Pathogenesis of SLE: immunopathology in man

Antibodies against native DNA are not only a disease-specific marker for systemic lupus erythematosus (SLE); in addition, there is good direct evidence that these antibodies also play a major part in pathogenic mechanisms leading to systemic and organ-specific disease manifestations. The origin of anti-dsDNA antibodies is still poorly understood, especially as dsDNA per se is not immunogenic. As recently shown, evidence is now accumulating that anti-dsDNA antibodies are not germline-encoded but antigen-driven, as demonstrated by the establishment of human anti-dsDNA antibody clones from SLE patients and sequence analysis. In sera of SLE patients there is an elevated level of nucleic acids, which indicates that defective clearance mechanisms for nucleic acids are present. The question as to whether these nucleic acids could serve as an antigen has been recently addressed by studies of plasma nucleic acids isolated from circulating immune complexes from SLE patients. These studies indicate that plasma nucleic acids in SLE patients have structures of amino acid sequences which have a striking homology with the gag-pol overlap region of HIV-1. Whether these nucleic acids play a role in the pathogenesis of SLE, indicating the involvement of a retrovirus in the pathogenesis, or whether they rather reflect an amino acid homology with an endogenous human retrovirus family is not yet known.