Looking at complement deficiencies, any one of the
many different complement components can be affected.
For example, if there is a defective gene
encoding the complement components C1q, C1r,
C1s, C2, C3, C4 or Factor I, there will be
impaired clearance of immune complexes.
And this can result in the condition, systemic
lupus erythematosus which is an autoimmune disease.
And typical infections seen when there is deficiency of these
particular complement components
include a number of pyogenic bacteria.
Deficiencies in the later complement components,
C6-- C5, C6, C7, C8, C9, Factor D, Properdin; this
will lead to a range of other types of infections,
particularly disseminated Neisseria infections.
MASP-2 deficiency, one sees an increased
instance of Streptococcus pneumoniae.
And in mannose binding lectin deficiency, which has
quite a high prevalence for a primary immunodeficiency,
in fact it’s one of the most prevalent primary
immunodeficiencies; there is usually no consequence.
So most people with mannose binding lectin
deficiency don’t even know they’ve got it.
And the same is true of another relatively common primary
immunodeficiency, which is selective-IgA deficiency.
Again, usually other parts of the
immune response compensate for the lack,
and one doesn’t see a greatly increased
instance of particular infections.
One interesting complement regulatory component
deficiency is paroxysmal nocturnal hemoglobinuria (PNH).
In this disease, there is a
mutation in the PIG-A gene.
This encodes an α-1,6-N-acetyl-glucosaminyltransferase,
which results in an
inability to synthesize the glycosyl
phosphatidylinositol, or GPI anchors.
And a lack of these GPI anchors mean that complement control
proteins, CD55 and CD59 are absent
from the surface of erythrocytes.
And this means that these erythrocytes are
susceptible to complement-mediated lysis.
So normally, CD55 which requires a GPI anchor to
hold it on to the cell surface of the erythrocyte,
this molecule CD55 inhibits the C3 convertase,
which is necessary for complement activation.
Likewise, CD59 which also requires a GPI
anchor to hold it on the surface of the
erythrocyte, this functions to prevent
insertion of the membrane attack complex.
So in the absence of these GPI anchors, neither of
these molecules is present on the surface of the
red blood cell, and the membrane attack complex can
cause lysis of the red blood cell resulting in PNH.
Hereditary angioedema is due
to a C1 inhibitor deficiency.
C1 inhibitor is required to regulate the
uncontrolled activation of the coagulation system.
So in its absence, there
is excessive clotting.
It’s also required to regulate
the complement system.
And in its absence there is excessive production of activated
complement components resulting in inflammation and cell lysis.
And it also is involved in
regulating the kinin system.
So there is excessive production of bradykinin
and endothelial cell activation as a result.