A systemic reaction known as serum sickness can result from the injection of large quantities of a poorly catabolized foreign antigen. This illness was so named because it frequently followed the administration of therapeutic horse antiserum. In the pre-antibiotic era, antiserum made by immunizing horses with Streptococcus pneumoniae was often used to treat pneumococcal pneumonia; the specific anti-pneumococcal antibodies in the horse serum would help the patient to clear the infection. In much the same way, antivenin (serum from horses immunized with snake venoms) is still used today as a source of neutralizing antibodies to treat people suffering from the bites of poisonous snakes.
Serum sickness occurs 7–10 days after the injection of horse serum, an inter
Drug-induced Serum val that corresponds to the time required to mount an IgG-switched primary
Sickness immune response against the foreign horse serum antigens. The clinical features of serum sickness are chills, fever, rash, arthritis, and sometimes glomerulonephritis (inflammation of the glomeruli of the kidneys). Urticaria is a prominent feature of the rash, implying a role for histamine derived from mast-cell degranulation. In this case, the mast-cell degranulation is triggered by the ligation of cell-surface FcγRIII by IgG-containing immune complexes and by the anaphylatoxins C3a and C5a released due to complement activation by these complexes.
fever, vasculitis, arthritis, nephritisforeign serum injectionLevelinplasmaTime (days) foreign serum proteins antigen:antibody complexes antibody against foreign serum proteins
Fig. 14.18 Serum sickness is a classic example of a transient immune complex-mediated syndrome. An injection of a foreign protein, such as horse antitoxin, leads to an anti-horse serum antibody response. These antibodies form immune complexes with the circulating foreign proteins. The complexes are deposited in small blood vessels and activate complement and phagocytes, inducing fever and inflammatory lesions in blood vessels in the skin and connective tissues (vasculitis), in the kidney (nephritis), and in joints (arthritis). All these effects are transient and resolve when the foreign protein is cleared.
The course of serum sickness is illustrated in Fig. 14.18. The onset of disease coincides with the development of antibodies against the abundant soluble proteins in the foreign serum; these antibodies form immune complexes with their antigens throughout the body. The immune complexes fix complement and can bind to and activate leukocytes bearing Fc and complement receptors; these leukocytes in turn cause widespread tissue damage. The formation of immune complexes causes clearance of the foreign antigen, so serum sickness is usually a self-limiting disease. Serum sickness after a second dose of antigen follows the kinetics of a secondary antibody response (see Section 10-14), with symptoms typically appearing within a day or two.
With the increasing clinical use of humanized monoclonal antibodies (such as anti-TNF-α used for the treatment of rheumatoid arthritis), cases of serum sickness are observed, fortunately rarely, in settings where the attempt to humanize the monoclonal antibody was not successful for selected patients because they produce uncommon Ig allotypes. In these individuals, symptoms are generally mild, and one of the most significant features of the anti-monoclonal antibody response is more rapid clearance of the antibody from the circulation, leading to reduction of its therapeutic effects.