Predicting Humoral Alloimmunity from Differences in Donor and Recipient HLA Surface Electrostatic Potential

Abstract

In transplantation, development of humoral alloimmunity against donor HLA is a major cause of organ transplant failure, but our ability to assess the immunological risk associated with a potential donor–recipient HLA combination is limited. We hypothesized that the capacity of donor HLA to induce a specific alloantibody response depends on their structural and physicochemical dissimilarity compared with recipient HLA. To test this hypothesis, we first developed a novel computational scoring system that enables quantitative assessment of surface electrostatic potential differences between donor and recipient HLA molecules at the tertiary structure level [three-dimensional electrostatic mismatch score (EMS-3D)]. We then examined humoral alloimmune responses in healthy females subjected to a standardized injection of donor lymphocytes from their male partner. This analysis showed a strong association between the EMS-3D of donor HLA and donor-specific alloantibody development; this relationship was strongest for HLA-DQ alloantigens. In the clinical transplantation setting, the immunogenic potential of HLA-DRB1 and -DQ mismatches expressed on donor kidneys, as assessed by their EMS-3D, was an independent predictor of development of donor-specific alloantibody after graft failure. Collectively, these findings demonstrate the translational potential of our approach to improve immunological risk assessment and to decrease the burden of humoral alloimmunity in organ transplantation.

Structure-based modeling of SARS-CoV-2 peptide/HLA-A02 antigens

“…For other important antigens with known structures in the PDB, such features can be derived from an annotated database connecting pMHC-I/TCR co-crystal structures with biophysical binding data (41), and were recently employed in an artificial neural network approach to predict the immunogenicity of different HLA-A*02:01 bound peptides in the context of tumor neoantigen display (42). A separate study has shown that the electrostatic compatibility between self vs foreign HLA surfaces can be used to determine antibody alloimmune responses (43). Given that antibodies and TCRs use a common fold and similar principles to engage pMHC-I molecules (40), it is likely that surface electrostatic features play an important role in recognition of peptide/HLA surfaces by their cognate TCRs in the context of SARS-CoV-2 infection.…”

A Combined HLA Molecular Mismatch and Expression Analysis for Evaluating HLA-DPB1 de novo Donor-Specific Antibody Risk in Pediatric Solid Organ Transplantation: Implications for Solid Organ & Hematopoietic Stem Cell Transplantation

“…As we work to disentangle and acquire a more nuanced understanding of additional and specific risk factors that may influence the development of dn DSAs or GVHD, the ultimate goal would be to integrate all relevant factors into a comprehensive risk analysis scheme. Specifically, this integrative approach would likely include both quantitative and qualitative components, reflecting numbers of epitope mismatches as well as immunogenicity of each specific epitope (whether based on physicochemical 11,20,50–53 or other characteristics and/or capacity of epitopes to be presented by the responder’s HLA molecules 54,55 ), levels of expression of these epitope-containing HLAs, as well as aspects of their regulation in various contexts. It is possible that additional metrics may be included in the future.…”

Approaches for the characterization of clinically relevant pre‐transplant human leucocyte antigen (HLA) antibodies in solid organ transplant patients

“…epitope load) (Mallon et al, 2015). While epitope load can be predicted by sequence-based epitope analysis, Mallon et al (2014), Mallon et al (2018) suggest that surface electrostatic properties are a better predictor of immunogenic potential. The electrostatic interactions between molecules can mediate high-affinity antibody-antigen binding and have a putative role in antibody affinity maturation (Mallon et al, 2014).…”