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CHaPtEr 21 The Human Complement System: Basic Concepts and Clinical Relevance 311

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immune defect may be overcome by development of acquired with primary C3 deficiency. The highest disease association is
immune defenses. Rheumatological diseases include SLE (15%), recurrent infection with N. meningitidis and S. pneumoniae, and
vasculitis, polymyositis, and Henoch-Schönlein purpura. SLE there is also an increased incidence of SLE. FH deficiency is
associated with C2 deficiency has some features that distinguish more commonly associated with renal disease compared with
it from other types of SLE; these features include equal expression C3 or FI deficiency (73% of individuals with FH deficiency
in males and females, early onset, increased photosensitivity, compared with 13% of individuals with FI deficiency and 26%
decreased renal disease, lower frequency of antidsDNA Ab, and of those with C3 deficiency).
higher frequency of anti-SSA/Ro and anti-C1q Ab. 56-58 Nephritic factors (NeFs) are autoantibodies specific to the
CP or the AP C3 convertase (C4b2a or C3bBb) or the AP C5
LP Deficiencies convertase that stabilizes these enzyme complexes and prevents
MBL deficiency was originally found as a serum defect in the normal regulatory control. The AP C3Nef induces unregulated
opsonization of yeast in pediatric patients with recurrent infec- complement activation, resulting in acquired C3 deficiency. NeFs
tions. There are multiple MBL polymorphisms in the population, are often associated with MPGN type II. C3NeF is also associated
in both the promoter and coding regions, and MBL deficiency with partial lipodystrophy, a condition in which fat is lost from
is common (estimated to be 14% in the normal Swedish popula- the waist upward.
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tion). In addition to the association of MBL deficiency in
children with recurrent infections, there is a two- to threefold Deficiencies of Complement Receptors
increased frequency of MBL deficiency in SLE, and these individu- Deficiencies of CR1 (CD35) and CR2 (CD21)
als have more frequent and more severe infections during the The complete genetic deficiencies of CR1 or CR2 have not been
course of their disease. Serious infectious complications are also reported. However, partial deficiencies of CR1 on erythrocytes,
more frequent in the subgroups of patients with cystic fibrosis B lymphocytes, and polymorphonuclear leukocytes and of CR2
and RA with MBL deficiency. on B lymphocytes have been reported in patients with SLE.
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A single homozygous MASP-2 deficiency has been reported. Decreased CR1 on erythrocytes may be acquired as a result of
The patient was asymptomatic until the age of 13 years when immune complex clearance. 3,4,56,59
he was diagnosed with ulcerative colitis. Additional autoimmune
manifestations developed along with recurrent severe infections Leukocyte Adhesion Deficiency: CR3 and CR4 Deficiency
with S. pneumoniae. Leukocyte adhesion deficiency (LAD; Chapter 22) is a syndrome
caused by mutations of the common β 2 -integrin chain, CD18,
AP DEFICIENCIES found in LFA-1, CR3, and CR4. Defects are related to adhesion
and activation of phagocytic cells, and the clinical presentation
Individuals with complete deficiencies of factor D or P have includes childhood infections with pyogenic bacteria.
been reported. Patients with factor D deficiency have presented
with recurrent infections by Neisseria and other organisms. Deficiencies of Regulatory Proteins
Properdin deficiency is X-linked, and patients most commonly Hereditary Angioedema: C1-INH Deficiency
have severe childhood infections with N. meningitidis. 18,56,59 Hereditary angioedema (HAE) is found in individuals with het-
erozygous (autosomal dominant pattern of inheritance) deficiency
C3 Deficiencies of C1-INH. C1-INH is a serine protease inhibitor (serpin) with
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C3 is central to all three complement activation pathways. regulatory activity for C1r, C1s, MASP-1, and MASP-2 of the
Nineteen families with primary inherited deficiency of C3 have complement system; factor XII (Hageman factor) and kallikrein
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been reported. The most common presentation is recurrent of the contact system; factor XI and thrombin of the coagulation
life-threatening infections in early childhood (before the age of system; and plasmin and tissue plasminogen activator (tPA) of
2 years), sometimes followed by immune complex disease. The the fibrinolytic system. Although previous studies implicated a
infections observed are primarily respiratory tract infections C2 product (C2 kinin) as a mediator, more recent data, including
(48%) and meningitis (34%) with a variety of pathogens, studies in a C1-INH deficient mouse model, indicate that bradyki-
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especially encapsulated bacteria. The organisms most often nin is the primary biological mediator of angioedema in HAE. In
involved are N. meningitidis and S. pneumoniae, but other the more common form of HAE (type I, 85% of patients), reduced
encapsulated gram-negative and gram-positive bacteria have also synthesis of C1-INH is found (5–30% of normal), along with
been observed. Recurrent infections are seen in more than 50% decreased serum C4 and C2. In type II HAE, an abnormal C1-INH
of patients with C3 deficiency. This clinical presentation is similar is synthesized, making antigenic levels normal or elevated with
to that seen in hypogammaglobulinemia. Individuals with C3 reduced functional activity and decreased C4 and C2. Clinically,
deficiency may develop renal disease (26%), including membra- type I and type II HAE are indistinguishable.
noproliferative glomerulonephritis (MPGN) and mesangiocapil- HAE presents in childhood or adolescence as recurrent episodes
lary glomerulonephritis (MCGN) and autoimmune disease (26%), of swelling that are subcutaneous and/or submucosal, nonpainful,
most commonly SLE. nonpruritic, and nonpitting. Urticaria is not present. Episodes
are self-limiting, usually peaking at 24 hours and resolving over
Acquired C3 Deficiency: Genetic Deficiencies of FH and FI 2–5 days. Attacks are variable in frequency, severity, duration
and C3 and C4 Nephritic Factors and location, and initiating factors are poorly understood. The
Factors H and I are required to control C3 convertase in the most common areas involved are the extremities, face, genitals,
fluid phase of the AP. Complete deficiency of either protein and respiratory and gastrointestinal tracts. Intestinal attacks are
results in C3 cleavage and depletion to very low levels. C5, factor often associated with vomiting and diarrhea and are extremely
B, and P levels may also be reduced. The clinical presentation painful (partial obstruction from the bowel wall edema). Laryngeal
of patients with FH or FI deficiency resembles that of patients attacks may result in life-threatening respiratory tract narrowing.