Epitope analysis of HLA-DQ antigens: what does the antibody see?

Human leukocyte antigen (HLA)-DQ has emerged as the alloantibody most frequently associated with the generation of de novo donor-specific antibody (DSA), antibody-mediated-rejection, and unfavorable transplantation outcome.

The generation of HLA-DQ de novo DSA was interrogated in 40 transplant recipients who were immunologically naive before their failed transplantation. Eplet and epitope analyses were performed using HLAMatchmaker and Cn3D software.

Ten DQA and thirteen DQB eplets or eplet combinations were identified. All but one revealed an epitope footprint that includes both the DQα and DQβ chains. Four examples are illustrated in detail, representing a range of different epitope landscapes. A disparity between antigen density and mean fluorescence intensity values for some alleles within an eplet group was noted, with mean fluorescence intensity values of the lowest fluorescence bead being one tenth of the highest fluorescence bead, despite the fact that the amount of antigen on these beads were not significantly different.

Our data support the need for changing the manner in which HLA-DQ antigens and antibodies are evaluated for organ transplantation. The current nomenclature system does not reflect the true nature of HLA-DQ polymorphism. Moreover, epitope immunogenicity likely involves more than the mere presence of a specific eplet. Because our field contemplates the use of epitope matching as an approach to improve organ allocation and overall outcomes, it is imperative to have accurate characterization of the immunogenicity of each epitope. This will pave the way to identifying acceptable mismatches and will allow risk stratification for generating de novo HLA-DSA after transplantation.