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The classical complement pathway was the first
pathway described and then named based on its ability to “complement” the
activity of antibodies. Its components were named in the order in
which they were discovered not in their order of activation. Listed
in the order of activation, they include: C1, C4, C2, C3, C5, C6,
C7, C8, and C9. As shown in Figure 189-1,
only the initiation of activation by the first three components
(C1, C4, and C2) is unique to the classical pathway.
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The C1 component is made up of a multimolecular complex comprised
of one C1q, two C1r, and two C1s subunits, held together by calcium
ions. C1q provides the recognition function, and C1r and C1s are
proenzymes activated when C1q binds.
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Classical Component Deficiencies
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Deficiencies of the early classical components may present with
recurrent pyogenic infections but those with deficiency of the early
components (C1, C4, or C2) more commonly present in adolescence
or older with autoimmune disease. Greater than 90% of individuals
with a C1q deficiency, 75% with a C4 deficiency, and 15% of
those with a C2 deficiency develop systemic lupus erythematosus
(SLE). Furthermore, patients with a complement deficiency have an
earlier age of onset of symptoms, greater photosensitivity, and
fewer renal symptoms, and their antinuclear antibody titers are
often normal.
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An acquired deficiency of C1q may occur in patients with autoantibodies
that react with the collagen-like region of the C1q molecule. Many
of these patients have hypocomplementemic urticarial vasculitis
syndrome, but anti-C1q autoantibodies are also found in about
30% of patients with SLE. Activation of complement by immune
complexes can also cause a transient deficiency of C1q and other
classical components. Deficiencies of C1r and C1s are rare and may
be partial or combined. They predispose the patient to recurrent
pyogenic infections as well as immune complex disease.
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Because the pathological processes in autoimmune disorders involve
activation and consumption of complement in vivo, it is difficult
to discriminate between individuals with an inherited complement
deficiency, versus those with a low complement due to the disease
itself.
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C4A and C4B, the two haplotypes of human C4, are each coded by
a different gene, located in the major histocompatibility complex.
The number of C4 gene copies in the population is variable. Partial
deficiencies of C4 are common and usually without consequence,
but total deficiency of either type can result in disease. C4A deficiency
with normal C4B has a lower, but still significant (15%),
incidence of lupus and rheumatoid arthritis. There is evidence that C4B
deficiency is associated with a higher incidence of bacterial infections,
or with Henoch-Schönlein purpura. Note that the proteins
C4A and C4B are not the same as the fragments of C4 (C4a and C4b)
that are generated during complement activation.
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C2 deficiency is the most common complement
deficiency among those of European ancestry. C2-deficient patients
have increased susceptibility to infections and often present with
a history of pneumonias or other bacterial infections. Type I C2
deficiency, the most common form, is due to a 28-base pair deletion
in the C2 gene that results in stopping synthesis prematurely. These
patients have no detectable C2 protein, no C2 function, and no CH50
activity. There is no effect on the alternative pathway (AP), but
the lectin pathway (LP) would be at least partially impaired. Type II
C2 deficiency results from a variety of causes, including single
nucleotide polymorphisms, or small deletions or insertions that lead
to low C2 production, low function, and variable amounts of C2 protein.
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Hereditary Angioedema
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Hereditary angioedema (HAE) results from deficiency of the classical
pathway control protein, C1-inhibitor (C1-INH), which inactivates
the two C1 enzymes, C1r and C1s, as well as the lectin pathway mannan-binding
lectin-associated serine proteases and enzymes associated with the
coagulation pathway (XIIa, kallikrein, and plasmin).4 Lack
of control by this inhibitor produces bradykinin, thought to be
the mediator of HAE. Two forms of C1-INH deficiency have been defined:
Type I patients (70–80% of HAE patient total)
generally have less than half of the normal C1-INH level and function,
whereas type II (20–30%) have normal or elevated
C1-INH protein that consists largely of dysfunctional C1-INH. Both
forms of HAE are transmitted as an autosomal dominant trait: one
allele codes for normal protein and the other produces no protein
or the dysfunctional form. Edema occurs when local activation of complement
or coagulation enzymes depletes the already marginal stores of C1-INH
in the circulation. The result leads to production of bradykinin,
which causes the symptoms of edema, further described in Chapter 193. Recurrent angioedema, a family
history consistent with C1-INH deficiency, consistently low C4 levels, and
low or dysfunctional C1-INH confirms the diagnosis of hereditary
angioedema (HAE). The CH50 and C2 may also be low, but C3, C1q,
and the late complement proteins are normal in HAE. In children,
the onset of HAE is generally in the early teens, but earlier onset
has been reported.
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Acquired angioedema (AAE) is rare in children,
but must be ruled out when the family history is negative. Type
I AAE is also characterized by low levels and function
of C1-INH and low C4, but unlike hereditary angioedema, acquired
angioedema patients have low C1q levels. The initiation of AAE is
triggered by a decrease in the inhibitor due to hypercatabolism
through an underlying disease process, often a lymphoproliferative
disorder. Type II AAE occurs when an autoantibody binds
to the C1-INH protein and blocks its function. A third form of hereditary
angioedema that is not related to C1-INH, but appears to be estrogen
dependent, has been reported. This form is associated with gain-of-function mutations
in the gene encoding coagulation factor XII (F12).