ABSTRACT
The question of how pathogenic autoantibodies are generated and expanded in diseased subjects remains of central importance in autoimmune research. Antibodies to components of the cell nucleus, including DNA, are a manifestation of systemic lupus erythematosus (SLE), a prototype of systemic autoimmune diseases [1]. They play a demonstrable role in the pathogenesis of the disease [2]. Evidence that the tissue injury is autoimmune in nature includes correlation of serum auto-antibody titers with disease activity, presence of immune complexes in the glomeruli, transfer of the disease to SCID recipient mice by human lupus autoantibodies, and multiple abnormalities of the immune system, such as changes in the ratios of T-cell subsets. However, while some anti-DNA antibodies can cause glomerulonephritis in SLE patients, not all antibodies to DNA are pathogenic [3]. For example, there is a high frequency of autoreactivity in the human preimmune repertoire and in B cells derived from human cord blood or fetal liver [4]. It is generally agreed that complement-fixing anti-DNA antibodies are more nephritogenic than other subsets, but there is less agreement about other features such as epitope specificity (denatured DNA, native DNA), crossreactivity, avidity/affinity and charge. Inasmuch as certain idiotype families may be enriched in pathogenic autoantibody subsets, expression of specific idiotopes has also been useful in identifying nephritogenic anti-DNA antibodies [5-7]. However, studies of antibody genes were required to understand the potential link between the early appearance of the autoantibody repertoire and sustained generation of pathogenic autoantibodies. This chapter discusses recent advances in defining the molecular mechanisms responsible for production of human aggressive antibodies in systemic autoimmunity.
