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C1 inhibitor (C1 INH) deficiency 122 C1q binding assay for circulating immune
factor XIa, and factor XIIa. C1 INH is an α 2 globulin and
is a normal serum constituent that inhibits serine protease.
The 104-kDa C1 INH interacts with activated C1r or C1s to
produce a stable complex that prevents these serine protease
molecules from splitting their usual substrates. Either C1s or
C1r can split C1 INH to uncover an active site in the inhibitor
that becomes bound to the proteases through a covalent ester
bond. By binding to most of the C1 in the blood, C1 INH
blocks the spontaneous activation of C1. C1 INH binding
blocks conformational alterations that would lead to spontaneous
activation of C1. When an antigen–antibody complex
binds C1, the inhibitory influence of C1 INH on C1 is
relinquished. Genes on chromosome 11 in humans encode C1
INH. C1r and C1s subcomponents disengage from C1q following
their interaction with C1 INH. In hereditary angioneurotic
edema, C1 INH formation is defective. In acquired
C1 INH deficiency, catabolism of C1 INH is elevated.
C1 inhibitor (C1 INH) deficiency
The absence of C1 INH is the most frequently found
deficiency of the classic complement pathway and may
be seen in patients with hereditary angioneurotic edema.
This syndrome may be expressed as either a lack of the
inhibitor substance or a functionally inactive C1 INH. The
patient develops edema of the face; of the respiratory tract,
including the glottis and bronchi; and of the extremities.
Severe abdominal pain may occur with intestinal involvement.
Because C1 INH can block Hagemann factor (factor
XII) in the blood clotting mechanism, its absence can
lead to the liberation of kinin and fibrinolysis resulting
from the activation of plasmin. The disease is inherited as
an autosomal-dominant trait. When edema of the larynx
occurs, the patient may die of asphyxiation. When abdominal
attacks occur, watery diarrhea and vomiting may occur.
These bouts usually span 48 hours and are followed by a
rapid recovery. During an attack of angioedema, C1r is activated
to produce C1s, which depletes its substrates C4 and
C2. The action of activated C1s on C4 and C2 leads to the
production of a substance that increases vascular permeability,
especially that of postcapillary venules. C1 and C4
cooperate with plasmin to split this active peptide from C2.
Of the families of patients with hereditary angioneurotic
edema, 85% do not have C1 INH. Treatment is by preventive
maintenance. Patients are given inhibitors of plasmin
such as ε-aminocaproic acid and tranexamic acid. Methyl
testosterone, which causes synthesis of normal C1 INH in
angioneurotic edema patients, is effective by an unknown
mechanism.
C1q
An 18-polypeptide-chain subcomponent of C1, the first
component of complement. It commences the classical complement
pathway. The three types of polypeptide chains are
designated A, B, and C. Disulfide bonds link these chains.
The triple helix structures of the C1q molecule are parallel
and resemble the stems of six tulips in the amino terminal
half of the structure. They then separate into six globular
regions that resemble the heads of a tulip. The molecule is
arranged in a heterotrimeric rod-like configuration, bearing
a collagen-like triple helix at its amino terminus and
a tulip-like globular region at its carboxyl terminus. The
combination of six of the rod-shaped structures leads to a
symmetric molecular arrangement comprised of three helices
at one terminus and the globular (tulip-like) heads at the
Clq.
other terminus. The binding of antibody to C1q initiates the
classic complement pathway. It is the globular C-terminal
region of the molecule that binds to either immunoglobulin
M (IgM) or IgG molecules. A tetramer comprised of two
molecules of C1r and two molecules of C1s bind by Ca 2+
to the collagen-like part of the stem. The C1q A chain and
C1q B chain are coded for by genes on chromosome 1p
in humans. The interaction of C1q with antigen–antibody
complexes represents the basis for assays for immune complexes
in patients’ serum. IgM, IgG 1, IgG 2, and IgG 3 bind
C1q, whereas IgG 4, IgE, IgA, and IgD do not.
C1q autoantibodies
Autoantibodies are detectable in 14 to 52% of patients with
systemic lupus erythematosus (SLE), in 100% of patients
with hypocomplementemic urticarial vasculitis syndrome
(HUVS), in patients with rheumatoid arthritis (RA) (5% of
patients with uncomplicated RA and 77% of RA patients
with Felty’s syndrome), in 73% of patients with membranoproliferative
glomerulonephritis type I, in 45% of patients
with membranoproliferative glomerulonephritis types
II and III, in 94% of patients of mixed connective tissue
disease, and in 42% of patients with polyarteritis nodosa.
Lupus nephritis patients usually reveal the immunoglobulin
G (IgG) isotype. Rising levels of C1q autoantibodies
portend renal flares in patients with SLE. The rare HUVS
condition can occur together with SLE and is marked by
diminished serum C1q and recurrent idiopathic urticaria
with leukocytoclastic vasculitis.
C1q binding assay for circulating immune
complexes (CICs)
There are two categories of methods to assay circulating
immune complexes: (1) the specific binding of CICs to
complement components, such as C1q, or the binding of
complement activation fragments within the CICs to complement
receptors, as in the Raji cell assay; and (2) precipitation
of large and small CICs by polyethylene glycol. The
C1q binding assay measures those CICs capable of binding
C1q, a subcomponent of the C1 component of complement,
and capable of activating the classical complement
pathway.