A new categorization of HLA DR alleles on a functional basis

In this analysis, we introduce a new categorization of HLA DR alleles which are important members of HLA class II genes encoding cell surface glycoproteins that function to present antigenic peptides to T cells. We have grouped all HLA DR molecules into seven different functional categories on the basis of their ability to bind and present antigenic peptides to T cells and their association with susceptibility or resistance to disease. This novel categorization of DR alleles on the basis of function allows for the prediction of seven similar subregion structures (supertypes or supermotifs) within pocket 4 of HLA DR peptide binding groove as the molecular basis for grouping these alleles. The physicochemical characteristics of HLA DR supertype residues, charge in particular, may influence the selectivity for binding peptide, dominate promiscuous T-cell recognition of antigenic peptides, and affect HLA DR disease associations. To rationalize the functional categories of DR alleles, we have further combined the seven DR supertype patterns into three groups based on the charges of residues within the supertypes. Grouping HLA DR alleles into functional categories may assist in understanding the mechanistic basis of autoimmunity, resolving current paradoxes in HLA disease associations, and developing new immunotherapy strategies.