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Immune Complexes, Complement And Disease


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.

Immune Complexes, Complement And Disease, glomerular basement membrane, Mast cells, basophils, and platelets, Haemolytic disease of the newborn

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.

Immune complex diseases
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.