A HYPOTHESIS FOR THE HLA-B27 IMMUNE DYSREGULATION IN SPONDYLOARTHROPATHY - CONTRIBUTIONS FROM ENTERIC ORGANISMS, B27 STRUCTURE, PEPTIDES BOUND BY B27, AND CONVERGENT EVOLUTION

Several human rheumatic diseases occur predominately in persons who ca rry the histocompatibility (HLA) class I allele B27. They have also be en related to Gram-negative enteric microorganisms. In addition, the r ecent recovery of peptides bound to B27 has allowed an understanding o f the structural requirements for their binding. Using the accumulated data base of protein sequences, we have tested a series of hypotheses . First, we have asked whether the primary amino acid sequence of the hypervariable regions of HLA-B27 shares short sequences with the prote ins of Gram-negative enteric bacteria. The data demonstrate that, uniq ue among the HLA-B molecules, the hypervariable regions of HLA-B27 une xpectedly share short peptide sequences with proteins from these bacte ria. Second, we have asked whether the enteric proteins tend to satisf y the structural requirements for peptide binding to B27 in those regi ons of the sequence shared with B27. This hypothesis also tends to be true, especially in an allelically variable part of the B27 sequence w hich is predicted to bind B27 if it were to be presented as a free pep tide. We conclude that HLA-B27 and enteric Gram-negative bacteria have undergone a previously unappreciated form of convergent evolution whi ch may be important in the process leading to these rheumatic diseases . Moreover, the regions of the enteric bacterial proteins which are co ntiguous with the short sequences shared with B27 tend to have structu res which are also predicted to bind B27. These observations suggest a mechanism for autoimmunity and lead to the prediction that the B27-as sociated diseases are mediated by a subset of T-cell receptors, B27, a nd the peptides bound by B27.