832
c h a p t e r
35
Molecular Immunology
FIGURE 35-23
(Also see color figure.) A cartoon representation of complement protein
Cl. The Cl complex consists of one Clq, two Clr, and two Cls molecules.
The formation of the complex requires the presence of Ca2+. Clq contains
six polypeptide chains that form a globular structure that binds to
antigen-antibody complexes at one end of each chain.
bind to Cl can be those formed with epitopes on the
surfaces of microbes, those formed on B cells by re-
action with the surface IgM, or those formed with for-
eign proteins or other macromolecules. Immunoglobu-
lins such as IgGl, IgG2, IgG3, and IgM are capable of
initiating complement activation via C 1; IgG4, IgA, and
IgE do not activate complement. The activated Cl con-
sists of three different polypeptides: Clq, Clr, and Cls.
Within the complex are two C lr and two Cls molecules
bound to a single Clq molecule. Clq is often described
as a tulip-like structure because it contains a “stalk” with
amino acid sequences that are collagen-like and six glob-
ular structures that form a tulip blossom at one end of
the stalk. A cartoon structure for the Clq, C lr2, Cls
2
is shown in Figure 35-23. Both C lr and Cls are precur-
sors to proteolytic enzymes. Activation of C lr occurs as
a result of the binding of the IgG or IgM antigen com-
plexes to Clq. The globular domains of Clq bind to a
site in the Fc region of the immunoglobulin molecule.
This is followed by proteolysis of a single peptide bond
in the C lr molecule. The activated C lr subsequently cat-
alyzes proteolysis of a single peptide bond in C
1
s, creat-
ing activated Cls. Association of the components of Cl
requires the presence of Ca2+.
In vitro,
a distinction be-
tween the classical, alternative, and lectin pathways can be
made by blocking formation of Cl by chelating Ca2+ with
EDTA.
The next step in the sequence of classical pathway acti-
vation is cleavage of components C4 and C2. Two products
these cleavages, C4b and C2a, form the “classical path-
way” C3 convertase. Proteolysis of C3 leads to a second
convertase. The second convertase is the C5 convertase
and is composed of C4b, C2a, and C3b. This convertase
cleaves C5 to form C5b and C5a.
As in the alternative pathway, C5b, in conjunction with
C
6
,
Cl,
C
8
, and C9, forms the MAC.
The Lectin Pathway
The lectin pathway has been described
in vitro,
but its
physiological significance remains unclear. This pathway
is initiated by binding of a lectin, the mannose binding
protein (MBP or serum collectin) to mannose or N-acetyl
glucosamine residues on the surface of the invading for-
eign cells. MBP is structurally similar to Cl and, as a
consequence of its binding to the sugar residues, activates
the first proteinase precursor of the lectin pathway, the
MBP-associated serine proteinase (MASP-1). MASP-1 is
homologous to C lr and Cls and can proteolytically ac-
tivate MASP-2, the second proteinase precursor of the
lectin pathway that is similar to Cls. MASP-1 can also
activate C2 and C4, not directly but with the participation
of MASP-2.
Activation of C2 and C4 produces the C3 convertase
and, via the same reactions sequences of the “classical
pathway,” leads to formation of the MAC.
Formation of C3b C4b, by any of the pathways, re-
sults in “tagging” of the foreign cells by covalent link-
ing of these molecules to the foreign cell surfaces via
thioester bonds. This tagging or opsonization marks the
foreign cells for phagocytosis by macrophages and the
other phagocytic cells of the immune system. Alterna-
tively, destruction of foreign cells is caused by the MAC.
Antigen-antibody complexes are cleared from the blood
by binding to complement receptors on erythrocytes. The
red cell-bound Ag-Ab complexes are removed along with
the erythrocytes by the liver.
Complement deficiencies are associated with several
diseases. Alternative pathway deficiencies are rare, but
when they exist more than one-half of factor D or
properdin-deficient individuals suffer from
Neisseria
in-
fections of which 75% are fatal. Individuals with deficien-
cies in the MAC components, e.g., C5, C
6
,
Cl,
and C
8
,
are also susceptible to infection with
Neisseria.
Deficien-
cies in C 1, C4, and C2 are associated with
systemic lu-
pus erythematosus
and
glomerulonephritis. Hereditary
angioedema,
a disease characterized by recurrent submu-
cosal and subcutaneous edema, is caused by a deficiency in
Cl inhibitor. Complexes and interactions similar to those
of the complement system are also characteristic of the
clotting system (Chapter 36).
35.11
Cytokines
Cytokines
are a group of cell-derived proteins or pep-
tide molecules that transmit signals between cells of the
