Role of complement

Immune complex-mediated tissue injury is thought to be mediated in the initial stages by activation of primarily the classical pathway of the complement system. In the Arthus reaction the formation of immune complexes in and around the wall of microvessels (Figure 1) results in the activation of complement and the generation of C3a and C5a as well as assembly of the membrane attack complex C5-C9. Depletion of complement (e.g. with cobra

Macropiwge

Macropiwge

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Figure 1 Some of the mechanisms involved in the pathological changes associated with an Arthus reaction. Although considered to be driven primarily by complement components (in particular C5a), recent studies suggest that the mast cell Fc receptor plays a crucial role (see text for details). Evidence that amines, PAF and LTB4 contribute to the edema formation and neutrophil accumulation has been obtained from pharmacological studies. A similar approach (using neutralizing antibodies) has demonstrated a role for the cytokines and chemokines listed.

Neulrcjphil

Figure 1 Some of the mechanisms involved in the pathological changes associated with an Arthus reaction. Although considered to be driven primarily by complement components (in particular C5a), recent studies suggest that the mast cell Fc receptor plays a crucial role (see text for details). Evidence that amines, PAF and LTB4 contribute to the edema formation and neutrophil accumulation has been obtained from pharmacological studies. A similar approach (using neutralizing antibodies) has demonstrated a role for the cytokines and chemokines listed.

venom factor) reduces the magnitude of the Arthus reaction and has led to the idea that C5a plays a key role in orchestrating the early stages of the reaction. Thus, generation of C5a could act on mast cells to release bioactive amines which increase vascular permeability and C5a itself increases permeability by a mechanism that depends on circulating neutrophils. This would supply more plasma proteins, including complement components, leading to further C5a generation. In support of this idea, both antibodies to C5a and soluble CR1, which inhibits the generation of C5a, provide partial protection against immune complex-induced lung and skin inflammation in animal models. However, this concept has been challenged recently by studies in mice genetically deficient in complement components C3, C4 or C5. In these animals the Arthus reaction is indistinguishable from that in wild-type controls, suggesting that complement is not required.

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