Type III hypersensitivities are immune-complex reactions that were first characterized by Nicolas Maurice Arthus (1862–1945) in 1903. To produce antibodies for experimental procedures, Arthus immunized rabbits by injecting them with serum from horses. However, while immunizing rabbits repeatedly with horse serum, Arthus noticed a previously unreported and unexpected localized subcutaneous hemorrhage with edema at the site of injection. This reaction developed within 3 to10 hours after injection. This localized reaction to non-self serum proteins was called an Arthus reaction. An Arthus reaction occurs when soluble antigens bind with IgG in a ratio that results in the accumulation of antigen-antibody aggregates called immune complexes.
A unique characteristic of type III hypersensitivity is antibody excess (primarily IgG), coupled with a relatively low concentration of antigen, resulting in the formation of small immune complexes that deposit on the surface of the epithelial cells lining the inner lumen of small blood vessels or on the surfaces of tissues. This immune complex accumulation leads to a cascade of inflammatory events that include the following:
- IgG binding to antibody receptors on localized mast cells, resulting in mast-cell degranulation
- Complement activation with production of pro-inflammatory C3a and C5a
- Increased blood-vessel permeability with chemotactic recruitment of neutrophils and macrophages
Because these immune complexes are not an optimal size and are deposited on cell surfaces, they cannot be phagocytosed in the usual way by neutrophils and macrophages, which, in turn, are often described as “frustrated.” Although phagocytosis does not occur, neutrophil degranulation results in the release of lysosomal enzymes that cause extracellular destruction of the immune complex, damaging localized cells in the process. Activation of coagulation pathways also occurs, resulting in thrombi (blood clots) that occlude blood vessels and cause ischemia that can lead to vascular necrosis and localized hemorrhage.
Systemic type III hypersensitivity (serum sickness) occurs when immune complexes deposit in various body sites, resulting in a more generalized systemic inflammatory response. These immune complexes involve non-self proteins such as antibodies produced in animals for artificial passive immunity, certain drugs, or microbial antigens that are continuously released over time during chronic infections (e.g., subacute bacterial endocarditis, chronic viral hepatitis). The mechanisms of serum sickness are similar to those described in localized type III hypersensitivity but involve widespread activation of mast cells, complement, neutrophils, and macrophages, which causes tissue destruction in areas such as the kidneys, joints, and blood vessels. As a result of tissue destruction, symptoms of serum sickness include chills, fever, rash, vasculitis, and arthritis. Development of glomerulonephritis or hepatitis is also possible.
Autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis can also involve damaging type III hypersensitivity reactions when auto-antibodies form immune complexes with self antigens.
Parker, N., Schneegurt, M., Thi Tu, A.-H., Forster, B. M., & Lister, P. (n.d.). Microbiology. Houston, Texas: OpenStax. Access for free at: https://openstax.org/details/books/microbiology