It has long been known that antibodies do not bind to the whole of the HLA antigen but instead bind to specific epitopes on the antigen surface. Each HLA antigen potentially has many sites or epitopes that can bind antibody. These epitopes may be private to a given HLA antigen or they may be shared by more than one HLA antigen, i.e. they may be public. In recent years it has become possible to identify the polymorphic amino acid residues that define many of these public and private HLA epitopes. This has enabled the development of laboratory based and in-silico strategies for assessing HLA compatibility at the epitope level.
One laboratory based strategy for defining epitopes has been described by El-Awar and Terasaki et al. They have used single antigen beads (SAB’s) to define a set of 103 epitopes on HLA class I antigens. Their assays were performed with mouse monoclonal antibodies directed against HLA as well as with anti-HLA from sensitized patients and multiparous women. Where alloantisera was used, is was first absorbed out using SAB’s or cell lines before being eluted for testing in a Luminex assay.
An example of an in-silico assay is that proposed by Kosmoliaptsiset et. al. They have described an epitope definition system based on interlocus and intralocus comparison of patients and donors to identify amino acid differences but also crucially, they have carried out an assessment of the physiochemical properties of the amino acid mismatches and the role these may play in clinical outcome. They have applied their scheme to kidney transplantation in the UK.
The most widely known in-silico strategy in the field of HLA is however the HLA Matchmaker algorithm (http://www.hlamatchmaker.net/) as proposed by Duquesnoy. Two versions of HLAMatchmaker have been described, the ‘triplet’ and ‘eplet’ versions. In the triplet version, epitopes are defined by linear sequences of triplets of amino acid residues in alloantibody-accessible positions of the HLA molecules (the a-helices and b-loops of the protein chain). The eplet based version of HLAMatchmaker defines epitopes as those residues located within a diameter of about 3-3.5 Å around a non self residue. Although some of these eplets consist of amino acids in linear sequences as described in the triplet model, many consist of amino acids from discontinues regions of the sequence, brought together by the folding of the molecule. In HLAMatchmaker, Donor-Recipient HLA compatibility is based same intralocus and interlocus comparisons of triplets or eplets.
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