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.

Vadim Jucaud

doi:10.1155/2017/2748614

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.

Highlights

Human Leukocyte Antigen (HLA) incompatible transplantation frequently leads to the formation of HLA donor-specific antibodies (DSAs)
For all loci combined (Table 3(a)) or separate (Tables 3(b) and 3(c)), there are no significant differences in the eplet mismatch score (EpMS), hydrophobicity mismatch score (HMS), electrostatic mismatch score (EMS), and acid mismatch score (AMS) between mismatches that led to the formation of a DSA and those that did not
This study reveals that comparing the predicted binding affinity of HLA class II mismatched-derived self or nonself peptides helps distinguishing immunogenic HLA class II mismatches that lead to the formation of DSA from nonimmunogenic ones after HLA mismatched kidney transplantation

Summary

Introduction

Human Leukocyte Antigen (HLA) incompatible transplantation frequently leads to the formation of HLA donor-specific antibodies (DSAs). The development of DSA requires the activation of the transplant recipient’s adaptive immune system against allogeneic HLA (allo-HLA), a process known as the indirect allorecognition pathway (reviewed in [8, 9]). This alloreactive response involves both B and T cell compartments of the immune system, the cognate CD4+ T cell helper function, to produce long-lasting IgG alloantibodies [8, 10, 11]. The indirect allorecognition initiates when the B cell receptors (BCR) of allospecific B cells bind to their cognate allo-HLA This binding induces B cells to internalize and process the allo-HLA into allo-HLA-derived peptides (alloHLApep). The costimulatory signal provided by allo-TFH induces B cell proliferation and differentiation into memory B cells

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Results

Conclusion