Figure 1. Activation of the Arthus reaction. (1) Intradermal injection of antigen combines within hours to antibody from the blood and forms immune complexes. The complexes bind to C1q, the first component of complement, which triggers activation of the whole complement cascade. A number of the complement components subsequently formed are small cationic peptides called anaphylatoxins (C3a, C4a and C5a), which lead to the recruitment and activation of mast cells, macrophages and neutrophils. (2) Release of histamine, lysosomal enzymes and free radicals can induce local tissue damage. C3b acts as an opsonin, binding to immune complexes which are adsorbed on to CR1-expressing phagocytes, which are further activated causing additional inflammatory damage to nearby vessel walls. (3) Immune complexes in complement-deficient individuals can bind directly to endothelial cells and platelets, upregulating P-selectin and other inflammatory mediators, which in turn trigger migration of neutrophils to sites of immune complex formation. (4) Immune complexes bind directly to Fc receptors or, if coated with inactivatable C3biC3 aC3b (iC3b) fragments, to Mac-1 (CR3) receptors, inducing spreading of the phagocytes, which ultimately leads to the release of inflammatory mediators.

Figure 2. Potential therapeutic target sites to prevent type III hypersensitivity reactions. (1) Formation of immune complexes and binding to C1q activates complement. Both C1q and C3b bind to the complexes to limit the size and help to solubilize them, respectively. (2) However, release of intracellular components (e.g. calreticulin, decorin and proteochondroitin sulfate) can inhibit C1q-mediated complement activation by competing with complexes for C1q binding. (3) The generation of later-stage proinflammatory complement components C5a and C5b–C9 can be blocked by inhibiting cleavage of C5 with anti-C5 monoclonal antibodies. (4) The presence of immune complexes leads to local upregulation of P-selectin and increased surface expression of FcR and Mac-1 receptors on inflammatory cells. (5) Specific monoclonal antibodies and specifically engineered peptides may inhibit the action of these inflammatory mediators, the objective being to reduce the release of chemokines by cells and impair neutrophil accumulation at sites of immune complex deposition.