Background: Transplant patients often produce human leukocyte antigen (HLA) antibodies against their donors and produce more specificities than can be accounted for by HLA antigen mismatches. We theorize that the presence of extra, otherwise unexplainable specificities could be accounted for if antibodies reacted to more than one epitope (primary and mimetic) on distinct HLA molecules. The theory states that mimetic epitopes consist of the same three amino acids that comprise the primary, sterically placed approximately the same distance apart as are the corresponding amino acids of the primary.
Methods: A mimetic epitope table containing all primary epitopes and corresponding mimetic epitopes was built. Then, the HLA specificities of monoclonal and single patient antibodies were determined. These specificities that could not be defined by unique position or amino acid epitopes alone were then used to query the mimetic epitope table.
Results: A single antibody from a transplant patient and three monoclonal antibodies produced reactions that can best be explained as the result of one antibody reacting to the same amino acids at two distinct sites on the molecule. Those position and amino acid combinations (pos/aa) are the primary and mimetic epitopes. Using computerized methods of searching, mimetic epitopes were found in five additional kidney transplant patients who produced nondonor-specific antibodies in addition to donor-specific antibodies.
Conclusions: Epitopes on the HLA molecule that mimic the primary epitope have been found. We suggest that these mimetic epitopes explain the additional antibodies often found on HLA immunization resulting from allograft rejections, pregnancies, and transfusions.