1.6.3 Acute inflammation mediated by immune complexes

Type III hypersensitivity develops when immune complexes are formed in large quantities, or cannot be cleared adequately by the reticulo-endothelial system, leading to serum-sikness type reactions.

Repeated cutaneous injection of antigen was shown by Arthus in 1903 to initiate, within hours, acute local inflammation. This form of inflammation, called the ''Arthus reaction'', was ultimately shown to require immune complexes. Deposition of immune complexes in local tissues with resultant inflammation is common in rheumatic diseases. The combination of IgM or IgG antibodies with antigen activates the complement cascade, generating active peptides such as C5a, which, in addition to dilating capillaries and increasing vascular permeability, contracts smooth muscle and mobilizes phagocytic cells. Binding of immune complexes to neutrophils and macrophages also activates the respiratory burst with generation of toxic oxygen products such as hydrogen peroxide, hydroxyl radical, hypochlorous acid, and chloramines. Lysosomal proteolytic enzymes, together with toxic oxygen products, produce a potent system that can damage protein and lead to blood vessel damage with haemorrhagic necrosis and local tissue destruction.

When large amounts of antigen enter the circulation (as following administration of heterologous serum), a serum sickness reaction may ensue. As antibody is produced, antigen-antibody complexes are formed. Such complexes may localize to small vessels, resulting in local inflammation and vasculitis. Phagocytosis of immune complexes by macrophages can result in release of cytokines, such as IL-1 and TNF- , which initiate fever. Deposition of immune complexes in the glomerular basement membrane can lead to glomerulitis. By similar mechanisms arthritis may result. Rheumatoid arthritis has many characteristics of a local immune complex reaction, whereas systemic lupus erythematosus has many clinical features of serum sickness.

Diseases resulting from immune complex formation can be placed broadly into three groups:

1. The combined effects of a low-grade persistent infection (such as occur with -haemolytic Streptococcus viridans or staphylococcal infective endocarditis, or with a parasite such as Plasmodium vivax, or in viral hepatitis), together with a weak antibody response, leads to chronic immune complex formation with the eventual deposition of complexes in the tissues.

2. Immune complex disease is a frequent complication of autoimmune disease where the continued produced of antibody to a self-antigen leads to prolonged immune complex formation. The mononuclear phagocyte, erythrocyte, and complement systems (which are responsible for the removal of complexes) become overloaded and the complexes are deposited in the tissues, as occurs in systemic lupus erythematosus.

3. Immune complexes may be formed at body surfaces, notably in the lungs following repeated inhalation of antigenic material from moulds, plants or animals. This is exemplified in Farmer's lung and Pigeon fancier's lung, where there are circulating antibodies to the actinomycete fungi found in mouldy hay, or to pigeon antigens. Both diseases are forms of extrinsic allergic alveolitis, and they only occur after repeated exposure to the antigen.

The main diseases in which immune complexes are important are summarized in Table 1.14. The sites of immune-complex deposition are partly determined by localization of the antigen in the tissue, and partly by how ciculating immune complexes become deposites.

 
Table 1.14:  Some of the main diseases in which immune complexes are implicated

Experimental models are avaible for each of the three mains types of immune complex disease descrined above: serum sickness induced by injections of foreign antigen, to represent the presence of a persistent infection; the NZB/NZW mouse, for autoimmunity; and the Arthus reaction, for local damage by extrinsic antigen. Care must be taken when interpreting animal experiments as the erythrocytes of rodents and rabbits lack the receptor for iC3b (known as CR1) which readily binds immune complexes that have fixed complement. This is present on primate erythrocytes.