Pathogenic autoantibodies: emerging insights into tissue injury

Accumulating evidence is emerging that B lymphocytes and autoantibodies are critical in the development of autoimmune disease. Even in certain disorders initially thought to be T cell-mediated, these immune components are now considered key players in the disease pathogenesis, and new autoantibody specificities have been added to the growing list of targets including cell surface receptors and ion channels that may be involved in a variety of neuropsychiatric and cardiovascular disorders. Studies of autoantibodies penetrating living cells suggest a dosage effect in generating a biological outcome in vivo. Some autoantibodies, such as those directed to double-stranded DNA, can bind to a variety of surrogate antigens located in different cellular compartments, and this may have different biological consequences. This polyreactive behavior could be related to their conformational diversity, or to the fact that the epitope recognized is distributed among other macromolecular antigens. In addition, recent studies revealed unsuspected mechanisms of pathogenesis, wherein autoantibodies have been described that can activate neuronal, endothelial cells or B lymphocytes. Other autoantibodies inactivate the target antigens, or exhibit a catalytic activity, releasing toxic oxygen products that may be linked to arthritic or atherosclerotic injury.