Page 332 - Clinical Immunology_ Principles and Practice ( PDFDrive )

312 Part two Host Defense Mechanisms and Inflammation

Recurrent attacks continue throughout the life of the patient the FI and FB genes. Although complement factors are not the
and may involve multiple sites or progress from one site to another. only genes linked to ARMD, they are estimated to account for
Diagnosis of HAE is suggested by family history and clinical more than 50% of cases. Up to 10% of cases of advanced ARMD
findings. Confirmation is based on decreased C1-INH functional may carry a rare variation in FH or FI. These variants commonly
activity (<10–35% of normal). It is important to note that lead to haploinsufficiency. These findings are driving the develop-
although C1-INH protein is decreased in type I HAE, it can be ment of new complement-based therapeutics that could provide
normal or even elevated in type II HAE. C4 levels are below protection from a very common form of age-related visual loss.
normal in 95% of patients with HAE. Acquired forms of C1-INH
deficiency have been described, usually in older patients with COMPLEMENT IN DISEASE
lymphoproliferative diseases. These are usually caused by auto-
antibodies to C1-INH and are distinguished from HAE by a lack Measurement of Complement in a Clinical Setting
of family history and decreased C1q as well as C4. The manage- Laboratory tests for complement include functional assays for
ment and treatment of HAE are discussed in Chapter 42. the CP (CH 50 ), the AP (AH 50 ), and the LP (LP 50 ). Functional
and antigenic assays for each of the individual components are
Paroxysmal Nocturnal Hemoglobinuria: DAF and available in specialty laboratories. The CH 50 is a hemolytic assay,
CD59 Deficiency in which sheep erythrocytes sensitized with rabbit Ab are
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired incubated with serial dilutions of the patient’s serum. The titer
disorder in which a somatic mutation in the Pig-A gene in a is the dilution at which 50% of the sheep erythrocytes are lysed.
clone of bone marrow stem cell results in defective synthesis of The CH 50 requires all of the CP and terminal components
GPI-anchored proteins. PNH is characterized clinically by (C1–C9). A comparable assay for the AP uses a buffer that blocks
intravascular hemolysis and venous thrombosis. DAF and CD59 CP activation and employs rabbit erythrocytes in place of
are GPI-anchored complement regulatory proteins expressed sensitized sheep erythrocytes. Rabbit erythrocytes spontaneously
on erythrocytes, and PNH erythrocytes are highly susceptible activate the human AP and are lysed in the assay. The AH 50
to lysis. Studies of individuals with isolated DAF and CD59 requires all of the AP and terminal components (factor B, D
deficiencies indicate that hemolysis is more highly associated and P and C3–C9). The combined use of the CH 50 and AH 50 is
with CD59 deficiency. The basis for thrombosis in PNH is poorly the most effective screening method for genetic deficiencies of
understood. A mAb to C5 has been approved by the U.S. Food complement components. Complete deficiency will generally
and Drug Administration (FDA) to treat PNH. result in titers of <5% in one or both assays. Because C3–C9 are
common to both pathways, the combined results of the two
Control of Localized Complement Activation: assays can rapidly determine whether the deficiency is one of
Atypical Hemolytic–Uremic Syndrome, Age-Related these shared components, one of the CP components (C1, C2,
Macular Degeneration C4) or one of the AP components (factors B, D, P) (Fig. 21.8).
HUS is a rare disease characterized by microangiopathic hemolytic Properdin deficiency results in low, but not absent, lysis in the
anemia, thrombocytopenia, and acute renal failure. “Typical” AH 50 , and patients with C9 deficiency may have values up to
HUS is found in children and is caused by E. coli, mainly O157:H7, 30% of normal in the CH 50 . Deficiencies of FH and FI and
producing a shiga-like toxin. Atypical HUS affects older children nephritic factors often result in very low C3 levels, leading to
and adults and is not associated with an enteropathic infection. reduced titers in both assays.
Recently, mutations in the complement regulatory proteins FH, LP function (and MBL deficiency) is determined by using a
FI, or CD46 have been identified in approximately 50% of patients specific ELISA, in which the patient’s serum is placed into wells
with atypical HUS. FH mutations associated with HUS are coated with mannan. Binding MBL and activation of the LP
clustered in the C-terminal end of the molecule in CCP20, a results in the deposition of C4b and C4d that are detected with
region that is required for FH binding to polyanions and endo- mAbs. MBL levels may also be determined antigenically.
thelial cells. The ability of FH to regulate fluid-phase AP activation Heterozygous C1-INH deficiency, as described above, is
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is not affected, and C3 levels are normal. These findings have associated with the clinical syndrome of HAE. The diagnosis
led to the hypothesis that local complement regulation is essential can be made on the basis of clinical findings and family history.
for preventing renal disease following endothelial cell injury and C1-INH activity is reduced in these patients, and C4 protein is
that FH acts locally after binding to exposed matrix or damaged also low in 95% of patients, especially during attacks of edema.
endothelium. FH and the membrane protein CD46 are both In type I HAE (85% of cases), C1-INH protein levels are low,
cofactors for FI-mediated cleavage of C3b. but in type II HAE (15% of cases), an abnormal C1-INH protein
An additional FH polymorphism (Tyr/His402) identified by is made, and antigenic levels are normal or elevated. There is an
genetic screening has been shown to be associated with the acquired form of C1-INH deficiency associated with lymphoma,
development of ARMD, a major cause of blindness in older in which low C1-INH is accompanied by decreased C1q as well
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adults. This polymorphism is located in CCP7 in a region of as C4 and C2.
FH that binds heparin and CRP. 28,64,65 As is the case for the Complement levels may also be decreased in diseases or
mutations associated with atypical HUS (aHUS), this region of conditions in which complement is activated, leading to consump-
FH is not required for regulation of the fluid-phase AP convertase. tion. In contrast to genetic deficiencies, complement consumption
ARMD develops when abnormal deposits of protein, termed characteristically results in low, but not absent, functional activity.
drusen, form in the retina. Recent findings support the view that In addition, multiple components of one or more pathways are
the local inflammatory response, including complement activation expected to be low, and these decreased levels of complement
with MAC deposition, damages the retina, leading to vision loss. are often correlated with disease activity. The most commonly
Additional genetic analyses identified protective FH and FI used and most readily available complement tests are C3 and
variants, as well as protective and high-risk polymorphisms, in C4 protein and the CH 50 . Diseases accompanied by CP activation