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COMMENTARY
Making autoantibodies safe
*Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom; and Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines, La Jolla, CA 92037
The human immune system is extraordinarily good at generating antibodies to recognize an almost infinite range of antigens. Antibodies to antigens found on the cells and tissues of the host are repressed by tolerance mechanisms in health, but in autoimmune diseases they can become prominent. Although there is debate in a number of instances about whether autoantibodies are a cause or effect of disease, in many cases it has been established that autoantibodies directly lead to morbidity and even mortality. Although there is no known way to specifically "switch off" the generation of a particular autoreactive antibody response, work by Collin et al. (1) in this issue of PNAS suggests a strategy for reducing the adverse consequences of autoantibodies (1).
Once an antibody (IgG) has engaged a foreign molecule via its variable antigen binding arms (Fab), the subsequent elimination of the target largely depends on the "effector functions" of the constant stem region (Fc). A wide variety of receptor molecules interact with different sites on the Fc, resulting in a range of fates for the bound antigen (2, 3). One of the key effector systems is complement. This central pathway recognizes "nonself" molecular patterns, including arrays of antibody displayed on an antigen surface, and targets them for destruction via a highly efficient array of cell-killing machinery. A specialized Fc adaptor molecule called C1q can bind to a defined binding site on the Fc (4), whereas a separate domain of C1q is associated with enzymes that trigger the rapid activation of the complement pathway. In this way C1q represents a molecular link between the new world of the adaptive immune system and the evolutionarily ancient killing mechanisms of the complement system (5). A second key effector system is provided by
To whom correspondence should be addressed. E-mail: raymond.dwek@bioch.ox.ac.uk
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