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C H A P T E R 113

HUMAN LEUKOCYTE ANTIGEN AND HUMAN

NEUTROPHIL ANTIGEN SYSTEMS

Ena Wang, Sharon Adams, David F. Stroncek, and Francesco M. Marincola

This chapter reviews human leukocyte antigen (HLA) and human T cells. There is, however, some substance to the name, because
neutrophil antigen (HNA) systems. A general background of the HLAs, by virtue of being densely packed on the cell surface, are
structure, function, and nomenclature of both systems and their exposed to recognition in a foreign environment such as allotrans-
relevance in clinical hematology is presented. Analysis of HLA gene plantation or xenoinfusion performed to induce anti-HLA antibodies
products is applied in clinical settings (1) to select compatible donor- as diagnostic reagents.
recipient pairs for transplantation, (2) to select HLA-compatible
single-donor platelet products for thrombocytopenic patients refrac-
tory to standard transfusion of random pooled platelets, (3) to screen ORGANIZATION OF THE HUMAN
for genetic factors that may contribute to the prevalence of diseases, LEUKOCYTE ANTIGEN GENES
and (4) for forensic purposes in which the identity of individuals may
contribute to solving legal disputes or criminal investigations. In HLA genes constitute a string of coding sequences that regulate the
addition, we discuss new applications that have broadened the rele- expression of molecules with similar but not identical function.
vance of HLA in the area of immune pathology. HLA phenotypes Residing in a region that spans approximately 4000 kilobases of the
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determine the suitability of patients for epitope-specific immuniza- short arm of chromosome 6 (Fig. 113.1), HLA contains several genes
tion. Tetrameric HLA/epitope complexes (tHLA) allow enumeration and pseudogenes characterized by sequence homology and functional
of antigen-specific T-cell responses. Furthermore, molecular identifi- similarity. Of them, 47 are officially recognized by the World Health
cation of T-cell epitopes associated with distinct diseases and charac- Organization (WHO) nomenclature committee and include classic
terization of the communication between immune effector cells HLA class I and class II genes associated with antigen processing such
through HLA–HLA ligand interactions extend the relevance of HLA as proteasomal units PSMB8 and PSMB9, or peptide transport TAP1
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to biologic fields. These biologic fields encompass natural killer (NK) and TAP2. Both HLA and HLA-associated genes can be physically
and cytotoxic T-cell function, antigen recognition in the context of grouped into three subregions according to chromosomal location.
infection, autoimmunity, graft-versus-neoplasia (GVN) effect, and In centromeric to telomeric direction, the first is HLA class II region
autologous cancer rejection. Finally, the recognition that polymor- comprising the α-and β-chains of HLA-DR, HLA-DQ, HLA-DP,
phism extends to other protein families relevant to immune pathology HLA-DM, and HLA-DO as well as TAP and PSMB. Sandwiched
including cytokines, their receptors, and killer cell-inhibitory recep- between the class II and class I region, class III region encodes for
tors has broadened the significance of immunogenetics beyond HLA. functionally unrelated genes such as complement components, heat
Thus this chapter emphasizes the importance of viewing human shock proteins, and tumor necrosis factor. The reason for their genetic
pathologic conditions through the kaleidoscopic complexity of link to the HLA complex is unknown, but their immunologic func-
human polymorphism. tion seems more than coincidental. The class I region is mostly
telomeric and includes HLA-A, HLA-B, and HLA-C loci; the non-
GENETICS, STRUCTURE, AND FUNCTION OF classic HLA-E, HLA-F, and HLA-G loci; and several pseudogenes.
General terminology separates HLA genes into classic and non-
HUMAN LEUKOCYTE ANTIGEN MOLECULES classic. Classic HLA genes have been well characterized and are clearly
associated with presentation of antigen to immune cells. They are
HLAs embrace a family of genes clustered in the short arm of chro- further subdivided into class I (HLA-A, HLA-B, HLA-C) and class
mosome 6 as the human version of the major histocompatibility II (HLA-DR, HLA-DQ, and HLA-DP). In general, HLA class I and
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complex (MHC), initially identified in mice as responsible for graft II genes have very similar structure and function. They contain six
rejection between genetically unrelated strains (transplantation anti- to eight exons coding for functionally distinct domains (Fig. 113.2).
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gens). Credit for the description of the human MHC goes to three The first exon encodes a leader sequence; the following exons (exons
individuals. In 1952, Jean Dausset observed that serum of individuals 2 to 4) are highly polymorphic and encode extracellular domains
who had received several transfusions contained hemagglutinins responsible for peptide binding and T cell-antigen receptor (TCR)
(HAs) specific to the donors’ leukocytes. In 1958, Rose Payne noted engagement. Because they are exposed on the cell surface, these
that the only requirement for the development of HAs against leu- domains are also responsible for alloreactivity. The last exons encode
kocytes was a history of previous transfusion or pregnancy and a conserved transmembrane and small intracellular domains whose
concluded that these antibodies were directed against antigens on the functions are unclear.
surface of circulating leukocytes. This conclusion was concomitantly Only the heavy chain of HLA class I is encoded in the MHC
and independently confirmed by Jon van Rood, who observed that region. Genes encoding HLA-A, HLA-B, and HLA-C contain three
multiple pregnancies immunize mothers against leukocytes leaked exons coding for α 1, α 2 , and α 3 extracytoplasmic domains, one
from the fetus into the mother’s circulation. Based on these discover- transmembrane, and three cytoplasmic domains (Fig. 113.3). The
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ies, the term human leukocyte antigen was subsequently adopted. It associated class I light chain, β 2-microglobulin, is encoded on chro-
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should be clarified, however, that this historical name is misleading. mosome 15. By contrast, the HLA class II molecule is composed of
HLA molecule expression is neither limited to leukocytes nor do they a heterodimer of an α-chain and β-chain encoded in the MHC
display, in natural conditions, antigenic behavior. In fact, several are region. Although the genetics are different, the protein product is
expressed by most somatic cells, and, rather than being antigens, they structurally similar to HLA class I, with two helices resulting in the
chaperone protein bioproducts to the cell surface for recognition by antigen-presenting part of the molecule (Fig. 113.4).

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