pathway
complex composed of three individual protein subunits: C1q, C1r,
and C1s. 8–12 The largest of these subunits, C1q, is an 18-chain Before continuing with the discussion of the complement cascade at
molecule with six copies each of three chains: A, B, and C. the point of C3 cleavage by convertase, we turn our attention to the

261