The study by Hov et al.7 is intended to contribute to the overall understanding of the pathogenesis of PSC. By translating specific HLA associations into amino acid sequences, the first step in this direction can be made. This approach to HLA-encoded disease risk was first published by Todd, Bell, and McDevitt in 1987,11 who mapped

susceptibility for insulin-dependent diabetes to specific amino acid sequences of the HLA-DQβ polypeptide. This changed the way in which HLA associations were perceived. No longer were selleck chemicals they seen as unexplainable genetic anomalies; it was now possible to put these associations into a functional context. Subsequent advances in polymerase chain reaction–based genotyping, the publication of the crystal structures for the MHC class II molecule,12 and the development

of SCH727965 more sophisticated computer-based technologies for predictive modeling13 have completely revolutionized our approach to HLA in disease, and these new technologies have been widely applied. This can be seen with varying levels of sophistication in relation to “autoimmune” liver disease14-16 as well as nonliver diseases.17 The present study7 of the electrostatic modification of the HLA-DR molecule in PSC is the latest study to take this approach, and furthermore, it is one of many studies from this same group that have sought to define MHC-encoded susceptibility to PSC.1, 7, 18 Amino acid sequence variants for HLA-DRB1 were investigated

in 356 patients with PSC from a single center. The basic principle is not a novel one (see above, Todd et al.11), but the techniques applied learn more are up-to-date and this is the first study to consider all possible variants of HLA-DRB1 in PSC. Clearly aware of the previous studies, Hov et al.7 state “a consistent peptide-binding motif for the class II molecules associated with PSC has not been defined, and no attempts have been made to model how specific amino acids affect the structure and the electrostatic properties of the peptide-binding groove.” This statement is correct and forms the rationale for their study. The earlier studies of Farrant et al.,5 Olerup et al.,4 and Donaldson and Norris6 were all limited in scope. Farrant et al.5 proposed that susceptibility and resistance to PSC may be determined by the amino acid at position 38 of the second expressed DRB gene. In particular, they noted that the risk haplotypes encode the amino acid leucine at position 38, whereas the protective haplotypes encode alanine at position 38.