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The HLA System

The genes of the HLA system are located within the major his-tocompatibility complex (MHC) on the short arm of chromo-some 6. The MHC comprises more than 200 genes. For thepurposes of TRALI, the most significant genes of the MHC arethose that encode the HLA Class I and HLA Class II proteins.The primary functions of these proteins are antigen processingand presentation as well as recognition of self from nonself.19

HLA Class I proteins are present on most nucleated cells andplatelets (the product of nucleated megakaryocytes). These pro-teins are not typically present on mature red cells. The HLAClass I region of the MHC is comprised of the classical genesHLA-A, HLA-B, and HLA-C and the nonclassical genes HLA-E,HLA-F, HLA-G, HFE, HLA-J, HLA-K, HLA-L, MICA, and MI-CAB.20 Antibodies to the HLA-A and HLA-B antigens havebeen associated with TRALI.21 Antibodies to all other MHCClass I proteins (both classical and nonclassical) have not beenassociated with TRALI.

HLA Class I molecules are composed of a transmembraneglycoprotein α heavy chain and β2 microglobulin. β2 microglobu-lin is not encoded in the MHC. The β2 microglobulin gene ispresent on chromosome 15. The α polypeptide chain comprisesfive domains (Fig 5-1).19 Three of the five domains are extracel-lular. Those are the α1 and α2 peptide binding domains and theα3 immunoglobulin-like domain. The remaining two domainsof the α polypeptide are the transmembrane and intracellulardomains.

HLA Class II proteins are expressed on fewer cell types thanare HLA Class I proteins. The HLA Class II proteins are foundprimarily on a variety of immune cells, including B cells, acti-vated T cells, dendritic cells, and macrophages. Other cell typescan be induced to express HLA Class II molecules by inter-feron-8.19 The HLA Class II region of the MHC encodes forHLA-DR, HLA-DQ, and HLA-DP proteins. HLA-DR and HLA-DQ have been associated with TRALI.21

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HLA Class II molecules comprise two similar (α and β) glyco-protein chains. The α and β glycoprotein chains each comprisefour domains (Fig 5-1). Each has two extracellular domains(peptide binding and immunoglobulin-like), a transmembranedomain, and an intracellular domain. The outermost or peptidebinding domain contains the variable regions of the HLA ClassII molecules.

Historically, HLA antibodies have been divided into antiserato private epitopes and antisera to public epitopes. Functionally,antisera to private epitopes identified a single HLA molecule(eg, HLA-A1). Antisera that reacted with multiple HLA antigens(eg, HLA-A1, -A3, -A11, and -A36) identified public epitopes.22

The term “public epitope” is often used interchangeably with“cross-reactive group (CREG).” Technically, this interpretation isincorrect. All of the HLA Class I specificities can be divided intoCREGs (Table 5-1). However, more than one public epitope canbe present in a single CREG. This concept explains why an indi-vidual with a single allogeneic exposure can make antibodies toa single antigen, to a subset of antigens from a CREG, or to an

Figure 5-1. Stylized diagram of Class I and Class II MHC molecules show-ing α and β polypeptide chains, their structural domains, and attached car-bohydrate units. (Reprinted with permission from Gebel et al.20)

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entire CREG.22 Additionally, because a single allogeneic expo-sure can present multiple foreign HLA antigens (eg, 2 HLA-A, 2HLA-B, 2 HLA-C, 2 HLA-DR, and 2 HLA-DQ), a large numberof antibodies can be formed after a single pregnancy, transplan-tation, or transfusion.

The nomenclature of the HLA system can resemble a ran-dom group of letters and numbers. The letter(s) correspond(s) tothe HLA locus. The first 2 digits after the letter correspond tothe HLA antigen within the locus. The antigens were numberedin the order they were discovered. Thus, in general, HLA anti-gens with a low number tend to occur more frequently than doHLA antigens with a higher number. When an HLA assignmentis reported as a letter followed by one or two numbers (eg,HLA-A23), this represents an antigen level typing. This level oftyping was the most common typing available until the wide-spread availability of molecular typing. With molecular typing,it quickly became apparent that there were many different alle-les of each of the HLA antigens. In HLA nomenclature, an as-

Table 5-1. Cross-Reactive Groups

Group HLA Class I Specificities

1C A1, A3, A11, A29, A30, A31, A36, A80

2C A2, A23, A24, A68, A69, B57, B58

4C A23, A24, A25, A32, Bw4

5C B18, B35, B46, B49, B50, B51, B52, B53, B62, B63, B71, B72, B73, B75, B76, B77, B78

6C Bw6

7C B7, B8, B13, B27, B41, B42, B47, B48, B54, B55, B56, B59, B60, B61, B67, B81, B82

8C B8, B18, B38, B39, B59, B64, B65, B67

10C A25, A26, A32, A33, A34, A43, A66, A74

12C B13, B37, B41, B44, B45, B47, B49, B50, B60, B61