IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 25. Hypersensitivity - Type III

■ Immune complexes are formed whenever Antibodies encounter an antigen and are cleared by mononuclear phagocytes following Complement activation.

■ Antigen persistence in chronic infection or autoimmune disease can lead to immune complex disease.

■ Immune complex formation may occur in the bloodstream, leading to systemic disorders, or locally, for example, in the Lungs.

■ Complement promotes the dissociation of antigen-antibody bonds and maintains immune complexes in a soluble state.

■ Primate erythrocytes possess a receptor for C3b and play a crucial role in transporting complement-bearing immune complexes to the Spleen, where they are destroyed.

■ Complement deficiency results in The formation of large, poorly soluble complexes that become deposited in Tissues.

■ Positively charged Antigens have the capacity to bind to tissues, particularly glomerular basement membranes, promoting the local accumulation of complexes in the Kidneys.

■ Factors that increase Blood vessel permeability enhance the deposition of immune complexes in tissues.

Immune complexes are formed whenever antibodies meet an antigen and are normally cleared efficiently by mononuclear phagocytes, but occasionally they persist for long periods and become deposited in various tissues and Organs. The resulting tissue damage, mediated by complement and effector Cells, is termed a type III hypersensitivity reaction or immune complex disease.

The sites where immune complexes are deposited depend partly on the localization of the antigen within tissues and partly on the conditions governing The entry of complexes from the blood into tissues.

TYPES OF IMMUNE COMPLEX DISEASES

Diseases caused by the formation of immune complexes can be divided into three broad categories: those associated with persistent infection, those associated with autoimmune diseases, and those associated with the inhalation of antigenic material (Fig. 25.1).

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Fig. 25.1. The table lists the sources of antigen and the organs most commonly affected.

Persistent infection. The combination of a chronic infection with a weak humoral response leads to the continuous formation of immune complexes and ultimately to their deposition in tissues (Fig. 25.2). Diseases with this Etiology include leprosy, malaria, dengue hemorrhagic fever, Viral Hepatitis, and staphylococcal endocarditis.

Fig. 25.2. Immunofluorescence of immune complexes in an infectious disease. Sections of a renal artery from a patient with chronic hepatitis B, stained with a fluorescent antiserum against hepatitis B virus antigen (1) and a rhodaminated antiserum against IgM (2). The presence of both antigen and antibodies on the intima and media of the arterial wall indicates the deposition of complexes at this site. IgG and C3 deposits show a similar distribution. (Micrographs kindly provided by Dr. A. Nowoslawski.)

Autoimmune diseases. Immune complex disease is frequently a complication of autoimmune diseases, in which chronic complex formation is driven by the continuous production of antibodies to autoantigens. As the load of immune complexes in the blood increases, the system responsible for their clearance (mononuclear phagocytes, erythrocytes, and complement) becomes overwhelmed, and complexes begin to deposit in tissues (Fig. 25.3). Diseases with this etiology include rheumatoid Arthritis, systemic lupus erythematosus (SLE), and polymyositis.

Fig. 25.3. Immunofluorescence of immune complexes in an autoimmune disease. Kidney sections from a patient with systemic lupus erythematosus (type III hypersensitivity) (1) and a patient with Goodpasture's syndrome (type II hypersensitivity) (2). In both cases, antibodies were detected using a fluorescent anti-IgG antiserum. Complexes formed in the Circulation and deposited in the kidney form characteristic discrete masses (1). Antibodies to the basement membrane in Goodpasture's syndrome form a smooth, continuous layer lining the glomerular capillary basement membrane. (Micrographs kindly provided by Dr. S. Thiru.)

Inhalation of antigenic material. Upon exposure to external antigens, immune complexes can form On the surface of Body Cavities. Such reactions occur in the lungs following repeated inhalation of antigenic components of actinomycetes, as well as plant or animal antigens. Examples of such conditions include farmer's lung and pigeon fancier's lung, in which antibodies to actinomycete antigens (from moldy hay) or to Proteins in pigeon droppings are present in the blood. Both of these disorders are forms of extrinsic allergic alveolitis and develop only upon repeated exposure to the antigen. (Antibodies to these antigens belong predominantly to the IgG class rather than the IgE class, which is characteristic of type I hypersensitivity reactions.) When the antigen re-enters the body via the respiratory tract, local immune complexes form in the alveoli, leading to inflammation and fibrosis (Fig. 25.4). Precipitating antibodies to actinomycete antigens are detected in the serum in 90% of cases of farmer's lung, yet they are also present in some healthy individuals and absent in some patients. Thus, the Pathogenesis of this extrinsic allergic alveolitis clearly involves other factors, including type IV hypersensitivity reactions.

Fig. 25.4. When actinomycete antigens enter the lungs of sensitized individuals, immune complexes form within the alveoli (2). Complement fixation leads to cellular recruitment, inflammation, and fibrosis. Histological examination of the lungs in extrinsic allergic alveolitis (1) reveals confluent areas of cellular infiltration. Precipitating antibodies present in the serum of patients with pigeon fancier's lung (P, 3) are directed against antigenic proteins found in avian droppings.