Sensitization phase

Unlike Type II hypersensitivity reactions, the sensitization phase of Type III hypersensitivity reactions is characterized by IgM and IgG antibodies binding to soluble antigens with subsequent formation of immune complexes (Fig. 13.5). Persistent immune challenge, in some autoimmune diseases or under conditions of chronic antigen exposure (e.g., chronic parasitemia), induces the formation of immune complexes in excess of the capacity of normal immune clearance mechanisms (in the reticuloendothelial system).

Effector phase

Immune complexes formed in excess are deposited in the capillary walls where they stimulate complement activation (Fig. 13.5), generating anaphylatoxins and the C3b opsonin. One of the anaphylatoxins, C5a, is chemotactic for neutrophils and so neutrophils are recruited to the site where the immune complexes are localized. In addition, C5a binds to mast cells/basophils causing the release of vasoactive amines and associated increases in vascular permeability. As immune complexes filter between the contracted endothelial cells they become trapped in the vessel wall. Recruited neutrophils are activated as they try to phagocytose the immune complexes, following recognition of IgG Fc regions, or the deposited C3b opsonin. Activated neutrophils secrete inflammatory mediators, including reactive oxygen intermediates and the proteolytic enzymes, elastase, and collagenase. The latter enzymes damage the endothelium, exposing the subendothelium which now serves to activate the intrinsic coagulation pathway, leading to the generation of kallikrein and bradykinin. Bradykinin is a potent vasodilator. The combined effects of histamine and bradykinin on vascular permeability cause increased vascular permeability (Fig. 13.6). In addition, platelets bind to the subendothelium, interact with immune complexes, and aggregate at these sites. If uncontrolled, these events lead to formation of microthrombi, platelet activation and aggregation, vascular occlusion, and tissue necrosis.

Clinical manifestation

Localization of immune complexes

In systemic lupus erythematosus (SLE), complexes are mainly deposited in the kidney glomeruli to cause glomerulonephritis; in rheumatoid arthritis they are deposited in the joints; in farmer's lung they are deposited in the lung. Different hypotheses may help to explain the localization of complexes to these sites. It has been suggested that the kidney basement membrane acts to "trap" polyanionic antigens in a nonspecific manner so that the presence of excess antibodies that recognize these polyanionic antigens (anti-DNA antibodies in SLE) leads to immune complex deposition in the kidney basement membrane.

Deposition of immune complexes


Classical pathway of complement activation Release of C2b (kinin) and anaphylatoxins

Classical pathway of complement activation Release of C2b (kinin) and anaphylatoxins

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