| Autoimmune disorders are broadly divided in two groups. One demonstrates typical features of an abnormal immune response to self-protein. The identity of the target is easy to establish and an animal model may be developed by immunizing with the autoantigen. Molecular mimicry is thought to participate in the development of this type of autoimmunity. The disorders in the other category are still classified as autoimmune and display the presence of autoantibodies, however, the identity of autoantigen is either unclear, or gives no key to the mode of the disease development. Autoantigen is either ubiquitous or, conversely, cryptic. It does not elicit an immune reaction when introduced into animals. It is proposed that interactions with the idiotypic internal "image" of the antigen are more important in the development of this type of autoimmunity than the protein itself.; The autoimmune epitopes of the proteins that are subject to the direct interaction with the immune system experience positive selection. Positive selection is less pronounced in the idiotypic autoimmune disorders. We inquire whether the frequency of positive selection is depressed in the second group of proteins. The non-idiotypic autoantigens serve as a control for our comparison.; Ten representative autoantigens were chosen from ten autoimmune disorders, five in each category. A library of protein homologs from a range of species was assembled. Each of the protein lineages was analyzed with the PAML software package for the presence of positive selection sites. For each protein, the positive selection site locations were mapped in conjunction with the location of the autoepitopes.; We found that seven of ten proteins had positive selection sites, but none of them overlapped with the autoepitopes. Thus, we were unable to draw conclusions on the extent of selection related to the immune system pressure. There is a correlation between ligand-mediated autoimmune disorders and the absence of positive selection.; We found that the predominant majority of the autoimmune epitopes are a part of highly conserved sequences, such as functional domains. Finally, we found that positive selection sites are overwhelmingly located on the leader sequences. We outline further studies to establish the nature of the selective pressure on the leader sequences. |
