The HLA system in hematopoietic stem cell transplantation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 19

FIGURE 2.1
Map of the human major histocompatibility complex (MHC). The MHC is encoded on chromosome 6p21 and is organized into three major regions: class I,
class III and class II. The figure shows the location of each of the classical and non-classical HLA genes that have been described as playing a role in hematopoietic cell
transplantation.

3 domains, respectively; exon 5 encodes the trans-membrane portion, and
exons 6, 7 and 8 encode the cytoplasmic tail. These products give rise to the
“heavy” α chain of the mature HLA class I molecule, and define the HLA
phenotype (e.g. HLA-A1 or A2). The heavy chain is non-covalently bound
to a β 2 -microglobulin “light” chain whose gene resides on chromosome 15.
The delineation of the crystallographic structure of HLA-A2 in 1987 was
pivotal to understanding the structure-function relationship of MHC mole-
cules. Those landmark studies revealed that class I molecules are composed
of two α-helical regions that overlay an eight-strand anti-parallel β-pleated
sheet; together these form the functional groove of class I molecules for
peptide binding [6] .

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Sequence variation in exons 2, 3 and 4 define the allospecificity of HLA-
A, HLA-B and HLA-C antigens. As of March 2012, over 1757 HLA-A, 2338
HLA-B and 1304 HLA-C alleles are recognized by the World Health Orga-
nization Nomenclature Committee for Factors of the HLA System [7,8] .
The nucleotide substitutions in exons 2, 3 and 4 are commonly observed at
hypervariable positions that define the peptide binding groove and T-cell
receptor (TCR) contact residues of the α1 and α2 domains [9] . In addition to
interactions with the TCR, HLA-C and some HLA-B and A molecules serve
as ligands for natural killer inhibitory receptors (KIR). The specificity of
ligand-receptor interactions is defined by residues 77-80 for HLA-C and by
residues 77-83 (the Bw4 epitope) for HLA-B.

Non-classical MHC genes: HLA-E, F, G and MIC

In addition to the classical class I HLA loci, the class I region of the MHC
encodes a series of genes that are termed the “non-classical” class I genes,
HLA-E, HLA-F, HLA-G and the MHC class I-related chain A and B genes
(MICA and MICB, respectively). Known as the class 1b family [10] , these
genes share homology, but differ with respect to their specific regulation,
expression patterns and epigenetic profiles. Their role in transplantation is
emerging ( Table 2.1 ).

HLA-E HLA-E is an extensively studied MHC class Ib antigen. In contrast
to the classical MHC class I HLA-A, B, C genes, HLA-E is minimally poly-
morphic with only two non-synonymous functional HLA-E alleles, HLA-
E*01:01 and HLA-E*01:03. HLA-E*01:03 differs from HLA-E*01:01 by a sin-
gle amino acid substitution (gly to arg) at position 107 of the α2 heavy chain
domain [8] . Although the two alleles appear to be evenly distributed in the
human population (approximately 50% each), they differ with respect to