Role Of Preexisting Antibodies To Cxc Chemokines

Preexisting antibodies to chemokines, such as IL-8 or NAP-2, or possibly even to PF4 itself, may be present in some patients before heparin therapy (Sylvester et al., 1992; Bendtzen et al., 1995; Warkentin et al., 2006b). These antibodies may occur naturally or be induced in pathologic states, where they might have a regulatory role in inflammation (Reitamo et al., 1993). In some diseases, they are present at high concentrations. Antibodies to IL-8 are the most common (Reitamo et al., 1993). However, in some patients, true autoantibodies to PF4 alone can also be observed. In the absence of heparin, these antibodies usually do not demonstrate any clear pathogenicity. However, during heparin therapy, PF4 and other chemo-kines are released into blood from their storage pools. Heparin may further localize these chemokines onto blood cells and endothelium, with deleterious consequences. The amount of chemokine-heparin complexes bound to blood cells and ECs depends on different factors: the amount of releasable chemokines (i.e., the patient's clinical state); the type and dose of heparin used; the presence of activated cells with an increased capacity to bind chemokines; and, if present, the heparin-dependent antibodies, through their binding to chemokine-heparin complexes. As with antibodies against PF4-H complexes, these natural antichemokine antibodies could initiate cell activation and cell-cell interactions as well as generate circulating cell aggregates that could lead to vessel occlusion. Figure 4 shows the possible mechanism for pathogenic effects of these antichemokine antibodies, as antibody localization to the target cells is enhanced by heparin therapy. Finally, we can speculate that protamine sulfate, used for neutralizing heparin after CPB, could generate an immunologic stimulus for heparin-depen-dent immunization (Al-Mondhiry et al., 1985), especially as both protamine and heparin can induce thrombocytopenia, and protamine can induce specific antibody formation.

FIGURE 4 (See color insert) Possible effect of heparin for carrying preexisting antibodies to IL-8 onto platelets (and other blood cells), through the heparin binding sites or through the IL-8 receptors, targeting the deleterious consequences of these antibodies onto these cells. Abbreviation: IL-8, interleukin-8.

FIGURE 4 (See color insert) Possible effect of heparin for carrying preexisting antibodies to IL-8 onto platelets (and other blood cells), through the heparin binding sites or through the IL-8 receptors, targeting the deleterious consequences of these antibodies onto these cells. Abbreviation: IL-8, interleukin-8.

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