Immune Complexes, Complement And Disease
All the useful functions of antibody depend on
its ability to combine with the
corresponding antigen to form an immune complex (glance back at Fig. 20
to be reminded of the forces that bring this about). The normal fate of these
complexes is phagocytosis (bottom left), which is greatly enhanced if
complement becomes attached to the complex; thus, complex formation is an
essential prelude to antigen disposal.
However, there are circumstances
when this fails to happen, particularly if the complexes are small (e.g. with
proportions such as Ag2 :Ab1 or Ag3 :Ab2). This can occur if there is an excess
of antigen, as in persistent infections and in autoimmunity, where the
antibody is of very low affinity or where there are defects of the phagocytic
or the complement systems.
If not rapidly phagocytosed,
complexes can induce serious inflammatory changes in either the tissues (top
right) or in the walls of small blood
vessels (bottom right), depending on the site of formation. In both cases it is activation of complement and
enzyme release by polymorphs that do the damage. The renal glomerular
capillaries are particularly vulnerable, and immune complex disease is the most
common cause of chronic glomerulonephritis, which is itself the most frequent
cause of kidney failure.
Note that increased vascular
permeability plays a preparatory role both for complex deposition in vessels
and for exudation of complement and PMN into the tissues, underlining the close
links between type I and type III hypersensitivity. Likewise there is an
overlap with type II, in that some cases of glomerulonephritis are caused by antibody
against the basement membrane itself, but produce virtually identical damage.
Complexes of small size are formed in antigen excess, as occurs early in the antibody response to a large dose of
antigen, or with persistent exposure to drugs or chronic infections (e.g.
streptococci, hepatitis, malaria), or associated with autoantibodies.
Fc receptors (FcR) A family of receptors found at the
surface of many cell types that bind to the constant (known historically as the
Fc) region of antibodies (see Fig. 14). Fc receptors on macrophages and
neutrophils facilitate phagocytosis, and are responsible for the opsonizing
effects of antibody. Most Fc receptors bind much more efficiently to antibodies
that form part of an antigen–antibody complex, thus ensuring that free antibody
in serum does not fill up the receptors and interfere with their function.
PC Plasma cells are the last stage of
differentiation of activated B cells. Plasma cells are long-lived cells that
settle in the medulla of lymph nodes, or in the bone marrow, and produce
extraordinarily large amounts of specific antibody until they die.
Macrophages lining the liver (Kupffer cells) or spleen
sinusoids remove particles from the blood, including large complexes.
PMN Polymorphonuclear leucocyte, the principal
phagocyte of blood, with granules (lysosomes) that contain numerous antibacterial
enzymes. When these are released neighbouring cells are often damaged. This is
particularly likely to happen when PMNs attempt to phagocytose complexes that
are fixed to other tissues.
C3 The central component of complement, a series
of serum proteins involved in inflammation and antibacterial immunity. When
complexes bind C1, C4 and C2, C3 is split into a small fragment, C3a, which
activates mast cells and basophils, and a larger one, C3b, which pro- motes
phagocytosis by attaching to receptors on PMNs and macrophages (CR in figure).
Subsequent components generate chemotactic factors that attract PMNs to the
site. C3 can also be split via the ‘alternative’ pathway initiated by bacterial
endotoxins, etc. Complement is also responsible for preventing the formation of
large precipitates and solubilizing precipitates once they have formed (see
also Fig. 6).
Mast cells, basophils, and platelets contribute
to increased vascular permeability by releasing histamine, etc. (see Fig. 35).
The glomerular basement membrane
(GBM), together with endothelial cells and external epithelial ‘podocytes’,
separates blood from urine. Immune complexes are usually trapped on the blood
side of the basement membrane, except when antibody is directed specifically
against the GBM itself (as in the autoimmune disease Goodpasture’s syndrome) but small complexes can
pass through the basement membrane to accumulate in the urinary space.
Mesangial cells may proliferate into the subendothelial space, presumably in an
attempt to remove complexes. Endothelial proliferation may occur too, resulting
in glomerular thickening and loss of function.
The classic types of immune complex
disease, neither of which is much seen nowadays, are the Arthus reaction, in
which antigen injected into the skin of animals with high levels of antibody
induces local tissue necrosis (top right in figure), and serum sickness, in
which passively injected serum, e.g. a horse antiserum used to treat pneumonia,
induces an antibody response, early in the course of which small complexes are
deposited in various blood vessels, causing a fever with skin and joint
symptoms about a week later.
However, certain diseases are thought to represent essentially the same type of pathological reactions.
SLE Systemic lupus erythematosus, a disease of
unknown origin in which autoantibodies to nuclear antigens (which include DNA,
RNA and DNA/RNA-associated proteins) are deposited, with complement, in the
kidney, skin, joints, brain, etc. The immune complexes also stimulate
plasmacytoid dendritic cells to produce very high levels of type I interferons
which contribute to inflammation (see Fig. 24). Treatment is by
immunosuppression or, in severe cases, exchange transfusion to deplete
autoantibody.
Polyarteritis nodosa An inflammatory disease of small arteries
affecting numerous organs. Some cases may be due to complexes of hepatitis B
antigen with antibody and complement.
RA Rheumatoid arthritis features both local
(Arthus-type) damage to joint surfaces and systemic vasculitis. The cause is
unknown but complexes between autoantibodies and IgG (rheumatoid factor) are a
constant finding. Immune complexes
bind to macrophages within joints
inducing the release of tumour necrosis fact (see Fig. 24) and RA in many
patients can be effectively treated by administering antibodies to TNF-α. The
symptoms of RA are also alleviated by removing circulating B cells by
administering an antibody to the B-cell marker CD20.
Alveolitis caused by Actinomyces and other fungi
(see Fig. 30) may be due to an Arthus-type reaction in the lung (e.g. farmer’s
lung). Similar immune complex disease reactions occur in some individuals who
keep pigeons or other birds.
Thyroiditis, Goodpasture’s
syndrome, and other autoimmune
dis- eases can be caused by antibodies binding to ‘self’ antigens on these
tissues (a ‘type II’ hypersensitivity reaction), hence causing damage to the
organ.
Infectious diseases The skin rashes, joint pains and renal
complications of several infections can be caused by type III reactions. Very
high levels of antibody (most of it non-specific) are also associated with some
parasitic diseases such as malaria. In addition, widespread activation of
complement can occur in septic shock, induced by LPS from Gram-negative
bacteria, and in the haemorrhagic shock of viruses such as dengue, in both of
which it is associated with cytokines such as TNF. Complement, neutrophils and
cytokines are also thought to be involved in the pulmonary vascular leakage of
the adult respiratory distress syndrome (ARDS) that follows massive trauma.
Haemolytic disease of the
newborn
In general, mothers are tolerant to
the antigens carried by their fetus. However, women who do not carry the red
blood cell Rhesus antigen D (Rh negative) can sometimes become immunized
against this antigen by a Rh-positive fetus at birth, when blood cells of the
fetus can enter the mother’s circulation due to damage to the placenta. The
antibodies cross the placenta in a subsequent pregnancy and cause serious anaemia
in the fetus. This danger can be substantially reduced by administering anti-Rh
antibodies to the mother at the time of birth, thus rapidly removing the
circulating fetal blood cells from the mother’s circulation and preventing the
initial immunization.
Note that this is not really an
immune complex disease, but would be
classified as Gell and Coombs’ type II.
