Immune Complex–Mediated (Type III) Hypersensitivity
The reaction of antibody with antigen generates immune complexes. In general, these antigen-antibody complexes facilitate the clearance of antigen by phagocytic cells and red blood cells (see Chapter 12). In some cases, however, the presence of large numbers and networks of immune complexes can lead to tissue-damaging type III hypersensitivity reactions. The magnitude of the reaction depends on the levels and size of immune complexes, their distribution within the body, and the ability of the phagocyte system to clear the complexes and thus minimize the tissue damage. Failure to clear immune complexes may also result from peculiarities of the antigen itself, or disorders in phagocytic machinery. The deposition of immune complexes in the blood vessels or tissues initiates reactions that result in the recruitment of complement components and neutrophils to the site, with resultant tissue injury.
Immune Complexes Can Damage Various Tissues
The formation of antigen-antibody complexes occurs as a normal part of an adaptive immune response. It is usually followed by Fc receptor–mediated recognition of the complexes by phagocytes, which engulf and destroy them; by binding to red blood cells for clearance in the spleen or kidney; and/or by complement activation that results in the lysis of the cells on which the immune complexes are found. However, under certain conditions, immune complexes are inefficiently cleared and may be deposited in the blood vessels or tissues, setting the stage for a type III hypersensitivity response. These conditions include (1) the presence of antigens capable of generating particularly extensive antigen-antibody lattices, (2) a high intrinsic affinity of antigens for particular tissues, (3) the presence of highly charged antigens (which can affect immune complex engulfment), and (4) a compromised phagocytic system. All have been associated with the initiation of type III responses.
Uncleared immune complexes bind to mast cells, neutrophils, and macrophages via Fc receptors, triggering the release of vasoactive mediators and inflammatory cytokines, which interact with the capillary epithelium and increase the permeability of the blood vessel walls. Immune complexes then move through the capillary walls and into the tissues, where they are deposited and set up a localized inflammatory response. Complement activation results in the production of the anaphylatoxin chemokines C3a and C5a, which attract more neutrophils and macrophages (see Chapter 5). These in turn are further activated by immune complexes binding to their Fc receptors to secrete proinflammatory chemokines and cytokines, prostaglandins, and proteases. Proteases attack the basement membrane proteins collagen and elastin, as well as cartilage. Tissue damage is further mediated by oxygen free radicals released by the activated neutrophils. In addition, immune complexes interact with platelets and induce the formation of tiny clots. Complex deposition in the tissues can give rise to symptoms such as fever, urticaria (rashes), joint pain, lymph node enlargement, and protein in the urine. The resulting inflammatory lesion is referred to as vasculitis if it occurs in a blood vessel, glomerulonephritis if it occurs in the kidneys, or arthritis if it occurs in the joints.
Immune Complex–Mediated Hypersensitivity Can Resolve Spontaneously
If immune complex–mediated disease is induced by a single large bolus of antigen that is then gradually cleared, it can resolve spontaneously. Spontaneous recovery is seen, for example, when glomerulonephritis is initiated following a streptococcal infection. Streptococcal antigen–antibody complexes bind to the basement membrane of the kidney and set up a type III response, which resolves as the bacterial load is eliminated. Similarly, patients being treated for various conditions by injections of antibody can develop immune responses to the foreign antibody and generate large immune complexes. This was seen initially during the use of horse anti-diphtheria toxin antibodies in the treatment of diphtheria in the early 1900s. On repeated injections with the horse antibodies, patients developed a syndrome known as serum sickness, which resolved as soon as the antibodies were withdrawn. Serum sickness is an example of a systemic form of immune complex disease, which resulted in arthritis, skin rash, and fever.
A more recent manifestation of the same problem occurred in patients who received therapeutic mouse-derived monoclonal antibodies designed to treat cancers. After several such treatments, some patients generated their own antibodies against the foreign monoclonals and developed serum sickness–like symptoms. We know now that injection of the mouse antibodies caused a generalized type III reaction, and in many cases the therapeutic antibodies were actually cleared before they could reach their pathogenic target. To avoid this response, current therapeutic antibodies are genetically engineered to replace the mouse-specific regions of antibody proteins with the corresponding human sequences (they are then called humanized antibodies; see Chapter 12).
Auto-Antigens Can Be Involved in Immune Complex–Mediated Reactions
If the antigen in the immune complex is an auto-antigen (self antigen), it cannot be permanently eliminated; hence type III hypersensitivity reactions cannot be easily resolved. In such situations, chronic type III responses develop. For example, in systemic lupus erythematosus, persistent antibody responses to auto-antigens such as DNA and various nuclear proteins are an identifying feature of the disease, and complexes are deposited in the joints, kidneys, and skin of patients. Examples of conditions resulting from type III hypersensitivity reactions are found in Table 15-5.
| Autoimmune diseases |
| Systemic lupus erythematosus |
| Rheumatoid arthritis |
| Drug reactions |
| Allergies to penicillin and sulfonamides |
| Infectious diseases |
| Poststreptococcal glomerulonephritis |
| Meningitis |
| Hepatitis |
| Mononucleosis |
| Malaria |
| Trypanosomiasis |
Arthus Reactions Are Localized Type III Hypersensitivity Reactions
One example of a localized type III hypersensitivity reaction has been used extensively as an experimental tool. If an animal or human subject is injected intradermally with an antigen to which large amounts of circulating antibodies exist (or have been recently introduced by intravenous injections), antigen will diffuse into the walls of local blood vessels and large immune complexes will precipitate close to the injection site. This initiates an inflammatory reaction that peaks approximately 4 to 10 hours postinjection and is known as an Arthus reaction. Inflammation at the site of an Arthus reaction is characterized by swelling and localized bleeding, followed by fibrin deposition (Figure 15-14). Though not commonly used now, this was used as an in vivo assay to detect the presence of antigens and/or antibodies, especially in situations in which the antibodies or antigen had not been purified.
FIGURE 15-14 An Arthus reaction. This photograph shows an Arthus reaction on the thigh of a 72-year-old woman. This occurred at the site of injection of a chemotherapeutic drug, 3 to 4 hours after the patient received a second injection (15 days after the first). This response was accompanied by fever and significant discomfort.
A sensitive individual may react to an insect bite with a rapid, localized type I allergic reaction, which can be followed, some 4 to 10 hours later, by the development of a typical Arthus reaction, characterized by pronounced erythema and edema. Intrapulmonary Arthus-type reactions in the lung induced by bacterial spores, fungi, or dried fecal proteins in people with antibodies to these antigens can also cause pneumonitis or alveolitis. These reactions are known by a variety of common names reflecting the source of the antigen. For example, farmer’s lung develops after inhalation of actinomycetes from moldy hay, and pigeon fancier’s disease results from inhalation of a serum protein in dust derived from dried pigeon feces.