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CHaPtEr 21 The Human Complement System: Basic Concepts and Clinical Relevance 313

TABLE 21.4 Complement test research in this area is that most of the pathogenic effects of
Interpretation complement depend on the generation of C5a and the MAC.
Further, it is becoming recognized that regardless of the initial
Pathway CH 50 C4 C3 Related diseases activation mechanism, AP amplification is often needed to
Classical pathway ↓ ↓ ↓ SLE, serum sickness, produce sufficient quantities of these mediators to cause disease.
(CP) vasculitis, Subacute
Bacterial Endocarditis, Finally, systems biology approaches are increasingly revealing
MPGN (type I) that members of the complement cascade interact with other
Alternative pathway ↓ N ↓ Poststreptococcal inflammatory mediators, resulting in diseases that are a product
(AP) glomerulonephritis, of complex gene–environment interactions, such as asthma and
MPGN (type II) Alzheimer disease.
Fluid-phase activation ↓ ↓ N C4NeF, HAE,
of the CP cryoglobulinemia Systemic Lupus Erythematosus (Chapter 51)
Fluid-phase activation ↓ N ↓ FH or FI deficiency,
of the AP C3NeF, MPGN (type II)
Acute-phase ↑ ↑ ↑ Acute and chronic CLINICaL PEarLS
response inflammation
Decreased CH 50 ↓ N N Cryoglobulins, cold Complement Tests for Diagnosis and Monitoring
(sample collection activation, sample of Systemic Lupus Erythematosus (SLE)
problems) mishandling; coagulation-
associated activation A low C4 and C3 assist in the diagnosis of SLE.
Decreased CH 50 ↓ N ↓ Severe liver disease; Decreased C3 and C4 are associated with increased severity of disease,
(biosynthetic) decreased C3, C6, C9 and especially with lupus nephritis.
On serial observations, decreasing C3 and C4 levels predict and help to
N, normal; SLE, systemic lupus erythematosus; MPGN, membranoproliferative establish an SLE flare-up.
glomerulonephritis; HAE, hereditary angioedema; NeF, nephritic factor.
Note: Decreases in C4 may precede decreases in C3.
Remission after treatment of lupus often shows return toward normal
levels of C4, followed by increases in C3.
result in decreased CH 50 , C4, and C3 levels. The AP is usually Note: Patients with SLE who have partial C4 deficiency may have
spared. These are primarily immune complex–associated diseases, persistently low C4 levels.
both autoimmune and infectious, and are listed in Table 21.4. Complete absence of CH 50 implies the existence of a hereditary deficiency
In addition, 20% of cases of acute renal allograft rejection are of one of the classical complement pathway components, usually
associated with decreased CH 50 and C2. Another cause of selective C1q, C4, or C2.
CP activation is essentially a laboratory artifact, in which clotting
of the blood sample in the cold is associated with consumption
of the early CP. Plasma CH 50 is normal, but the serum CH 50 Complement plays a dual role in SLE. 56,57,66,67 There is a strong
value is markedly decreased. C3 and C4 antigenic tests are normal, association of genetic deficiencies of C1q, C1r, C1s, C4, C2, and,
but their functional activity is lost. to a lesser degree, C3 with SLE, indicating a protective role.
The AP is activated in gram-negative sepsis, poststreptococcal Three main complement-dependent mechanisms have been
glomerulonephritis, MPGN, IgA nephropathy, FH or FI deficiency, proposed: (1) complement-dependent clearance of immune
and PNH. Laboratory values may show decreased C3 with complexes; (2) modulating the adaptive immune system, par-
decreased or normal CH 50 , and normal C4 levels (see Table 21.4). ticularly through the development and maintenance of self-
AP activation is not always reflected in decreased C3 because tolerance in B lymphocytes; and (3) a requirement for complement
C3 is found at the highest concentration of all complement in the clearance of apoptotic cells and potential autoantigens
components and is an acute-phase reactant with elevated synthesis released from damaged cells. The pathogenesis of SLE results,
during disease states. in large part, from inflammatory response to immune complexes
In clinical practice, evaluation of complement levels may be formed by autoantibodies (e.g., Ab to double-stranded DNA
useful in a variety of circumstances. Initial consideration of [antidsDNA]) binding to antigens from dead and dying cells.
complement deficiency may be appropriate in patients presenting However, complement activation is believed to play a pathogenic
with autoimmune conditions or repetitive pyogenic infections role in tissue damage induced by autoantibodies in SLE. There
in the setting of a normal white blood cell (WBC) count and is evidence for complement activation in skin and renal lesions
immunoglobulinemia (see Table 21.3). The complement profile of patients with SLE, as well as in autoantibody-mediated
can also be helpful in differential diagnoses of SLE and its look- hemolytic anemia and thrombocytopenia.
alikes (see Table 21.4). Monitoring complement levels is frequently
used to follow disease activity in patients with SLE. Complement Antiphospholipid Syndrome (Chapter 61)
levels may predict renal disease activity and may reflect a response Antiphospholipid syndrome is characterized by antiphospholipid
to therapy in SLE. However, complement levels are rarely useful Ab, recurrent fetal loss, vascular thrombosis, and thrombocyto-
in isolation and should be taken in the context of clinical assess- penia. Antiphospholipid Abs are found in 50% of patients with
ment and other laboratory values as reflected in disease activity SLE, and thrombotic events occur in about 50% of them.
index scores (e.g., the Systemic Lupus Erythematosus Disease Antiphospholipid Abs identified in patients without SLE have
Activity Index 2000). similar clinical consequences. Disease pathogenesis has been
attributed to the procoagulant effects of antiphospholipid Abs.
Role of Complement in Specific A mouse model of antiphospholipid Ab syndrome has been used
Immunological Diseases to demonstrate that injection of pregnant mice with human IgG
Complement activation is involved in the pathogenesis of many antiphospholipid Ab results in fetal loss and wasting. In this
immunological diseases. A general concept emerging from current model, complement is required for pathogenesis, and treatment