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CHAPTER 137 restricted distribution, with varying levels of expression on B cells, den-
dritic cells, monocytes, macrophages, and endothelial cells. However,
HUMAN LEUKOCYTE class II antigens can be induced on many cell types through activation.
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The nonclassical class Ib antigens HLA-E, HLA-F, and HLA-G, and the
AND PLATELET ANTIGENS MHC class I chain-related antigens are much less polymorphic, their
function less understood, and their tissue expression more limited. In
addition the MHC region codes for a number of pseudogenes. This
chapter focuses on the classic class I and II molecules because of their
Myra Coppage, David Stroncek, Janice McFarland, and Neil Blumberg importance in transfusion and transplantation.
The two major classes of HLA antigens are homologous. However,
there are areas of high variability (polymorphism) that distinguish indi-
vidual HLA molecules (alleles) and confer antigen specificity. HLA anti-
SUMMARY gens are codominantly expressed so that each individual expresses two
antigens at each locus (A, B, DR, etc.). As of July 2014, many thousands
The human leukocyte antigens (HLAs) are highly polymorphic glycoproteins of HLA alleles had been characterized. Table 137–1 lists the number of
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encoded by the major histocompatibility complex on chromosome 6. Their known HLA alleles at each locus.
biologic function is presentation of antigenic peptides to T lymphocytes, and
there are two major classes: class I (A, B, and C loci) and class II (DR, DQ, and GENETICS OF THE MAJOR
DP loci). Class I antigens are present on almost all nucleated cells, whereas HISTOCOMPATIBILITY COMPLEX
class II antigens are primarily expressed on B cells and other antigen- The first sequence map of the MHC encompassed approximately
presenting cells such as dendritic cells, endothelial cells, and monocytes. These 3.6 Mbp on chromosome 6p21 and was divided into three regions: class I,
antigens play key roles in hematopoietic cell transplantation acceptance/ class II, and class III genes. Newer analysis confirming high linkage
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rejection and allosensitization to nonleukoreduced blood transfusions leading disequilibrium and conserved synteny led to the concept of an extended
to platelet transfusion refractoriness, with lesser, but distinct roles in solid- MHC (xMHC), and a new map was produced in 2004. The xMHC
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organ transplantation. Other clinically important lineage-specific white cell occupies approximately 7.6 Mbp, and is composed of five subregions,
antigens include those on neutrophils, which are much less polymorphic and which include the classical classes I, II, and III genes. Class II genes
less commonly a cause of clinical problems than the HLA system. Antibody to are the most centromeric and occupy approximately 1 Mbp of DNA.
neutrophil antigens plays a role in autoimmune neutropenia, and reactions The genes are ordered sequentially beginning with HLA-DP genes fol-
such as transfusion-related acute lung injury. Platelets also possess a relatively lowed by HLA-DM, TAP, HLA-DQ and lastly the HLA-DR genes. The
limited number of polymorphic antigens that are involved in clinical problems class III genes occupy space between the class I and class II genes. The
class III genes include genes that encode other proteins that participate
such as posttransfusion purpura and platelet transfusion refractoriness, and in immune response such as complement, heat shock proteins, tumor
neonatal problems such as alloimmune thrombocytopenia. necrosis factor, and other lymphocyte antigens. Telomeric are the class I
genes sequentially as MICA, MICB, HLA-B, HLA-C, HLA-E, HLA-A,
HLA-F, and HLA-G. Extended class I genes include histone clusters and
HUMAN LEUKOCYTE ANTIGENS (MAJOR zinc finger genes. Figure 137–1B is a representative map of the MHC.
HISTOCOMPATIBILITY COMPLEX) STRUCTURE AND FUNCTION

DEFINITION Class I Antigens
The HLA-A, -B, and -C molecules are transmembrane glycopro-
The human leukocyte antigens (HLAs) are highly polymorphic glyco- teins with an Mr 56,000. Each is a heterodimer composed of one α
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proteins encoded by a region of genes known as the major histocom- heavy chain (Mr 45,000) noncovalently bound to β -microglobulin
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patibility complex (MHC) located on chromosome 6p21 and covering a (Mr 11,000). The α heavy chain is the polymorphic glycoprotein encoded
region of approximately 7.6 Mbp. After ABO antigens, HLA antigens by the MHC genes. The extracellular region of the α chain consists of
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are the major barrier to transplantation. Their biologic function is to three domains (α , α , α ) based on folding and disulfide bonding (see
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present antigenic peptides to T lymphocytes. The MHC codes for several Fig. 137–1A). Antigenicity resides in the α and α domains, the areas
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groups of antigens. The best understood are the highly polymorphic, of highest polymorphism. These two chains form a platform composed
classical class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DR, of a single β-pleated sheet “floor” topped by two α helices with a cleft
HLA-DQ, and HLA-DP) antigens. Class I antigens are ubiquitous and or groove between them. The structure is supported by the third, α ,
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present on most nucleated somatic cells. Class II antigens exhibit more domain of the heavy chain in conjunction with β -microglobulin, which
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stabilizes the molecule on the cell surface. Class I HLA molecules pres-
ent peptide fragments from endogenously derived proteins (e.g., viral
Acronyms and Abbreviations: CDC, complement-dependent cytotoxicity; ELISA, infection, intracellular bacteria, or transformation) to CD8+ T cells.
enzyme-linked immunosorbent assay; GP, glycoprotein; GVHD, graft-versus-host dis- The highly polymorphic groove permits presentation of highly variable
ease; HLA, human leukocyte antigen; HNA, human neutrophil antigen; HPA, human peptides of nine amino acids average length. Class I HLA-A, -B, and -C
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platelet antigen; MHC, major histocompatibility complex; NAIT, neonatal alloim- antigens are found on most nucleated somatic cells. Platelets express
mune thrombocytopenia; NMDP, National Marrow Donor Program; PCR, polymerase HLA-A antigens, but lack some HLA-B and most HLA-C antigens. 9
chain reaction; PRA, panel reactive antibody; PTP, posttransfusion purpura; SSO,
sequence-specific oligonucleotide; SSP, sequence-specific primer; TRALI, transfusion- Class II Antigens
related acute lung injury; WHO, World Health Organization. The class II antigens are also transmembrane glycoproteins formed by
two noncovalently bound chains. Both the α heavy chain (Mr 34,000)
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