Defining the structural basis for human alloantibody binding to human leukocyte antigen allele HLA-A*11:01

Yue Gu,Julien Lescar,Paul A Macary,Angeline T H Goh,Rachel Z C Teo,Tanusya M Murali,Maryam Hamidinia,Abbas El Sahili,Kiren Purushotorman,Kathryn J Wood,Chien Tei Too,Nicholas R J Gascoigne,Jiawei Yap,Yee Hwa Wong,Brendon J Hanson,Chong Wai Liew,Anantharaman Vathsala,Conrad E Z Chan

doi:10.1038/s41467-019-08790-1

Yue Gu, Julien Lescar + Show 16 more

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https://doi.org/10.1038/s41467-019-08790-1

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Our understanding of the conformational and electrostatic determinants that underlie targeting of human leukocyte antigens (HLA) by anti-HLA alloantibodies is principally based upon in silico modelling. Here we provide a biochemical/biophysical and functional characterization of a human monoclonal alloantibody specific for a common HLA type, HLA-A*11:01. We present a 2.4 Å resolution map of the binding interface of this antibody on HLA-A*11:01 and compare the structural determinants with those utilized by T-cell receptor (TCR), killer-cell immunoglobulin-like receptor (KIR) and CD8 on the same molecule. These data provide a mechanistic insight into the paratope−epitope relationship between an alloantibody and its target HLA molecule in a biological context where other immune receptors are concomitantly engaged. This has important implications for our interpretation of serologic binding patterns of anti-HLA antibodies in sensitized individuals and thus, for the biology of human alloresponses.

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Our understanding of the conformational and electrostatic determinants that underlie targeting of human leukocyte antigens (HLA) by anti-HLA alloantibodies is principally based upon in silico modelling
The antibody was expressed as a recombinant human IgG1 and an antigen-binding fragment (Fab), and the specificity for HLA-A*11:01 confirmed by immunoblot
The true KD is likely to be in the nM range taking both quartz crystal microbalance (QCM) and enzyme-linked immunosorbent assay (ELISA) results into consideration

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Our understanding of the conformational and electrostatic determinants that underlie targeting of human leukocyte antigens (HLA) by anti-HLA alloantibodies is principally based upon in silico modelling. The lack of structural data on the fine-specificity and related function(s) of human monoclonal anti-HLA alloantibodies potentially complicates the development of prognostic assays and associated clinical countermeasures in solid-organ transplantation[4,9,10]. The allele reactivity of an anti-HLA-A*11:01 human antibody.

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