Complement Activation by Immune Complexes during Reperfusion

The idea that antibodies are involved in reperfusion injury initially came from observations after intestinal ischemia that C4-deficient animals were protected to a degree similar to those deficient in C3. Since C4 is unique to the classical pathway, which is typically activated by an immune complex, the hypothesis set forward was that immune complexes were formed during reperfusion (Figure 2). Supporting evidence has been developed using immunoglobulin-deficient RAG mice. These animals have injury reduced to levels seen in C4-deficient mice. Further, reconstitution of RAG animals with wild-type IgM will fully reproduce injury while reconstitution with wild-type IgG will not [5].

IgG, however, might play a role in augmenting IgM-mediated injury. Immunohistochemical staining for IgM and C3 on skeletal muscle demonstrates that IgM binding occurs

Figure 2 IR activates the classical complement pathway with formation of the membrane attack complex. (see color insert)

during ischemia while complement activation and injury occur during reperfusion [11]. This temporal sequence along with the histologic colocalization of IgM and C3 indicates that the observed IgM binding to tissue is the initiator of complement activation and subsequent reperfusion injury.

Most immunologists will agree that our understanding of IgM and its immunological interactions is at best elementary. IgM exists in circulation as a pentamer linked by cova-lent interactions to a J-chain. Identification of its role in mediating reperfusion injury presents a new paradigm and the opportunity to target a key mediator of this clinical phenomenon.

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