Page 324 - Hematology_ Basic Principles and Practice ( PDFDrive )

266 Part III Immunologic Basis of Hematology

Regulation of Complement Activation in certain human populations, the absence, or even haploinsufficiency,
of C4A, but not C4B, is associated with elevated risk for development
Activation of the complement system must be tightly regulated to of autoimmune diseases such as SLE and other lupus-like auto-
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prevent autologous tissue damage (see Table 24.1). Some of the immune disease. The reason for the protective effect of C4A is not
proteins involved in regulating complement action have been settled, but it is worth noting that the one indisputable functional
described (see Alternative Pathway, earlier). In addition to these regu- difference between C4A and C4B is in the nature of the covalent
lators, a number of other checkpoints limit the scope and target of bond formed upon target deposition. Whereas C4A transacylates
complement activation. onto amino group nucleophiles, forming amide bonds, C4B shows a
As a result of binding to antibody or pathogen, conformational strong preference for forming ester linkages to hydroxyl group
changes to C1q induce the enzymatic activity of C1r and C1s. Both nucleophiles. The approximately threefold greater propensity of C4A,
of these enzymes are regulated by the C1 inhibitor (C1-INH). relative to C4B, to bind to amino group–rich C1-bearing IgG
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C1-INH is a member of a family of serine protease inhibitors termed aggregates, as would be present in immune complexes in need of
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serpins. Serpins provide a bait sequence that mimics the active site complement-dependent clearance, is one possible reason for the
of the substrate. When C1r or C1s proteolytically attacks this association of C4A null states with SLE. Finally, as with C1q, mice
sequence, the net result is that their respective active site serine deficient in C4 are predisposed to SLE-like disease.
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hydroxyls become permanently covalently bound to the C1-INH bait C2 deficiency appears to be relatively benign. Humans lacking
site, thereby destroying their proteolytic activity. C1-INH works in C2 appear to have a normally functioning immune system, although
a similar fashion in regulating the activated MASP proteases of the autoimmune disorders and, less commonly, infections are observed
LP. Finally, C1-INH is also responsible for preventing spontaneous with increased frequency.
fluid-phase activation of C1 in plasma, but this activity can be over- In light of the central role of C3 in the complement cascade, it is
ridden by immune complexes. not surprising that C3 deficiency has dire consequences for the host
Although C1 is capable of cleaving multiple C4 molecules, only organism. Of all known cases of C3 deficiency among humans, no
approximately 10% of the produced C4b clusters about the targeted patients have been reported as disease free. Infectious complications,
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antigen. The rest is released into the fluid phase. C4b in the fluid predominantly pyogenic in nature, occur frequently and recurrently.
phase is rapidly bound by C4 binding protein (C4bp), which is a Streptococcus pneumoniae and Neisseria meningitidis are the major
cofactor for FI. Factor I cleaves C4b into two fragments, C4c and pathogens reported. In addition, SLE, vasculitic syndromes, and
C4d, which are quickly cleared from the circulation. glomerulonephritis have been documented in up to 21% of
In addition to their FI cofactor activities, the soluble regulators C3-deficient patients. Mice deficient in C3 show, similar to humans,
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C4bp and FH, respectively, promote the dissociation of the CP greatly increased susceptibility to streptococcal infection and death.
(C4b2a) and AP (C3bBb) C3 convertases into their constituent The 50% lethal dose (LD 50 ) is 50-fold less for C3-deficient mice than
components. This decay-dissociation is unidirectional because neither for C3-sufficient control subjects. This may be attributable in large
C2a nor Bb can reassociate on its own with their respective C3 part to the inability of mice deficient in C3 to effectively opsonize
convertase subunits. The membrane-bound regulators CR1 and DAF the bacteria. Moreover, the deficient mice have an impaired humoral
similarly possess decay-accelerating functionality toward both the CP response (see later section).
and AP C3 convertases. The importance of CR1 or CR1-like mol-
ecules in curbing the complement response can be witnessed in a
rather unexpected condition. Complement receptor 1–related gene Biologic Consequences of Complement Regulatory
(Crry) is a murine homologue of the human CR1 gene, although its Protein Deficiencies
near-ubiquitous tissue distribution more closely resembles that of
MCP (a somewhat more distant homologue). 54,55 Mice lacking Crry Deficiencies in C1-INH have been observed in the human popula-
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are unable to properly regulate C3. Crry-deficient mice spontane- tion. C1-INH deficiency can be inherited as an autosomal dominant
ously abort because of C3-dependent injury to the fetus. This pre- trait or can result from autoantibodies that recognize C1-INH, block-
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sumably is the result of uncontrolled C3 deposition on the placenta. ing its function. The inherited form of this deficiency is the cause
This observation in mice sheds light on the possibility that defective of hereditary angioedema. Patients with hereditary angioedema
MCP (or perhaps CR1) plays a role in recurrent fetal loss manifest experience chronic spontaneous complement activation leading to
in patients with antiphospholipid syndrome. the production of excess cleaved fragments of C4 and C2. The bio-
chemical cause of angioedema in these patients is not definitively
Biologic Consequences of Complement elucidated. One line of reasoning points to excess production of C2
kinin and bradykinin. The peptide C2 kinin is a breakdown product
Cascade Deficiencies of C2a after cleavage of C2. This peptide causes extensive swelling;
the most dangerous is local swelling in the trachea, which can lead
The important role of the complement system in preventing disease to suffocation. Bradykinin, which has similar actions to C2 kinin, is
is witnessed in cases in which components of the system are absent also produced in an uncontrolled fashion in this disease as a result of
either because of random mutation in the human population or by the lack of inhibition of another plasma protease, kallikrein, which
design in gene-targeted “knock-out” mice. Some complement cascade is activated by tissue damage and is regulated by C1-INH. Although
deficiencies have been described. This section focuses on the biologic C1 is unregulated in patients with hereditary angioedema, large-scale
consequences of deficiencies in complement cascade activation that cleavage of C3 is prevented by C4 and C2 control mechanisms and
have profound biologic consequences followed by a discussion on by regulation of C3 convertase formation on host cells. An increased
deficiencies in complement regulatory proteins. risk of infection is not associated with C1-INH deficiency. This
Homozygous deficiencies in C1q, the most common form of C1 disease can be fully corrected by infusion of purified C1-INH.
deficiency in humans, is a powerful susceptibility factor for the Acquired C1-INH deficiency may be associated with lymphopro-
development of systemic lupus erythematosus (SLE). 56,57 Patients liferative disorders and in most cases represents development of an
lacking C1q nearly always present with SLE. They have increased autoantibody that binds to and neutralizes C1-INH. In two examined
susceptibility to viral and bacterial infections, but it is not nearly as cases, autoantibodies abrogate C1-INH activity by preventing forma-
pronounced as in C3 deficiency (see later discussion). C1q knock-out tion of the C1s–C1-INH complex. However, after the complex
mice show increased mortality, with up to 25% of mice having his- formed, the autoreactive antibodies had no effect on C1-INH func-
tologic evidence of glomerulonephritis. tion. To date, there is no uniform, fully effective therapy for these
C4 in humans is encoded by two separate loci giving rise to two patients.
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distinct protein products, C4A and C4B. Complete C4 deficiency The role of FI in complement cascade regulation can be witnessed
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correlates with a 75% prevalence of SLE in humans. However, at least in patients with FI deficiency. In the presence of a cofactor protein,