The Immunogenicity of HLA Class II Mismatches: The Predicted Presentation of Nonself Allo-HLA-Derived Peptide by the HLA-DR Phenotype of the Recipient Is Associated with the Formation of DSA

Abstract

The identification of permissible HLA class II mismatches can prevent DSA in mismatched transplantation. The HLA-DR phenotype of recipients contributes to DSA formation by presenting allo-HLA-derived peptides to T-helper cells, which induces the differentiation of B cells into plasma cells. Comparing the binding affinity of self and nonself allo-HLA-derived peptides for recipients' HLA class II antigens may distinguish immunogenic HLA mismatches from nonimmunogenic ones. The binding affinities of allo-HLA-derived peptides to recipients' HLA-DR and HLA-DQ antigens were predicted using the NetMHCIIpan 3.1 server. HLA class II mismatches were classified based on whether they induced DSA and whether self or nonself peptide was predicted to bind with highest affinity to recipients' HLA-DR and HLA-DQ. Other mismatch characteristics (eplet, hydrophobic, electrostatic, and amino acid mismatch scores and PIRCHE-II) were evaluated. A significant association occurred between DSA formation and the predicted HLA-DR presentation of nonself peptides (P = 0.0169; accuracy = 80%; sensitivity = 88%; specificity = 63%). In contrast, mismatch characteristics did not differ significantly between mismatches that induced DSA and the ones that did not, except for PIRCHE-II (P = 0.0094). This methodology predicts DSA formation based on HLA mismatches and recipients' HLA-DR phenotype and may identify permissible HLA mismatches to help optimize HLA matching and guide donor selection.

Figure 1

Classification of each HLA mismatch based on the presence of DSA and the nature (self or nonself) of the predicted peptide with highest affinity for the recipient's HLA class II phenotype.

Figure 2

The indirect allorecognition pathway of allo-HLA class II by B cells and the presentation of self or nonself allo-HLA-derived peptide influence CD4+ T_FH cells helper function to lead to the formation of DSA. HLA mismatches can become immunogenic when they carry both a B cell epitope and a T cell epitope. B cell epitopes are located on the molecular surface of HLA, whereas T cell epitopes can be located anywhere, exposed or cryptic. B cells expressing a BCR specific for an allo-HLA can capture, internalize, and process the whole allo-HLA class II molecule and then present allo-HLA-derived peptides on the cell surface. Only when CD4+ T_FH cells recognize nonself antigenic determinants presented by B cells does the release of various cytokines promote B cell differentiation. This, in turn, may induce affinity maturation and Ig class switching, which eventually leads to the formation of DSA.