12.4D: Type III (Immune Complex) Reactions

Type III hypersensitivity occurs when there is little antibody and an excess of antigen, leading to the formation of small immune complexes.

Learning Objectives

• Describe Type III hypersensitivity reactions

Key Points

• It is characterized by solvent antigens that are not bound to cell surfaces (which is the case in type II hypersensitivity) but bind antibodies to form immune complexes of different sizes.
• Large complexes can be cleared by macrophages but small immune complexes cannot be cleared and they insert themselves into small blood vessels, joints, and glomeruli, causing symptoms.
• The cause of damage is as a result of the action of cleaved complement anaphylotoxins C3a and C5a, which, mediate the onset of the inflammatory response and eventual tissue damage.

Key Terms

• glomerulonephritis: A form of nephritis characterized by inflammation of the glomeruli
• immune complex: An immune complex is formed from the integral binding of an antibody to a soluble antigen. The bound antigen acting as a specific epitope, bound to an antibody is referred to as a singular immune complex.
• Arthus reaction: The Arthus reaction is a type of local type III hypersensitivity reaction which involves the deposition of antigen/antibody complexes mainly in the vascular walls, serosa (pleura, pericardium, synovium) and glomeruli.

Type III hypersensitivity occurs when there is little antibody and an excess of antigen, leading to small immune complexes being formed that do not fix complement and are not cleared from the circulation. It is characterized by solvent antigens that are not bound to cell surfaces (which is the case in type II hypersensitivity). When these antigens bind antibodies, immune complexes of different sizes form. Large complexes can be cleared by macrophages but macrophages have difficulty in the disposal of small immune complexes. These immune complexes insert themselves into small blood vessels, joints, and glomeruli, causing symptoms. Unlike the free variant, small immune complex bound to sites of deposition (like blood vessel walls) are far more capable of interacting with complement. These medium-sized complexes, formed in the slight excess of antigen, are viewed as being highly pathogenic.

Such depositions in tissues often induce an inflammatory response, and can cause damage wherever they precipitate. The cause of damage is as a result of the action of cleaved complement anaphylotoxins C3a and C5a, which, respectively, mediate the induction of granule release from mast cells (from which histamine can cause urticaria), and recruitment of inflammatory cells into the tissue (mainly those with lysosomal action, leading to tissue damage through frustrated phagocytosis by polymorphonuclear neutrophils and macrophages).

Immune complex glomerulonephritis, as seen in Henoch-Schönlein purpura is an example of IgA involvement in a nephropathy. The reaction can take hours, days, or even weeks to develop, depending on whether or not there is immunlogic memory of the precipitating antigen. Typically, clinical features emerge a week following initial antigen challenge, when the deposited immune complexes can precipitate an inflammatory response. Because of the nature of the antibody aggregation, tissues that are associated with blood filtration at considerable osmotic and hydrostatic gradient (e.g. sites of urinary and synovial fluid formation, kidney glomeruli and joint tissues respectively) bear the brunt of the damage. Hence, vasculitis, glomerulonephritis and arthritis are commonly-associated conditions as a result of type III hypersensitivity responses. As observed under methods of histopathology, acute necrotizing vasculitis within the affected tissues is observed concomitant to neutrophilic infiltration, along with notable eosinophilic deposition (fibrinoid necrosis).

Figure: Henoch-Schönlein nephritis IgA immunostaining: Immune Complex Glomerulonephritis, as seen in Henoch-Schönlein purpura; this is an example of IgA involvement in a nephropathy.

Often, immunofluorescence microscopy can be used to visualize the immune complexes. Skin response to a hypersensitivity of this type is referred to as an Arthus reaction, and is characterized by local erythema and some induration. Platelet aggregation, especially in microvasculature, can cause localized clot formation, leading to blotchy hemorrhages. This typifies the response to injection of foreign antigen sufficient to lead to the condition of serum sickness. An immune complex is formed from the integral binding of an antibody to a soluble antigen. The bound antigen acting as a specific epitope, bound to an antibody, is referred to as a singular immune complex. After an antigen-antibody reaction, the immune complexes can be subject to any of a number of responses, including complement deposition, opsonization, phagocytosis, or processing by proteases.

Red blood cells carrying CR1-receptors on their surface may bind C3b-decorated immune complexes and transport them to phagocytes, mostly in liver and spleen, and return back to the general circulation. Immune complexes may themselves cause disease when they are deposited in organs, e.g. in certain forms of vasculitis. This is the third form of hypersensitivity in the Gell-Coombs classification, called Type III hypersensitivity. Immune complex deposition is a prominent feature of several autoimmune diseases, including systemic lupus erythematosus, cryoglobulinemia, rheumatoid arthritis, scleroderma and Sjögren’s syndrome.