Immunity can be generated by active or passive means. Active immunity results from exposure to microbes such as Streptococcus and Pneumococcus or vaccination with dead or weakened microbes. In contrast, the administration of antibodies to correct an immunodeficiency or provide short-term immunity against microbial infections is called passive immunity. Transfer of antibodies in colostrum from mother to child or administration of pooled immunoglobulins are examples of natural and artificial passive immunity.

Heterologous Antisera to Provide Passive Immunity

The administration of antibodies to provide passive immunity is not a new concept. In the 1890s, Emil von Behring introduced the concept of passive immunity for the treatment of diseases. He demonstrated that equine polyvalent antiserum was efficacious in the treatment of diphtheria infections in children. In the early 1900s, equine antiserum therapy was used to treat streptococcal pneumonia, bacterial meningitis, and Haemophilus infections. By 1950, antibody therapy had been supplanted by antibiotics, which were cheaper to produce. However, equine antisera are still used for the neutralization of anthrax, tetanus, gas gangrene and diphtheria exotoxins; snake venoms; and the rabies virus. Immunogenicity is a major problem associated with heterologous antisera. Anaphylaxis and serum sickness have been frequently encountered in their use.

Serum Sickness

Serum sickness is caused by the administration of large amounts of any foreign protein. Within 7 to 10 days after administration, an immunoglobulin M (IgM) antibody response to the foreign protein develops. When equal molar concentrations of antigens and antibodies are generated, large complexes settle out in the internal elastic lamina of arteries and perivascular regions. Activation of the complement cascade and the release of cytotoxic factors from endothelial cells cause the necrosis of the capillary vessels in the skin and kidneys.

Patients develop clinical manifestations of fever, arthralgia, lymphadenopathy, and skin eruptions. Serious side effects also have been reported as a consequence of antibody therapy. High concentrations of infused antibody (0.5 to 2.0 mg/kg) can cause renal failure, aseptic meningitis, and thrombosis.

Pooled Human Immunoglobulin

To reduce the morbidity associated with heterologous antisera, fractionated human immunoglobulin is now used as a therapeutic agent. Pooled human immunoglobulin is prepared from a panel of 3000 to 10,000 donors and contains 95% intact, unmodified IgG with trace amounts of IgA and IgM. Preparations also contain the macrophage–granulocyte stimulating factor, interleukin 1 (IL-1), and complement regulators.

Initially, pooled human immunoglobulin was administered by the intramuscular (IM) route. Although effective in reducing the frequency of infections, it was difficult to maintain optimal antibody levels in blood. In 1981, intravenous preparations of human immunoglobulin (IVIG) became available. IVIG allows the infusion of large volumes of antibodies while reducing the cost and the pain associated with intramuscular administration.

IVIG has been used to treat immunodeficiencies, human immunodeficiency virus (HIV) infection in infants, lymphoproliferative malignancies, and infections in low-birth-weight infants. It is also used to treat a wide range of autoimmune diseases such as myasthenia gravis, systemic lupus erythematosus, and autoimmune neuropathies (Box 13-1).

Box 13-1

Diseases Treated with Pooled Human Immunoglobulin

Immune thrombocytopenia

Guillain-Barré syndrome

Kawasaki disease

Dermatomyositis

Kidney transplants with ABO blood group incompatibility

Sjögren syndrome

Common variable immunodeficiency

Chronic lymphocytic leukemia

Pediatric human immunodeficiency virus (HIV) infection

Alzheimer’s disease

Systemic lupus erythematosus (SLE)

IVIG is particularly useful in the treatment of diseases such as idiopathic thrombocytopenic purpura (ITP) and Kawasaki disease and for the prevention of erythroblastosis fetalis.

Idiopathic Thrombocytopenic Purpura

ITP is a pediatric disease that is associated with low platelet counts. Children often present with bruises all over the body, bleeding gums, and, occasionally, a bleeding nose. Patients with persistently low platelet counts are also at high risk of intracranial hemorrhage.

ITP is an autoimmune disease characterized by antibody-coated platelets. In most cases, coated platelets bind to Fc receptors on macrophages in the spleen and liver. Following phagocytosis, platelets are destroyed by the oxidative killing mechanism. In a small proportion of patients, the liver fails to remove the platelets, and circulating antibody–platelet immune complexes are created. Complexes localize in arterioles and capillaries, occluding vessels and causing tissue ischemia. Vessels in the heart, kidney, brain, pancreas, and spleen are common targets for immune complex deposition.

Treatment of Idiopathic Thrombocytopenic Purpura

Administration of IVIG reduces autoantibody levels and disease symptoms. The mechanism is both simple and elegant. Pooled IVIG saturates specialized neonatal Fc receptors (FcRn) on endothelial cells. When the receptor is engaged, IgG is internalized by pinocytosis and recycled to the cell surface, thus preventing lysosomal degradation (Figure 13-1).

Figure 13-1 The role of FcRn in recycling normal IgG after administration of pooled immunoglobulin preparations.

In contrast, serum autoantibodies binding to other Fc receptors on the same cells are internalized and destroyed, thereby arresting the disease process but not curing the disease.

Kawasaki Disease

Kawasaki disease is a self-limiting, febrile disease that is characterized by vasculitis of peripheral and coronary vessels. Patients present with a persistent rash, conjunctivitis, and lymphadenopathy. Individuals with Kawasaki disease have a high risk of heart failure, pericarditis, mitral or aortic valve insufficiency, and rupture of the coronary artery. In the last 5 years, Kawasaki disease has emerged as the leading cause of heart disease in the United States. Although the etiology of the disease is unclear, an immune response to a viral (parvovirus B19 or cytomegalovirus) or bacterial (Yersinia) infection is believed to activate an autoimmune response to vascular endothelial cells and cardiac myosin.

Treatment of Kawasaki Disease

Infusion of IVIG reduces the symptoms by inhibiting the formation of a C3 convertase. Microaggregates within the IVIG displace C3b from tissue-bound immune complexes to the fluid phase, which downregulates the inflammatory response. IVIG also downregulates an inflammatory response by scavenging the anaphylatoxins (C3a and C5b) via low-affinity F(ab′)₂ receptors in microaggregated immunoglobulin. In children with early disease, one regimen of IVIG may reduce the symptoms and progression of the disease for several years.

Erythroblastosis Fetalis

Pooled immunoglobulin is also used to prevent erythroblastosis fetalis in neonates caused by Rh factor incompatibility between mother and child (see Chapter 3). Generally, the mother is Rh negative (Rh–) and the fetus is Rh positive (Rh+). Spillage of fetal blood into the maternal circulation elicits an immune response that destroys the infant’s blood cells. When the fetal bone marrow cannot compensate for the destruction of red blood cells, severe anemia occurs. Administration of RhoGAM (anti-Rh) is sufficient to prevent the stimulation of the maternal immune response to Rh+ red blood cells from the fetus.