ACTIVATION OF COMPLEMENT BY COLD AGGLUTININS

Objective: To review recent reports on the interaction of cold agglutinins with the complement system and its relevance to cold agglutinin disease. Data Sources: Review articles and original papers have been selected for this contribution. Selection Criteria: The report focuses on experimental data available from in vitro studies as well as clinical findings regarding the mechanisms of cold agglutinin-induced complement activation. Results: Despite the observation that only few cold agglutinins (almost exclusively IgM molecules with anti-I specificity) induce in vitro hemolysis of human red blood cells with human serum (homologous system), the vast majority of these autoantibodies are able to initiate the classical pathway sequence with the fixation of C1 and to a lesser degree of C4. The ability of IgM cold agglutinins to activate, in principle, complement is demonstrated by their hemolytic efficiency in the presence of animal serum asa source of heterologous complement. In addition to the thermal amplitude of cold agglutinin binding, a possible interference with membrane regulatory proteins may render certain cold agglutinins hemolytically active in a homologous system, Conclusion: Despite a hemolytic inefficiency, cold agglutinin-induced fixation of early complement components up to C3 leads to an accelerated clearance of red cells from the circulation by hepatic sequestration. However, it is not yet clear, to what degree these cells are eliminated by the reticuloendothelial system or whether they return to the circulation. Dependent on the amount of membrane-bound C3 fragments these cells may even be protected against further cold agglutinin-induced complement attack.