Modification of Macromolecules

Modification of protein by a reactive metabolite (hapten) could lead to an immune response against the modified protein, including a response to the hapten. Antidrug antibodies have been reported in drug-induced lupus (Hahn et al. 1972); however, such antibodies are not a universal feature and are probably not pathogenic. Modification of a protein can also change the manner in which the protein is processed by antigen-presenting cells, and this can lead to the presentation of peptides that the immune system has not "seen" before and, therefore, have not been tolerized to. Such peptides are referred to as cryptic antigens. It has been suggested that an immune response against cryptic antigens could lead to an autoimmune response (Griem et al. 1998).

Drug-induced lupus has many of the characteristics of a graft-vs-host reaction (Gleichmann et al. 1984). Reactive metabolites presumably modify many different proteins, and there is no reason to believe that they would not also modify major histocompatibility complex II. In principle, modification of major histocompatibility complex II should induce a graft-vs-host reaction (Gleichmann 1982). However, this is a very difficult hypothesis to rigorously test.

Procainamide (Blomgren et al. 1972) and hydralazine (Dubroff et al. 1981) have been reported to induce a stable transition from the normal to the Z conformation of DNA. This form of DNA is immunogenic, and it has been proposed that this transition could be responsible for drug-induced lupus. However, these were test tube experiments, and there is no evidence that this transition occurs in vivo.

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